The last stages in the synthesis of the mineralo-corticoid aldosterone and the glucocorticoid cortisol take place in the adrenal cortex, and are catalyzed by two highly homologous enzymes which lie adjacent to each other on chromosome 8. CYP11B1 (11-beta hydroxylase) converts deoxy-cortisol to cortisol (the principal corticosteroid), a process involving 11-hydroxylation, and CYP11B2 (aldosterone synthase) converts deoxycorticoster-one to aldosterone (the principal mineralocorti-coid), a process involving 18-hydroxylation. The CYP11B1 promoter is responsive to plasma levels of adrenocorticotrophic hormone (ACTH) and thus CYP11B1 is constitutively active, regulated by negative feedback of cortisol on the hypotha-lamic/pituitary axis. The CYP11B2 promoter responds to the activity of the renin—angiotensin system, mediated via the action of angiotensin II on Type I angiotensin II receptors. In some families segregating hypertension, hypokalemia and hyperaldosteronism in an autosomal dominant fashion, an unequal crossover between these genes (Figure 25.2) results in a chimeric gene having the biological activity of CYP11B2 (thus, the ability to make aldosterone), but under the control of the ACTH responsive element normally controlling CYP11B1. Thus, CYP11B2 activity escapes in affected individuals from the control of the renin—angiotensin system and results in hyperaldosteronism. Because aldosterone does not suppress ACTH release, no negative feedback occurs to limit the production of aldosterone from the chimeric gene; however, the increased blood pressure acts to limit the release of renin from the kidney, leading to a low level of plasma renin. Pharmacological administration of glucocor-ticoids does suppress ACTH levels and as well as switching off the activity of CYP11B1, switches off the chimeric gene and resolves the hyperaldoster-onism (Lifton et al., 1992) Since not all patients with GRA have plasma levels of potassium below the conventionally determined normal range, several studies subsequently examined hypertensive cohorts of different ethnicities to determine whether undetected GRA was a common cause of essential hypertension; it was not (MacConnachie et al., 1998; McKenzie et al., 2000). Common polymorphisms in the CYP11B1 and CYP11B2 genes have been investigated for association with essential hypertension, but for these genes as for almost all others so investigated, the results from different studies are contradictory. However, a replicable association between polymorphisms at this locus and the efficiency of 11-beta hydroxyl-ation does appear to exist; it remains possible that the effect of the locus on 11-beta hydroxylation plays some causative role in the etiology of hypertension (see below).
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