HYPOTHESIS - ALDOSTERONE IS SYNTHESIZED BY AN ALTERNATIVE PATHWAY DURING SEVERE SODIUM DEPLETION - A NEW WINE IN AN OLD BOTTLE

1. The last three steps of aldosterone biosynthesis, 11 beta-hydroxyla tion, 18-hydroxylation and 18-oxidation, have been demonstrated to be catalysed by one enzyme, which is the cytochrome P450(11 beta) (CYP11B ) in cow, pig, sheep and bullfrog or cytochrome P450(aldo) (CYP11B2) i n rat, human, mouse and hamster.2. The related enzyme P450(11 beta) (C YP11B1) from rat, human, mouse and hamster adrenals displays 11 beta-h ydroxylation and 18-hydroxylation activities, but not 18-oxidation act ivity in vitro. No such enzyme has been reported in the cow, pig or sh eep to date. 3. Data showing the dissociation of aldosterone secretion from plasma angiotensin II (AngII) levels indicate the presence of ot her factor(s) that regulate aldosterone biosynthesis in response to ch anges in body sodium status. Thus, we propose the existence of a 'sodi um status factor' that regulates aldosterone biosynthesis in addition to AngII, K,(+) adrenocorticotropic hormone and atrial natriuretic pep tide. 4. We propose that during severe sodium deficiency there is a sw itch in the aldosterone pathway to a pathway using 18-hydroxy-deoxycor ticosterone (18-OH-DOC) rather than corticosterone as an intermediate. This switch may be mediated via the putative 'sodium status factor). 5. Two models of the hypothesis will be discussed in this paper: (i) a 'one-enzyme' model; and (ii) a 'two-enzyme' model. 6. The one-enzyme model proposes that P450(aldo) (P450(11 beta) as in the case of the co w, sheep and pig) changes its enzymatic activity during severe sodium deficiency (i.e. switching to the alternative aldosterone biosynthesis pathway). 7. The two-enzyme model proposes that, under normal circums tances, P450(aldo), synthesizes aldosterone from deoxycorticosterone, while during severe sodium deficiency the P450(11 beta) provides the s ubstrate (i.e 18-OH-DOC) for the P450(aldo).