Chlorbutol, a new inhibitor of aldosterone biosynthesis identified during examination of heparin effect on aldosterone production.
This study was designed to examine the mechanism whereby routine heparin therapy inhibits adrenal aldosterone production. In bovine adrenal glomerulosa cell suspensions, pure heparin, in concentrations up to 500 U/ml, had no significant effect on basal or angiotensin II-stimulated aldosterone production. A therapeutic preparation of heparin for parenteral use containing the preservative chlorbutol (2.8 X 10(-2) M) inhibited aldosterone production [67 +/- 8.7% (+/- SE); P less than 0.005]. Chlorbutol alone, in a dose-dependent manner, inhibited basal aldosterone production from 1548 +/- 355 to 316 +/- 152 pg/ml (P less than 0.001) and inhibited angiotensin II-stimulated production from 4950 +/- 724 to 589 +/- 257 pg/ml (P less than 0.001). To elucidate the inhibitory mechanism of chlorbutol, we used trilostane, an inhibitor of the conversion of pregnenolone to progesterone, and aminoglutethimide, an inhibitor of the conversion of cholesterol to pregnenolone. Aldosterone production was completely suppressed by each inhibitor. Pregnenolone accumulation in trilostane-treated cells fell from 9.70 +/- 1.66 to 1.40 +/- 0.28 ng/ml (P less than 0.005) with the addition of chlorbutol. Aldosterone accumulation from corticosterone added to aminoglutethimide-treated cells fell from 715 +/- 96 to 348 +/- 59 pg/ml (P less than 0.02) in cells incubated with chlorbutol. Thus, chlorbutol is a potent inhibitor of aldosterone production, inhibiting both the early biosynthetic phase and, to a lesser extent, the late phase. Since chlorbutol is a widely used pharmaceutical preservative and has a slow metabolic clearance, these findings may be of toxicological significance and may account for the inhibition of aldosterone production previously attributed to heparin.
D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism; D000450:Aldosterone / Q000096:biosynthesis*; D000804:Angiotensin II / Q000037:antagonists & inhibitors; D000818:Animals; D002417:Cattle; D002724:Chlorobutanol / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology*; D006854:Hydrocortisone / Q000096:biosynthesis; D066298:In Vitro Techniques; D010592:Pharmaceutic Aids / Q000494:pharmacology*; D011310:Preservatives, Pharmaceutical / Q000494:pharmacology*; D013997:Time Factors
D010592:Pharmaceutic Aids; D011310:Preservatives, Pharmaceutical; D000804:Angiotensin II; D000450:Aldosterone; D006493:Heparin; D002724:Chlorobutanol; D006854:Hydrocortisone