Journal
MOLECULAR AND CELLULAR ENDOCRINOLOGY
Volume 194, Issue 1-2, Pages 39-50Publisher
ELSEVIER SCI IRELAND LTD
DOI: 10.1016/S0303-7207(02)00214-9
Keywords
adrenocortical steroidogenesis (human); aldosterone; cytochrome P450; guanylyl cyclase; nitric oxide; pregnenolone
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Funding
- NHLBI NIH HHS [R29 HL 54717, R01 HL 54717] Funding Source: Medline
- NIDA NIH HHS [R29 DA 09857] Funding Source: Medline
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This study tested the hypothesis that nitric oxide (NO) inhibits the rate-limiting catalytic step in steroidogenesis, cytochrome P450 cholesterol side-chain cleaving enzyme (CYP11A1), independent Of Soluble guanylyl cyclase (GG-S) stimulation. To assess CYP11A1 activity, pregnenolone levels were quantified in murine adrenocortical Y1 cells in the presence of the 3beta-hydroxy-Delta(5)-steroid dehydrogenase inhibitor, 2alpha-cyano-17beta-hydroxy-4,4',17alpha-trimethylandrost-5-ene-3-one. The NO donor, (Z)-1-[2-(2-aminoethyl-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate(deta nonoate), inhibited vasoactive intestinal peptide-, forskolin- and 22alpha-hydroxycholesterol (22HC)-facilitated pregnenolonogenesis in the absence of GC-S activation and in the presence of a GC-S inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). CYP11A1 was also heterologously expressed in monkey COS7 cells. Deta nonoate inhibited 22HC-facilitated activity of the over-expressed enzyme in the absence of GC-S activation and in the presence of ODQ. The NO-independent, GC-S agonist, 1-benzyl-3-(5-hydroxymethyl-2'-furyl)indazole did not inhibit steroidogenesis. The IC50 for effects of free NO on CYP11A1 was potent and in the 0.4-2 muM range. These results support the hypothesis that NO inhibits the rate-limiting enzyme in steroidogenesis independent of GC-S activation. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
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