Alpha Hydroxy Acids

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Enzo Berardesca

University of Pavia, Pavia, Italy

Alpha hydroxy acids (AHAs) constitute a class of compounds that exert specific and unique effects on skin structures. The therapeutic utility of these acids continues to expand; when applied to the skin in higher concentrations they cause detachment of keratinocytes and epidermolysis while application in lower concentration reduces intercorneocyte cohesion and visible stratum corneum desquamation.

The smallest AHA is glycolic acid, which is constituted by two carbons (H2 C(OH)-COOH); lactic acid contains three carbons and converts to its keto form, pyruvic acid, and vice versa. Malic acid and tartaric acid consists of four carbon chains, while citric and gluconic acid have six carbon chains [1].

AHAs are found in nature in a variety of species including foods and plants (citric, malic, tartaric, glycolic), animals (cells and body fluids), and microorganisms such as bacteria, fungi, viruses, and algae. AHA are involved in many metabolic processes and participate in essential cellular pathways such as Krebs cycle, glycolysis, and serine biosynthesis. Furthermore, they promote collagen maturation and formation of glucosaminog-lycans. Their mechanism of action can be hypothesized via multiple effects [2]:

1. On stratum corneum: low concentration of AHAs diminish corneocyte cohesion. The effect occurs at the lower levels of the stratum corneum and may involve a dynamic process, operative at a particular step of keratinization, like the modification of ionic bonding. The effect is clinically evident as a sheetlike separation of the stratum corneum [3]. Indeed, intercorneocyte bonds are mostly noncovalent. In noncovalent bonds, the bonding force may be ionic or nonionic. AHAs reduce corneocyte cohesion by influencing ionic bonds via three mechanisms: (a) the distance between charges, (b) the number of charges, and (c) the medium between charges. When the stratum corneum becomes hydrated, the distance between corneocytes is increased and therefore cohesion is decreased. Another mechanism involved is the enzymatic inhibition, induced by AHAs, of the reactions of sulphate transferase, phosphototransferase, and kinases which leads to fewer electronegative sulphate and phosphate groups on the outer wall of corneocytes resulting in diminish-ment of cohesion forces. On the contrary, retinoids reduce intercorneocyte cohesion by breaking down already formed sulphate and phosphate bonds via induction or activation of sulphatase or phosphatase.

2. On keratinocytes: AHAs stimulate epidermal proliferation possibly by improving energy and redox status of keratinocytes. Changes detected on normal skin after treatment with AHAs [4] are similar to those noted during wound healing [5], in the rebound period after steroid-induced atrophy [6], and in retinoic acid-treated skin [7]. Increase in the overall thickness of viable epidermis as well as in the number of granular layers suggest a stimulation of epidermal turnover. The appearance of Hale's stainable material (GAGlike) in intercellular spaces between spinous and granular cells after treatment with an AHA like ammonium lactate has been reported also in retinoic acid treated skin [7,8].

3. On fibroblasts: at high concentration and in an appropriate vehicle, AHA induces epidermolysis, epidermal separation, and impact on the papillary dermis and reticular dermis that can lead to dermal changes including the synthesis of new collagen [1]. AHAs might turn on the biosynthesis of dermal glycosaminoglycans and other intercellular substances that could be responsible for eradication of fine wrinkles [9]. It has also been speculated that AHAs might promote collagen synthesis in human skin [9]. Ascorbic acid (an AHA in the lactone form) has been shown to stimulate procollagen synthesis in cultured human fibroblasts [10].

Because of these mechanisms, the cosmetic effects of AHAs on stratum corneum include an increase of plasticization and a decreased formation of dry flaky scales on skin surface. Indeed, a thinner stratum corneum is more flexible and compact; the increased flexibility obtained after topical application of AHAs is not related to an increased water content of the stratum corneum and is maintained even at low relative humidity [11]; this effect is also related to the free acid concentration of the formulation and is not dependent on transcutaneous penetration or sorption of the molecule [12]. The enhanced release of surface corneocytes is not equal for all AHAs and might lead in the long term to a stimulation of epidermal proliferation which increases thickness and metabolic activity of epidermis. The final cosmetic result of this process is an improvement of skin texture associated with increased skin firmness and elasticity.

Optimization of the formulation allows improvement of efficacy: pH is of great importance for achieving good therapeutical results. The suggested range is between 3.0 and 5.0, but lower pH values seem to be also very effective. The lower acid pH level reached in the stratum corneum after application of AHAs helps in dissolving desmosomes

Table 1 Mean Values (±SE) of CBF (Perfusion Units), TEWL (gm2/h), and Erythema (a* Value)




Betameth Glycolic Betameth Glycolic


Baseline 109.9 ± 14.9 Day 5 78.3 ± 9.9* Day 10 82.1 ± 13.9* Day 15 57.6 ± 6.5*

101.9 ± 12.7 19.6 ± 3.4 18.5 ± 3.7 17.1 ± 1.0 17.7 ± 0.9

52.6 ± 7.5 11.1 ± 1.5 10.8 ± 1.6 15.9 ± 0.7 16.3 ± 0.8

38.4 ± 5.4 12.2 ± 1.6 8.8 ± 1.7 16.9 ± 1.1 15.2 ± 0.9

35.3 ± 8.6 9.6 ± 1.6 8.6 ± 2.3 14.8 ± 0.8 14.5 ± 0.8

* Significant differences in CBF are recorded between glycolic acid-and betamethasone-treated sites during the study [17]. No significant differences appear concerning TEWL and erythema. All treatments induced a significant decrease of the parameters investigated during the study (TEWL, p < 0.01 glycolic, p < 0.005 betamethasone; CBF, glycolic p < 0.001, betamethasone p < 0.0001; erythema, glycolic p < 0.01, betamethasone p< 0.009).

Abbreviations: CBF, cutaneous blood flow; TEWL, transepidermal water loss; SE, standard error.

and/or other linkages between cells increasing therefore cell shedding and AHA activity [13]. Chronic treatment with low pH formula is likely to induce changes in the pH of living epidermis. Several enzymes (e.g., phosphatases, lipases, transforming growth factor beta) have maximum activity at pH 5 or lower and is possible that an acid environment may activate these mechanisms. Other important factors in the development of the product are free acid concentration (the higher the better) [12], the presence of an appropriate delivery system capable to increase penetration of AHA molecule, and the association between AHA and their salts.

Retinoic acid, a well-known and accepted drug for treating photoaging, shows benefits similar to AHAs after long term application. The mechanism of action is different and, even though clinical results may be similar, more complex. Retinoic acid has specific receptors (CRABP) on keratinocytes and fibroblasts; it binds to cell membranes and causes directly or indirectly stimulation of cell metabolism [14]. AHAs are hydrophilic (and diffuse freely throughout the intercellular phase) whereas retinoids are hydrophobic and thus require certain proteins in plasma and skin to act as carriers [14,15]. Retinoids have several side effects including photosensitivity, erythema, irritant dermatitis, and potential teratoge-nicity. Furthermore, from a cosmetic viewpoint, it takes several months to induce clinically evident cosmetic improvements [16]; AHAs are generally safer, less irritant, nonphotosen-sitizing, and give cosmetic results after 8 to 10 weeks.

Alpha hydroxy acids have been recently used to treat some skin diseases. Vignoli et al. [17] showed a reduction in psoriasis severity after treatment with glycolic acid as measured by visual scoring and noninvasive instruments (Table 1); in this study, a signifi-

Figure 1 Transepidermal water loss (1 SE) after SLS challenge (g/m2/h). Lower barrier damage is detected in AHA-treated sites compared to vehicle and untreated areas. (p < 0.006). Gluconolactone is significantly lower than glycolic acid at each time point. (hour0 = p < 0.01, hour24 = p < 0.03, hour48 p < 0.04) and than lactic acid at hour 48 (p < 0.04). (From Ref. 18.)

Figure 1 Transepidermal water loss (1 SE) after SLS challenge (g/m2/h). Lower barrier damage is detected in AHA-treated sites compared to vehicle and untreated areas. (p < 0.006). Gluconolactone is significantly lower than glycolic acid at each time point. (hour0 = p < 0.01, hour24 = p < 0.03, hour48 p < 0.04) and than lactic acid at hour 48 (p < 0.04). (From Ref. 18.)

cant improvement of transepidermal water loss (TEWL), erythema (a* value), and cutaneous blood flow after treatment with either 15% glycolic acid or betamethasone 0.05%. No significant differences appear in TEWL and erythema between glycolic acid and betamethasone; on the other hand, a significantly decreased CBF is recorded in the sites treated with betamethasone confirming the higher effect of corticosteroid in terms of vasoconstriction and reduction of inflammation.

Prolonged treatment with AHAs can also lead to stratum corneum barrier fortification and increased resistance to chemical irritation; sodium lauryl sulphate (SLS) irritation has been shown to be reduced in AHA-treated sites; a recent study [18] shows that AHAs can modulate stratum corneum barrier function and prevent skin irritation; and the effect is not equal for all AHAs, being more marked for the molecules characterized by antioxidant properties (Fig. 1). This effect has been shown by other keratolytic compounds such as urea [19] and can be related to the increased production of stratum corneum lipids such as ceramides induced by the treatment [20].

Over the years a number of cosmetic or dermatological compounds have gained attention for the capability to treat skin disorders and in particularly skin aging. AHAs are certainly the most intriguing class of compounds that are beginning to be incorporated into the new generation of cosmetic products. Even though many mechanisms are still far from being completely understood and much work remains to be done, the future is promising for these simple molecules.

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