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Detoxify the Body

Detoxify the Body

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Oxygen detoxification

E. histolytica lacks catalase and glutathione-dependent enzymes normally associate with oxygen-related detoxification (Fahey et al. 1984). It contains a single copy of an iron-containing superoxide dismutase (Tannich et al. 1991) to remove superoxide ion and several peroxiredoxins capable of removing both hydrogen peroxide and organic peroxides, including phospholipid hydroperoxides that would otherwise damage the cell membranes. Peroxiredoxins depend on thioredox-in and thioredoxin reductase and candidate genes for both of these have been found. Other proteins that may protect the organism from intracellular peroxide have also been identified, including genes encoding rubrerythrin and flavoprotein A, which may detoxify nitric oxide (Bruchhaus I, unpublished analyses). The redundancy of anti-oxidant pathways underscores the sensitivity of this amitochondrial organism to the presence of oxygen. Experimental evidence suggests that only low levels of oxygen can be tolerated and in the...

Detoxification of Saponins

Many plants constitutively produce triterpenoid, steroid or steroidal glycosylated compounds that are generally inhibitory to fungi (Figure 4.9). These are known by the general term saponin because of their soap-like properties, derived from the plant Saponaria officinalis, the extracts of which were once used to make soap (Osbourn, 1996). Saponins make complexes with membrane sterols, resulting in pore formation and leakage of cell constituents. The leaves and green fruits of the tomato plant contain high levels a steroidal glycoalkaloid, called tomatine (Figure 4.10). The pathogenecity of Septoria lycopersici (Anamorphici) on tomato plants was attributed to the production of a glycosyl hydrolase, tomatinase (Arneson and Durbin, 1967), which detoxifies tomatine by removing a single terminal glucose molecule by hydrolysis of a (3,1-2 linkage. The targeted gene-disruption technique was used to test the role of saponins in pathogenecity. The root-infecting fungus Gaeumannomyces graminis...

Detoxification

Detoxification is a process in which the body is allowed to free itself of a drug. During this period, the symptoms of withdrawal are also treated. Detoxification is the primary step in any drug treatment program, and is used as the initial phase in treating alcohol, heroin, inhalant, sedative, and hypnotic addictions. The goal of detoxification is to clear the toxins out of the body so that the body can adjust and heal itself after being dependent on a substance. In order for the recovering person to stay abstinent on a long-term basis, detoxification needs to lead into long-term community residential program treatment or outpatient drug treatment lasting three to six months. Buprenorphine A medication that blocks some of the withdrawal effects during heroin detoxification. Detoxification A process in which the body is allowed to free itself of a drug while the symptoms of withdrawal are treated. It is the primary step in any treatment program for drug or alcohol abuse. Lofexidine A...

The Molecular Pathogenesis of Human Prostate Cancer

Recent studies of the earliest molecular steps in the development of human PCA have generated new evidence supporting causative roles for prostate inflammation and diet in prostatic carcinogenesis. These new findings have provided new clues as to how PCAs likely arise, and new insights into how the disease might be prevented. A new lesion, termed proliferative inflammatory atrophy (PIA), in which prostate epithelial cells undergo regenerative proliferation in response to inflammatory damage, appears to be a precursor to prostatic intraepithelial neoplasia (PIN) and to PCA (7). PIA lesion cells exhibit many signs of stress, including the induction of carcinogen-detoxification enzymes such as glutathione S-transferases GSTA1 and GSTP1 (7). Somatic inactivation of GSTP1, encoding the human GST, renders prostate epithelial cells vulnerable to

New Opportunities for PCA Prevention

The convergence of PCA epidemiology, indicating a possible role for prostate inflammation, and a significant role for the diet, in PCA development, with molecular pathology, revealing that neoplastic prostate cells may have acquired an increased vulnerability to carcinogen damage, provides an opportunity for the discovery and development of rational new approaches to PCA prevention. Possible strategies include reduced exposure to genome damaging oxidants and other carcinogens, and intake of antioxidant micronutrients, including vitamin E, selenium, and carotenoids such as lycopene, which may be able to intercept reactive oxygen species before they inflict genome damage in the prostate. Administration of anti-inflammatory agents, when distributed into prostate tissues, may reduce oxidant production by prostate inflammatory cells. Consumption of cruciferous vegetables, containing the isothiocyanate compound, sulforaphane, an inducer of GSTs and other carcinogen-detoxification enzymes,...

Compounds Of Metallic Elements

A metal complex or coordination compound is formed by the association of a metal atom or ion and another chemical species, called ligand, which may be either an anion or a polar molecule. The ligands such as BAL (2,3-dimercaptopropanol) and D-penicillamine ((CH3)2C(SH)CH(NH2)CO2H)) serve important biological functions, where -SH groups of the ligand easily bind to a metal. Because of this, they can be used as detoxifying agents in case of, for example, mercury exposure. Another example is EDTA (ethylenediami-netetraacetic acid) used in lead detoxification.

Potential Strategies To Improve The Health Of Homeless People

Other strategies include adapting the health care system to better meet the unique needs of homeless adolescents, single men and women, or families. As discussed in Section 3.5 above, a cornerstone of this effort is the use of multidiscipli-nary teams providing coordinated care at outreach sites, in combination with more traditional clinic-based health care services. For homeless people with severe mental illness, the availability of ACT services is vital, but the effectiveness of less resource-intensive systems of mental health care for homeless people needs to be assessed. For those with addictions, the availability of detoxification beds, post-detoxification stabilization programs, and longer-term (6 to 12 month) residential addiction treatment programs are important issues. In designing these services, the heterogeneous needs of different subgroups of homeless people (e.g., street youth, single men, single women, and mothers with young children) must be taken into account.

Ammonium Assimilation

The metabolism of ammonium into amino acids and amides is the main mechanism of assimilation and detoxification of ammonium. Glutamic acid formation is a port of entry of nitrogen into organic compounds and occurs in the chloroplasts or mitochondria. Ammonium assimilation in root

Segmental Duplications And Evolution

Finally, a recent survey of segmental duplications in the human genome found that approx 6 of transcribed exons are located in recently duplicated sequence (2). Genes associated with immunity and defense, membrane surface interactions, drug detoxification, and growth and development were preferentially enriched, suggesting that gene duplication plays a major role in the evolution of these functions. Thus, in contrast to the popular conception in which single nucleotide polymorphisms and small mutations are the major method of evolutionary change, larger genomic rearrangements may instead represent the driving force behind much of recent primate evolution, facilitated by the presence of abundant highly homologous duplicated sequences throughout the genome (68).

Glutathione Stransferase

In addition to DNA repair, resistance to alkylating agents and other therapies can come about through detoxification. The family of glutathione-S-transferase (GST) enzymes catalyze the conjugation of electro-philic compounds with glutathione. These include various carcinogens, chemotherapeutic agents, and their metabolites 97,128-134 . There are 5 families of GSTs a(GSTA), m(GSTM), p(GSTP), 9(GSTT) and Z(GSTZ) 130,131 . Earlier work demonstrated the importance of the GSTP, GSTM, and GSTT isoforms in resistance to chemotherapeutic agents such as BCNU and cisplatin however, there were conflicting reports in the literature as to the isoforms most involved in therapy resistance in various human and animal cancers 97,129,131-133,135,137-144 . Work in our laboratory agreed with data obtained in other laboratories in that cells from some tumors demonstrated over-expression of one or more of these genes, while others did not 145 . Furthermore, even when BCNU resistant cells were cloned from a...

Morphological Changes Accompanying Aging In S Ratti

Accumulation of age-pigment (lipofuscin) seen during mammalian aging. There is a similar increase in autofluorescence with age in free-living S. ratti morphs (Gardner et al., 2004). By contrast, little such autofluorescence was seen in parasitic females, even in 11-month-old individuals (Gardner, Gems and Viney, submitted). Lipofuscin accumulation reflects organismal failure to detoxify and excrete molecular waste products. The paucity of autofluorescence in S. ratti parasitic females suggests reduced generation, and or increased excretion, of damaged molecular constituents. This is consistent with aging occurring in the two S. ratti female morphs, but at very different rates. The parasitic and free-living females morphs of S. ratti are genetically identical. Therefore differences between these morphs must be due to differences in gene expression. This being so, these differences in intestinal pathology might reflect differences in regulated biochemical processes which determine...

Feeding ecology and diet

In all species, the predominant diet is shoots and leaves of forest trees. Sloths feed on Cecropia, the most abundant tree of the Amazonia forest. Regenerating agricultural land river margins and natural gaps may sometimes be important (despite the biting ants that swarm in the tree's hollow stems), but it is never the sole food source. The idea that Bradypus sloths feed only on Cecropia probably arises because an open growth form makes a sloth in a Cecropia easier to see than in almost any other kind of rainforest tree. When feeding, the forelimbs are used to pull leaves slowly towards the mouth. Sloths are highly specialized for an existence that centers around squeezing as much energy as possible out of a low-intake rate of highly indigestible food. This is because leaves eaten by Bradypus sloths are, though energy-rich, also rich in tannins and fiber. Digestion must therefore be a simultaneous process of detoxification and energy extraction. The gut is extensive, making up 30 of...

Examples Of Metabolic Determinations

Similarly, Phormia can be used to study the age-dependent capability of xenobiotics via the GSH-S-transferase (GST) system for detoxification (Collatz and Flury, 1992). Using the analgetic drug Paracetamol, we were able to show that both a reduced GSH level and a diminished activity of GST lead to an increasing mortality of old flies after drug injection.

Genetically Modified Nonfood Plants

It so happens that soil microbes are often able to detoxify these pollutants by degrading petrochemicals and immobilizing heavy metals. However, there are potential problems with spraying contaminated soils with these microbes, for fear of creating yet another environmental problem. This is where GM plants may come to the rescue. Why not isolate the relevant bacterial genes and transfer them to plants Plants do not move, can grow fast, and, through their roots, absorb polluted water, thereby concentrating toxic chemicals inside their cells. When engineered with bacterial genes, these GM plants would be able to survive. After their detoxification job was achieved, they could be harvested and burned under controlled conditions. And yes, this has been done. There now exist fast-growing GM poplar trees able to detoxify petrochemicals and salts of various heavy metals. Their positive effects have been tested on a small scale, and research is being pursued for other pollutants...

Antineoplastic And Chemopreventative Effects

Several mechanisms appear to be involved. Notable among these is a depression in nitrosamine formation and a reduction in carcinogen bioactivation (Milner 2001). This is thought to involve an inhibitory effect on CYP2E1, one of the isoenzymes responsible for the activation of a number of carcinogens (Yang et al 2001). Some of the organosulfur compounds may also aid detoxification by enhancing glutathione S 2007 Elsevier Australia

Ethical Issues in the Quality of Care

Evant systems such as criminal justice, social rehabilitation, education, and or employment. If such demedicalization occurred, outcome measurements for health would be established that specifically addressed only those activities and results for which the system could reasonably be responsible. For example, safe detoxification and or supervised withdrawal for the chemically dependent could be one valid outcome measure.

General Considerations In Assay Performance

The MTD doses used in these studies often tend to be several orders of magnitude higher than the expected human exposure levels. It has been argued that such doses are irrelevant for safety assessment and risk evaluation because they may overwhelm or saturate the body's defense and protective mechanisms, such as the detoxification pathways, DNA repair mechanisms, and others. In certain cases, administration of unusually high doses may lead to the saturation of primary detoxification pathways, which in turn may lead to the formation of unusual metabolites through alternate metabolic pathways a situation unlikely to be encountered during normal human exposure The target tissues available for analyzing genotoxicity depend on the objective of the study and the type of assay used. Bone marrow and liver are the two most commonly used tissues for these analyses. Bone marrow, by virtue of its high mi-totic rates, has been a favorite for cytogenetic analysis. Another feature that makes...

Importance of Identifying Transcriptional Regulatory Networks in Toxicogenomics

The liver is the first organ that encounters toxins that have been absorbed through the intestines. One of the major roles of the liver is detoxification and metabolism of xenobiotics 7 . Particularly with regard to predicting the toxic action of xenobiotic compounds, identification of all targets of liver-specific TFs (for review see Schrem et al. 8, 9 ) would constitute great progress in toxicogenomics. Substances could be grouped mechanistically by targeting the same TF pattern, and prediction of toxic action would then be possible through analyses of changes in TF binding prior to observable damage to the tissue.

Liudvikas Jagminas md facep

Decontamination is defined as the reduction or removal of chemical, biological, or nuclear agents so they are no longer hazards. Agents may be removed by physical means or be neutralized chemically (detoxification). Decontamination of the skin is the primary concern, but decontamination of other systems must also be done when necessary. To ensure appropriate and timely patient care as well as optimal response, emergency personnel must understand decontamination procedures and the proper use of personal protective equipment.

Possible Chemopreventative Effects

A chalcone flavonoid, xanthohumol and a flavone isomer of xanthohumol found in hops act as antiproliferative agents in vitro (Miranda et al 1999, Stevens & Page 2004). In vitro data has demonstrated that hops induces detoxification enzymes, in particular quinone reductase, which may contribute to its chemoprotective effects (Dietz et al 2005). A review concluded that this compound has the ability to protect in the initiation, promotion and progression stages of cancer (Gerhauser 2005b).

Cytochrome P450 Induction

Colupulone, a beta-bitter acid, was reported to induce the cytochrome P450 system and increase mRNA levels of cytochrome 2B and 3A in rats (Shipp et al 1994). Another study found that the flavonoids from hops inhibit the cytochrome P450 system in humans, in particular cytochromes 1A1, 1 b1, 1A2, but not 2E1 or 3A4 (Henderson et al 2000). A recent review concluded that hops inhibits phase 1 detoxification and enhances phase two by inducing quinone reductase (Gerhauser et al 2002, Stevens & Page 2004). The clinical significance of these findings is unknown.

Neuropsychiatric complications

Delirium tremens (DTs), an indication of physical dependence, can be precipitated by abrupt withdrawal of alcohol in a heavy drinker, caused, for example, by the end of a drinking bout, efforts to give up drinking without professional advice, intercurrent illness, hospital admission, or arrest imprisonment. Confusion, fever, visual or tactile hallucinations, and fits may occur. Delirium tremens is a medical emergency with an appreciable mortality, and should be treated by physicians. Treatment includes correction of any fluid or electrolyte imbalance, or hypoglycaemia, and a 5-day reducing course of a benzodiazepine, such as chlordiazepoxide, to counteract withdrawal symptoms by sedation and prevention of fits. These drugs have potential for dependence and abuse, and should not be continued after detoxification. Parenteral vitamins, thiamine being most important, are also given to prevent other neurological complications.

Uses And Interpretation Of Data

The in vitro micronucleus assay provides an easy method for assessing the influence of different genotypes on induction of genotoxicity. These studies involve genetically engineered cell lines, as well as human and rodent genetic variants. To investigate the effect of metabolism on genotoxicity of nitroarenes and aromatic amines, sublines of Chinese hamster cells stably expressing human NAT1 or NAT2 N-acetyltransferases or Salmonella typhimurium O-acetyltrans-ferase were compared for sensitivity to micronucleus induction (78). Cells expressing human NAT2 N-acetyltransferase had the highest sensitivity to chromosome damage induced by nitroarenes. Norppa (79) discussed how the in vitro micronucleus assay (among other cytogenetic methods) can be used to study the effect of human polymorphisms, such as in the detoxification enzyme glutathione S-transferase.

Model Body Size And Scaling

However, metabolism or detoxification and excretion of a drug are not directly correlated with body size but, more accurately, to metabolic rate of the animal (see Schmidt-Nielsen29 30 for more details). Kleiber31 in 1932 was the first to demonstrate that in a log-log plot of mammalian body weight to metabolism, the graph forms a straight line with a slope of 0.75.

In Cocaine and Opioid Dependence

The two major stages of treatment where pharmacotherapeutics can be used are (1) induction of initial abstinence and (2) maintenance of abstinence. Initial abstinence can be accomplished either abruptly (forced abstinence usually in the context of detoxification) or through a gradual decrease of use (extinction of competitive drug-seeking). Early abstinence following the successful detoxification is associated with the emergence of affective and physical disturbances, intensive drug-craving, and heightened susceptibility to stress and drug-related environmental stimuli. These abnormal responses, which frequently contribute to relapse after a period of abstinence, can be individually modeled in the laboratory.

Summary And Directions For The Future

Preclinical research brings overwhelming evidence documenting the role of glutamatergic neurotransmission in the neurobiology of opioid and cocaine dependence and suggests that glutamatergic agents, in particular NMDAR antagonists, may be a useful addition to the treatment of these disorders. To date, the progress in applying results of preclinical studies to clinical medication development has been slow but noteworthy. The results from clinical studies of opioid dependence, both detoxification and relapse prevention, are encouraging (32-34,37,52). Efficacy trials of NMDAR antagonists for opioid dependence, including currently available dextromethorphan and memantine, are justified based on these findings.

Xenobiotics And The Human Liver

The liver is the key organ for biotransformation of xenobiotics that enter the human body, either intentionally (e.g., pharmaceuticals) or unintentionally (e.g., environmental pollutants). All blood-borne xenobiotics are firstly metabolized by the liver, a process known as first-pass metabolism. The major consequence of the metabolic transformation is the formation of water-soluble metabolites that are removed from the body. In general, the xenobiotic is firstly oxidized (phase I metabolism) and then conjugated to highly polar molecules such as glucose, sulfate, cysteine, and glutathione (phase II metabolism). The highly polar metabolites are then transported directly from the hepatocytes into the biliary canaliculi (phase III metabolism) to be excreted as bile, or are released back into the bloodstream to be excreted into the urine via the kidneys. In the intestine, the metabolites may be deconjugated by gut bacterial flora and reabsorbed, leading to a repeat of the metabolic...

Stevensjohnson syndrome

The exact mechanism producing SJS and TEN is unclear. Patients with SJS and TEN induced by anticonvulsants or sulfonamides may have an alteration in the detoxification of reactive drug metabolites. CD8 cells predominate in the lesions of blistering reactions, suggesting a cell-mediated cytotoxic reaction against epidermal cells (32). Tumor necrosis factor-a, perforin, granzyme B (GrB), and Fas Ligand (FasL) have been shown to be increased in the early stage of disease, further supporting a cytotoxic mechanism (33).

Initial Clinical Trials With Frozen Lysates

In our phase I and II trials (comprising 19 and 25 patients, respectively) with frozen lysates, lysates and DETOX adjuvant were given sc. Nine of the 44 patients (5 of 19 and 4 of 25, respectively) (20.5 ) with measurable metastatic disease had major responses, 3 complete response (CR) (6.8 ), and 6 partial response (PR) (13.6 ). One additional patient in the phase II trial (2.3 ) had 17 mo stability of lung nodules developing brain metastases at that juncture which we felt was also a response to treatment, because the lung nodules had been growing before treatment. Table 1 lists the patients who responded, the duration of response and survival, as well as their further treatment after active specific immunotherapy was discontinued. Note that 7 of 44 patients (15.9 ) treated with frozen lysates in these two trials lived at least 1 yr, with a median survival in this responding cohort of 2 yr. Combining data from the phase I and II trials, the median duration of remission solely on...

Initial Clinical Trials With Melacine

Our first phase II trial with the lyophilized Melacine preparation, including DETOX, administered sc to 20 patients, without cyclophosphamide pretreatment, yielded an objective response rate of 15 , with 0 CR, 3 PR (15 ) and 1 minor response (5 ) (between 25 and 50 shrinkage of all lesions). There was also a mixed response (5 ), not included in the group of objective responses 33 shrinkage of a liver metastasis but > 25 increase of an axillary lymph node mass, subsequently resected. This patient (DG), and his response, have lasted for more than 10 yr with monthly maintenance treatments (Table 2).

Model Plant Species For The Genomicsbased Studies

Been carried out using microarray and macroarray based methods by several groups (Table 1). Two types of arrays have been made available for genomic studies in rice, namely oligonucleotides array as well as cDNA array. There are numerous examples wherein detailed studies have been taken in rice using these approaches. Analysis of salt stress-inducible ESTs from salt tolerant rice cultivar Dee-geo-woo-gen revealed several proteins showing homology to proteins functional for detoxification, stress response and signal transduction in plants (Shiozaki et al. 2005). Comparative analysis between different rice genotypes has also been attempted employing salinity tolerant (CSR27 and Pokkali) and sensitive (PB1) cultivars of rice (Sahi et al. 2003). This study highlighted that genes such as SalT, glycine rich RNA binding proteins, ADP ribosylation factor, NADP dependent malic enzyme, Mub ubiquitin fusion protein, tumor suppressor genes, wound inducible genes, ethylene response element binding...

Adjunctive therapy with lysates in resected stage ii and iii disease

In 1990 and 1991, we attempted to study Melacine with the Southwest Oncology Group in a phase III randomized trial vs no treatment in resected stage III melanoma, to see whether relapse-free and overall survival could be improved. This was at a time when the ECOG 1684 study with IFN-a-2b (INTRON-A) had not yet been completed. When the SWOG joined the Intergroup IFN-a study for stage III and deeply invasive (> 4 mm) melanoma, retaining Melacine only for resected intermediate thickness (> 1.5-4.0 mm) stage II disease (SWOG 9085), our plans had to be revised. To obtain data that might support a subsequent randomized study of our own, we treated 44 consecutive patients with resected stage III melanoma from January 1992 to December 1993 over a period of 48 wk with frozen lysates + DETOX (first 17 patients) or Melacine (final 27 patients), preceded by 350 mg m2 of cyclophosphamide. An additional 23 patients referred to us with resected stage II melanoma were also treated in a separate...

Immunohistological Studies

We also studied the immunohistology of lesions that were undergoing rejection after vaccine therapy in a group of seven patients, compared with a group of six untreated melanoma patients, and other control subjects, including a patient who had a DETOX-induced granuloma at the site of injection, which allowed us to compare the rejection site

Crossspecies Gene Protein Comparative Expression Profiling

Cial for the interpretation of cross-genome expression profiles in an integrated health and ecological risk assessment. A core set of homologous genes should include genes involved in xenobiotic activation detoxification mechanisms, perturbations of cell homeostasis mechanisms, oxidative damage, cell injury, death, and regeneration and genes controlling critical signalling mediator molecules for these biological processes. Phase I and Phase II enzymes metabolize most environmental xenobiotic chemicals, and much is known about their chemical substrates, inducers, and inhibitors. Phase I enzymes, the cytochromes P450 (CYPs), both bioactivate and also detoxify xenobiotics. The primary step involved in the activation process mediated by CYP proteins is oxidation, or bioactivation of xenobiotics to electrophiles. Phase II enzymes conjugate some of these oxidized metabolites to form water-soluble excreta-ble substances. We propose to begin our compilation of cross-species gene protein...

Clinical Implications

The potential role of NMDA receptor antagonists in addiction becomes more evident when considering the findings, discussed earlier, that NMDA receptor antagonists may reverse opiate tolerance and dependence when administered over days. The ability to accelerate the extinction of tolerance and physical dependence (and perhaps sensitization) would offer a means to speed up the detoxification process and perhaps reverse some of the physiological processes responsible for addiction. Although very intriguing, further research is necessary in order to more firmly establish the conditions under Evidence demonstrating that NMDA receptor antagonists may inhibit the expression of physical dependence under certain circumstances suggests that these drugs may be useful in acute detoxification. Preliminary clinical research offers conflicting views on this possibility. Whereas two studies suggest that NMDA receptor antagonists may block some symptoms of withdrawal in opiate addicts (110,185), two...

Application Of Biomarkers For Human Risk Assessment

McGlynn et al (153) have reported that mutant alleles at two AFBj detoxification gene loci (epoxide hydrolase EPHX and GSTM1) were significantly overrepresented in individuals with detectable serum AFB1-albumin adducts in a cross-sectional study. Mutant alleles of EPHX were also significantly overrepre-sented in persons with HCC in a case-control study. The relationship of EPHX to HCC varied with HBsAg status and suggested that a synergistic effect may exist. Mutations of p53 at codon 249 were only observed among HCC patients with one or both mutated EPHX and GSTM1 genotypes. These results indicate that individuals with mutant genotypes at EPHX and GSTM1 may be at greater risk of developing AFB1 adducts, p53 mutations, and HCC when exposed to AFB1. Hepatitis B surface antigen carriers with these high-risk genotypes may be an even greater risk than carriers with low-risk genotypes. These findings further support the existence of genetic susceptibility in humans to AFB1 exposure and...

T187m R227q F234l F194l

The HSD3B2 gene may play dual competing roles in prostate cancer etiology the enzyme product (noted above), is one of the two enzymes that irreversibly inactivates DHT in the prostate however, it is also responsible for production of the adrenal androgen androstenedione, which can undergo further conversion to T.41 A complex dinucleotide repeat polymorphism exists in intron 3, for which multiple alleles have been described with substantial variation in frequency across race ethnicity.75 In preliminary studies, several of these occur more frequently in prostate cancer patients than in healthy men.75 The number of candidate genes and their polymorphic variants in this pathway will continue to grow. The androgen-signaling pathway is highly intricate and complex, involving not just genes involved in androgen biosynthesis, transport, activation, and detoxification but also genes encoding coactivator proteins and a whole series

Process Of Therapeutic Change

Jillian had multiple hospitalizations, a record of assaulting others followed by jail time, a pattern of cutting herself, chronic suicidal ideation, and debilitating depression. She was admitted to the hospital this time for detoxification from pain medications and for escalating suicidal ideation. There were many signs of depression, including increased irritability, weight loss, and fatigue. She was highly stressed by severe financial difficulties. Shortly before her admission, she had an argument with an officer at the bank that stemmed from her opinion that he had

Regenerative Hyperplasia

Vestigators postulated that the difference observed between the gavage and drinking water studies can be explained solely by toxicokinetics. When given as a single bolus dose by gavage, the treatment resulted in a high rate of production of toxic metabolites in the liver that overwhelmed cellular detoxification mechanisms and killed the hepatocytes. When given in drinking water, ingestion was in small sips throughout the day. The chemical was probably not cytotoxic or carcinogenic under these conditions, as delivery to the target tissue was at rates low enough to allow detoxification, even though the cumulative dose was 329 mg kg day. The authors concluded that a model that assumes that tumor formation is secondary to proliferative effects describes the pattern of tumors more accurately than the linearized multistage model. They derived an NOAEL of 1800 ppm for induced cell proliferation and mouse liver tumors. Using a UF of 1000, a level of 0.18 ppm was considered a level below which...

Metabolic Activation Of Carcinogens

Not directly react with DNA but require metabolic activation to chemically reactive, usually short-lived intermediates (termed ultimate carcinogens mutagens). Activation may occur during phase-I metabolism (functionalization), whereas phase-II metabolism (conjugation) is primarily associated with detoxification by many toxi-cologists and pharmacologists. However, this view is oversimplified, as numerous examples are known for activation via various conjugation reactions (Glatt, 2000a King et al., 1997 Ritter, 2000 van Bladeren, 2000). It is probable that the role of phase-II reactions in the activation is underestimated for technical reasons (different state of knowledge of the various enzyme classes differences in membrane penetration between phase-I and phase-II metabolites). Indeed, using bacterial and eukaryotic target cells engineered for expression of individual human sulfotrans-ferase (SULT) forms, we demonstrated an activation to mutagens by these enzymes for more than 100...

Significance to humans

The rediscovery of squid giant axons by J. Z. Young in the 1930s allowed experiments that demonstrated much of what is known about the basic functioning of nerves. The giant axons of squid nerves have been widely used as one of the primary bases of neurobiology. Cephalopods are also being used increasingly as models in other biomedical fields, including sensory biology, information processing, and biochemistry. They are even being used as a source of information regarding the detoxification of nerve gas. The results of an electronic search of scientific literature for the word squid may be dominated by biomedical studies based on inshore squid as a convenient and interesting model.

Adriaan S Potgieter MD

In all but two of the studies, patients had to have already withdrawn from alcohol and started the study medication immediately after the acute period of detoxification (which, on average, lasted between 3 and 14 d). The reason for not starting during the acute withdrawal period was to isolate the drug effect from possible confounding effects of concomitant psychotropic and anticonvulsive detoxification medications. Exceptions to this policy were in the trial performed in Spain by Gual and collaborators (4), who introduced the study medication from the first day of weaning, and in the UK study by Chick and collaborators (5), who allowed a period of stabilization or washout of up to 5 wk after the

Integration Of Clinical Services

Substance misuse contributes to poor health in many ways and is the major determinant of low uptake of health services. Therefore, addiction counseling and treatment programs must be readily available and of high quality. Addiction counselors have an important role to play in attracting people to medical care and in encouraging their persistence. The integration of substance abuse treatment, detoxification and harm reduction services with primary care can improve access to primary medical care and adherence to recommended interventions (Broadhead, et al., 2002 Heller, et al.,2004 Samet et al., 2003 Sweeney, et al., 2004).

Developmental Effects Of Prenatal Exposure

The effects produced by metals depend on the timing and duration of exposure, on their distribution and accumulation in various organs such as the nervous system, and on the ability to interfere with specific developmental processes. Effects may be enhanced by biochemical, physiological, and anatomical changes occurring during development, which may result in a modified metabolism of the metal itself (Rice and Barone, 2000). Interesting interactions between environmental and congenital factors have been documented genetic polymorphisms can affect fetal susceptibility to teratogens or maternal ability to detoxify and excrete xenobiotics (Garcia, 2000).

The Role of HNFs in CYP Monooxygenase Expression

The foetal liver, the major site of haematopoiesis during embryonic development, acquires additional detoxification functions near birth. The response to xenobiotic exposure with expression of several cytochromes P450 (CYP) monooxygenases and drug efflux transporters is a vital hepatic function. Expression of the genes for these proteins is regulated by nuclear receptors such as the pregnane X receptor (PXR). The expression of several xenobiotic response genes as well as of HNF-4alpha is increased in foetal hepatocytes stimulated by the hepatic maturation factors oncostatin M (OSM) and matrigel. To determine the contribution of HNF-4alpha to xenobiotic responses in the foetal liver, foetal hepatocytes containing floxed HNF-4alpha alleles were cultured, and the HNF-4alpha gene was inactivated by infection with an adenovirus containing the Cre gene. As a consequence, expression of CYP3A11 and PXR was suppressed by inac-tivation of HNF-4alpha. An HNF-4alpha binding site was characterized...

Practical Issues of Peptide Immunization Assessed in Early Human Clinical Trials

The choice of adjuvant is another consideration studied in peptide vaccine trials, particularly as peptides themselves are typically only weakly immunogenic. Due to recent renewed enthusiasm for peptide-based tumor vaccines coupled with the search for adjuvants that promote cellular as well as antibody responses, the list of adjuvants being studied continues to grow. The choice of adjuvant has largely been determined by preclinical models. Similar to alum, oil-based incomplete Freund's-type adjuvants, such as Montanide ISA-51 (Seppic, Paris, France) and TiterMax (CytRx Corp., Norcross, GA), have been used in human peptide vaccine studies (56,58), with their adjuvant effect likely mediated by a depot effect, increasing the half-life of the peptide antigen at the site of immunization. Other pro-inflammatory biologic adjuvants such as BCG, Detox (mycobacterial cell-wall skeleton plus a lipid moiety) (Corixa Corp., Seattle, WA), and influenza virosomes have been used as adjuvants in...

Chemoprotection And Antimutagenic Effects

An in vitro study on human bronchial cells found that rosemary extract and its constituents, carnosol and carnosic acid, may have chemoprotective activity through decreasing carcinogen activation via inhibition of the enzyme cytochrome P450 (CYP1A1) and increasing carcinogen detoxification by induction of phase II enzymes (Offord et al 1995). Carnosol has been found to also restrict the invasive ability of mouse melanoma cells in vitro by reducing MMP-9 expression and activity (Huang et al 2005).

Tissue Distribution Of The Human Sult1a Subfamily

Fractions of stomach, small intestine, and colon (Windmill et al., 1998). From the histological studies, SULT1A mRNA and protein were detected in epithelial cells lining the lumen of the stomach and the gastric pits and in the epithelial cells lining the lumen surface and the crypts of Lieberkuhn of the small intestine and colon. Similarly, SULT1A1 and SULT1A3 were detected in lung cytosols, and histological studies using hybridization histochemistry and immunohistochemistry localized SULT1A mRNA and protein to the epithelial cells of the respiratory bronchioles. The widespread localization of SULT1A mRNA and protein throughout the human gastrointestinal tract and lung suggests they may play a significant role in the extrahepatic detoxification and activation of drugs and xenobiotics (Windmill et al., 1998 Windmill, K.F., Hall, P.M., McManus, M.E., unpublished data).

Overview Of Biomarkers

Biomarkers of susceptibility are mainly concerned with factors in kinetics and dynamics of uptake and metabolism of exogenous chemicals. The enzymes involved in activation and detoxification of these xenobiotics are divided into two categories phase I enzymes, mainly the superfamily of cytochrome P450 mixed function oxidase enzymes, and phase II enzymes, which act on an oxidized substrate to conjugate them with various moieties, such as glucuronic acid, glutathione, and sulfate (62-64). Genetic differences in the expression of these metabolic enzymes could be a major source of interindividual variation in susceptibility to disease (65-67). Therefore, the determination of genotype and phe-notype of these metabolic enzymes in different populations is being studied to determine if an association exists between exogenous exposure and formation of specific disease in specific metabolic genotype subsets. Many studies over the past several years have found that genes involved in xenobiotic...

TF Tn and sTn Vaccines

Several trials with TF, Tn, and sTn vaccines have been reported from other centers, and a large multicenter phase III trial with an sTn vaccine has been completed. George Springer's pioneering trials in breast cancer patients with vaccines containing TF and Tn purified from natural sources and mixed with typhoid vaccine (as adjuvant) began in the mid-1970s (34,89,90). DTH and IgM responses against the immunizing antigens and prolonged survival compared to historical controls were reported. MacLean immunized 10 ovarian cancer patients with synthetic TF conjugated to KLH plus immunological adjuvant Detox (monophosphoryl Lipid A plus BCG cell-wall skeletons) and described augmentation of IgG and IgM antibodies against synthetic TF in 9 of 10 patients (85). Lower levels of antibody reactivity against TF from natural sources were detected in some of these cases. MacLean has also immunized patients with breast and other adenocarcinomas with sTn-KLH plus Detox (13,51,91). Induction of IgM...

Sultdependent Activation And Inactivation Chemical Background

Thyroid Hormone Cell Background

Most ultimate mutagens are electrophiles, which find reaction partners in the numerous nucleophilic sites present in DNA (and other macromolecules Miller, 1970). The sulfo acceptor sites of the substrates of SULTs are nucleophilic and, therefore, are not reactive toward DNA, which lacks significant electrophilic sites. In this regard, SULTs are not suited to detoxify ultimate mutagens. However, SULTs may compete with other enzymatic and spontaneous (e.g., autoxidative) reaction pathways, including those generating electrophilic products, for the same substrates. Therefore, sulfoconjugation can be beneficial via the sequestration of potential proximate toxicants. In fact, this situation is rather common. With various classes of chemicals, for example aromatic amines, sulfoconjugation is involved in both the activation as well as the sequestration of progenotoxicants (Figure 13.2).

Pathophysiology of HHV6 reactivation in DRESS

Because several drugs associated with DRESS were metabolized to reactive oxidative metabolites, their role was evoked in the causation of the DRESS. Most previous studies done on lymphocytes from patients with DRESS, demonstrated a susceptibility to the toxic effects of oxidative drug metabolites (Shear et al., 1988 Green et al., 1995 Leeder, 1998). An increased risk associated with higher starting doses or concurrently administrated drugs in the case of lamotrigin or abacavir, for instance, brought clinical arguments. But genetic analysis of different genes, such as epoxide hydroxylase, implicated in detoxification did not corroborate previous studies (Gaedigk et al., 1994).

Plant Mechanisms Of Aluminum Avoidance Or Tolerance

Considerable evidence supports organic acid release as a mechanism of aluminum avoidance in plants (179,188,193,194). Hue et al. (195) used elongation of cotton (Gossypium hirsutum L.) taproots as a measure of aluminum toxicity to document the aluminum detoxification effect of several low-molecular-weight organic acids or anions. The relative ameliorative capacity of the organic acids followed closely the stability constants of the aluminum-organic acid complexes in the order The formation of stable rings (5-, 6-, and to a lesser extent 7-membered structures) between aluminum and organic anions or molecules seems to be responsible for the detoxification (195). Structure of an aluminum-citrate complex is shown below. Cuenca et al. (253) showed that the tropical woody species, Clusia multiflora Knuth., inoculated with AMF accumulated less aluminum in roots instead aluminum was bound to the cell walls of the fungal mycelium and in vesicles. Using 27Al-NMR, aluminum was found to be taken...

Carotenoids

In animals, carotenoids have many functions. In addition to providing direct photoprotection via absorption of blue light, carotenoids act as powerful fat-soluble antioxidants linked to oxidation prevention, as well as playing a role in cellular communication, including stimulation of gap-junction communication, which is important for cancer prevention by regulating cell growth, differentiation, apoptosis and angiogenesis. Carotenoids may also be involved in detoxification of carcinogens, DNA repair and immunosurveillance. These properties are believed to contribute to their antioxidant, immune-enhancing, anticarcinogenic and photoprotective activity.

Figure 228

SER is the principal organelle involved in detoxification and conjugation of noxious substances The sER is particularly well developed in the liver and contains a variety of detoxifying enzymes related to cytochrome P450 that are anchored directly into sER plasma membranes. The degree to which the liver is involved in detoxification at any given time may be estimated by the amount of sER present in liver cells. The sER is also involved in

Health Care System

Access to addiction treatment is therefore a vital issue for a large proportion of homeless people. A number of treatment modalities for adults have been shown to be effective in controlled studies admission to a post-detoxification stabilization program results in longer periods of abstinence than direct release into the shelter system (Kertesz, et al., 2003), and abstinence-contingent work therapy in a long-term residential setting has been shown to improve outcomes (Milby, et al., 2000). Studies have examined the effectiveness of case management for homeless people with addictions, with mixed results (Morse, 1999).

Nitrite Reductase

The assimilation of nitrate is an energy-consuming process, using the equivalent of 15 mol of adenosine triphosphate (ATP) for each mole of nitrate reduced (16). The assimilation of ammonia requires an additional five ATP per mole. In roots, as much as 23 of the respiratory energy may be used in nitrate assimilation compared with 14 for ammonium assimilation (17). However, nitrate can be stored in cells without toxic effects, but ammonium is toxic at even low concentrations and must be metabolized into organic combination. Consequently, ammonium metabolism for detoxification may deplete carbon reserves of plants much more than nitrate accumulation.

Amidation

Glutamine is formed from amidation of glutamic acid (glutamate), and asparagine is formed by amidation of aspartic acid (aspartate). Often, when the external supply of ammonium is high, asparagine, a metabolite unique to plants, will dominate among the amides, as plants respond to conserve carbon in the detoxification of ammonium.

Pseudocheiridae

All have short, stocky limbs, short round ears, and tails that are bare at the lower side at least about the final third of their lengths. Many species have dorsal stripes, though these are not always clearly seen when the fur itself is rather dark. Fur colors differ from light gray cream, to orange, to dark brown. One species is greenish due to a mix of yellow, black, and white hairs. Internally, all species (including Petauroides) have a large cecum for fermenting their leaf-based diet, and their cheek-teeth are formed in the shape of cutting edges, scissorlike, to both cut and grind xerophytic leaves (e.g., Eucalyptus, which at least some species can detoxify).

Metallothioneins

The metallothionein (MT) family consists of 4 isoforms MT-1 and MT-2 are expressed in all eukar-yotes and MT-3 and MT-4 are expressed in mammals. These proteins are involved in metal detoxification. They can also act as scavengers of reactive oxygen species and are thought to protect cells against damage from radiation and some therapeutic agents, particularly cisplatin 161 . Finally, MT appears to protect cells from apoptosis induced by a variety of stimuli including etoposide, oxidative stress, and metals, although the mechanism of this protection is unclear 162 .

Present Complaints

During 1998, Dianne was admitted for detoxification (one-week hospitalization) and subsequently treated in a day-care programme at an addiction treatment facility. She kept on drinking however, her depressive and anxiety symptoms only increased and her relationship with Mick deteriorated.

Metallothioneins MTs

MTs, which were originally isolated from equine kidney, are low-molecular-weight, cysteine-rich, intracellular proteins that have the capability to bind toxic metals (Margoshes and Valee, 1957). MTs are rich in cysteine, and therefore, thiol groups, which gives them avid metal-binding characteristics (Waalkes and Perez-Olle, 2000). They can bind essential metals such as Cu and Zn, as well as toxic metals such as Cd, Pb, and Hg (Nordberg and Nordberg, 2000). MT can integrate as many as 7 divalent metal atoms (e.g., Zn2+) or 12 monovalent atoms (e.g., Cu+) (Binz and Kagi, 1999). The metal content of MTs can vary, depending on the stability constants of different metals, and does not have to contain only one type of metal. Thus, MTs can exist as mixed metal proteins, carrying multiple metal species. It has been reported that up to 18 different metals can associate with MTs, although the stability constant of the different metals varies (Kagi and Kojima, 1987 Nath et al., 1988). For...

Disease Prevention

In any zebrafish colony, the appearance of disease could impact the whole colony, resulting even in death of the entire colony. Thus, disease prevention in a colony is critical. In an aging colony, this takes on a great urgency as one cannot readily replace the old fish that die and several years of work can be destroyed through introduction of a lethal pathogen or water impurity. Several filtration and detoxification methods are used in zebrafish facilities (Figure 27.1). These include methods such as ultraviolet filtration, to kill pathogenic bacteria from reaching the tank, and biological filters, to harvest bacteria that can denitrify the water. Accordingly, it is best to maintain an aging colony as an isolated colony in a barrier facility.

Glutathione

Glutathione (GSH) is responsible for carrying out a variety of physiological and metabolic functions, including, but not limited to, the detoxification of elec-trophilic compounds, free radicals, and metals. It is the most abundant nonprotein thiol in many species and contains six possible metal binding sites (Wang and Ballatori, 1998). As summarized by Ballatori, GSH can affect the transport, disposition, and overt toxicity of metals in four ways (1) it functions in the mobilization and delivery of metals between ligands (2) it functions to transport metals across cellular membranes (3) it serves as a source of cysteine, and (4) it serves as a cofactor for redox reactions (Ballatori, 1994). Although GSH is able to bind a large number of endogenous compounds, here we will be concerned only with its ability

Functions In Plants

Within plants, calcium is present as Ca2+ ions attached to carboxyl groups on cell walls by cation-exchange reactions. As approximately one third of the macromolecules in the primary cell wall are pectin (9), it can be seen that a large proportion occurs as calcium pectate. Pectin may also join with anions, such as vanadate, and serve to detoxify these ions. The Ca2+ cation will also join with the organic anions formed during the assimilation of nitrate in leaves these anions carry the negative charge that is released as nitrate is converted into ammonium (46). Thus, there will be formation of calcium malate and calcium oxalacetate and, also very commonly, calcium oxalate in cells.

Modeling The Data

Figure 11 illustrates the relationships between the frequency distribution and the sigmoid model of a dose-response relationship. The biological basis for this model is the observed variability among individuals within a given population. The frequency distribution shows that a given effect will be demonstrated by a few individuals in the population at low doses and that a few individuals will be more resistant and will require very high doses before demonstrating the same effect. Most individuals will, however, demonstrate the effect in the middle range of doses as illustrated in Figure 13. The relative susceptibility or resistance is considered to be related to genetic differences, health status, differences in detoxification or elimination rates, differences in absorption rates, different volumes of distribution, or other biological variables that make one individual different from another. These differences are not sufficiently great to consider any individual as not belonging to...

Aftercare

After the patient has completed detoxification, he or she needs further treatment either at an outpatient, inpatient, residential, or day hospital program in order to remain drug-free for the long term. Patients are treated by trained health care professionals, and some patients are also counseled by people who are recovering from addiction themselves. Many patients also benefit from 12-step programs or self-help groups, such as Alcoholics Anonymous (AA) or Narcotics Anonymous (NA). Most opioid users are treated with ambulatory or outpatient detoxification or residential treatment followed by outpatient counseling. Some people who have abused opioids and have undergone detoxification and counseling are able to remain drug-free. Many, however, relapse, even after receiving psychotherapy. People recovering from opioid addiction can receive methadone or LAAM as maintenance therapy to prevent relapse. Similar to the aid these medications can give patients during detoxification, when taken...

Hg and Other Metals

More recent studies by a number of investigators have examined the role selenoproteins in mediating the binding and transport of mercury in blood and tissues. Yoneda and Suzuki (1997) first reported the detoxification of mercury by selenium via binding in an equi-molar complex with a specific plasma protein in rats. They observed that both elements appeared to first from a complex and then bind to basic amino acids in the protein. This binding was inhibited by addition of polylysine. Subsequent studies using extended X-ray absorption fine structure (EXAFS) by Gailer et al. (2000) using plasma from rabbits demonstrated the formation of an Hg-Se-S chemical species.

Laboratory Studies

Models of Physiological Dependence Development of Medication to Assist in Detoxification Physiological dependence, and the emergence of a withdrawal syndrome upon cessation of drug use, is a common feature of several substance-dependence syndromes (in particular, opioid dependence). Medications are frequently used to alleviate the signs and symptoms of withdrawal, a treatment known as medical detoxification. Most patients who enter treatment for opioid dependence need to undergo detoxification, but its efficacy is not predictive of the long-term course of opioid dependence. Without further treatment, however, the majority of patients would relapse in the first few months after detoxification. Sufficient relief of withdrawal symptoms is necessary in order to retain patients until detoxification is complete, and a good experience during this phase of treatment may foster patients' commitment to long-term treatment. The effects of DXM were later studied by Rosen et al. (20) in the...

Clinical Trials

NMDA Receptor Antagonists in the Treatment of Drug Withdrawal 4.1.1. Opiate Detoxification Laboratory animal studies consistently show that NMDAR antagonists in, particular channel blockers attenuate the severity of opioid withdrawal in dependent animals (1,3). The results of human laboratory studies are less decisive. Several preliminary trials have evaluated the utility of clinically available agents for opioid detoxification. The first published clinical study was conducted in Turkey by Koyuncuoglu and Say dam (32). Forty-eight patients seeking opioid detoxification were randomly assigned to dextromethorphan (360 mg d) or chlorpromazine (96 mg d), which was used as an active control. Both group received diazepam as an adjunct treatment. There was a major group difference in treatment retention. At the end of the 8-d trial, 68 of patients treated with DXM were still in treatment, whereas none treated with chlorpromazine completed the study. In fact, in the chlorpromazine group,...

Cancer

For a DNA-reactive chemical to induce a mutation, a number of conditions have to be met. Some are depicted in Figure 2. The first question is whether the phase I reaction of biotransformation results in the formation of a DNA-reactive intermediate. Secondly, does the reactive intermediate escape the various enzymatic and nonenzymatic detoxication processes Thirdly, does it react with DNA or with another molecule Although the reaction with water or other small molecules represents detoxification, the formation of protein adducts can be indirectly genotoxic, for instance by disturbing chromosome segregation or by cytotoxicity followed by regenerative hyperplasia. At all crossroads shown in Figure 2, numerous factors modulate the rate of the process (12). Genetic polymorphisms in tumor suppressor genes and proto-oncogenes can result in large differences in the susceptibility of individuals to develop cancer. As indicated in Figure 1, this could be caused by a reduction of the number of...

Pharmacokinetics

Nonlinearity in cancer dose-response relationships can result from saturation of a metabolic pathway. When an activation pathway is saturated, the dose response relationship can plateau at a level less than 100 lifetime risk, as in the frequently noted (1, 8, 89) case of vinyl chloride (88). When a detoxification or de-activation pathway saturates, the classic hockey stick dose-response curve can result. Data permitting, these effects can be formally taken into account through physiologically based pharmacokinetic (PBPK) modeling. The aim of the PBPK model in cancer risk prediction is to obtain a better estimate of effective dose than the administered dose, using model parameters measured in or estimated from experiments subsidiary to the bioassay. A cancer dose-response relationship for the bioassay or occupational dataset can then be expressed in terms of effective dose. If sufficient information and understanding permits the development of a PBPK model for the exposure circumstance...

Peer Involvement

North America's first Supervised Injection Site (SIS) was opened in Vancouver in September 2003 (Wood, et al., 2004). Although the primary impetus to open the facility was the issue of drug-dependent people injecting in public spaces, there is an excellent opportunity to link the SIS with health and counseling services. There are already nurses on the premises to deal with injection-related complications as well as a counselor to provide on-site addiction counseling. Links to public health interventions and detoxification programs are also in place.

Genetic Modifiers

To the phenotype of the proband, is consistent with the presence of either environmental or genetic modifiers. Genetic modifiers are probably more likely than shared environment to account for familial clustering of cancer sites in Ashkenazi Jewish mutation carriers, for example, since intrafamilial differences in environment are large in such families with recent immigration histories (4). Although there has also been considerable interest in finding genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers, the number of published studies is still fairly modest. The underlying reason for this may be that there is still a paucity of validated low-risk common alleles for breast or ovarian cancer in the general population, and until such alleles are identified, testing candidate single nucleotide polymorphisms (SNPs) as modifiers of BRCA1 and BRCA2 remains a fairly high-risk endeavor. Candidate modifier genes include those involved in detoxification of environmental...

Indicator Plants

Aluminum has been shown to interfere with iron metabolism. It blocks the incorporation of iron into heme resulting in poor hemoglobin production and anemia (384). Aluminum also appears to disrupt the mechanisms that control intracellular iron homeostasis. The result may be altered iron distribution in the cell leading to increased levels of reactive or free iron and iron-induced oxidative stress (384-386). Normally, increasing intracellular free iron concentrations coordinately stimulate the synthesis of the iron storage protein ferritin, and inhibit the synthesis of transferrin receptors that control iron uptake. Studies suggest that aluminum antagonizes the ability of intracellular iron to regulate the translation of mRNAs for both ferritin and the transferrin receptor. Under these conditions, the amount of free iron in the cell becomes elevated relative to the amount of its storage and detoxification by ferritin, thus increasing the risk for iron-induced oxidative stress. Aluminium...

Hepatoprotective

The hepatoprotective properties of rosemary extract are attributed to its antioxidant properties and improving detoxification systems dependent on glutathione S-transferase (Sotelo-Felix et al 2002). Rosemary extract has been shown to reduce thioacetamide-induced cirrhosis (Galisteo et al 2000) and azathioprine-induced toxicity in rats (Amin & Hamza 2005), as well as partially prevent carbon tetrachloride induced liver damage in both rats (Sotelo-Felix et al 2002) and mice (Fahim et al 1999, Sotelo-Felix etal 2002).

Drosophlia Immunity

Toll Pathway Human Versus Drosophila

Detoxification Mechanisms Other defense mechanisms also exist. One source of exogenous molecular attack is from the nonbiological world of chemicals. Many chemicals to which an organism can be exposed through the air, food, or other means may not amplify by growing within the host, but may react in damaging ways with the organism's own biochemistry. There are a number of metabolic systems that serve to inactivate or detoxify exogenous molecules that have certain properties. As an example, the cytochrome P450 (CYP) genes serve this function (the name comes from the history of the discovery of these enzymes). Cytochrome P450s comprise a phylogenetically old class of heme-containing monooxygenases largely expressed in the liver that function to detoxify xenobiotic (exogenous) hydrocarbon molecules. The class of CYP genes appears to have evolved from related steroidogenic ancestral genes at the time of the separation of animals and plants (the latter are still found in prokaryotes and are...