Nitric oxide potently inhibits the rate-limiting enzymatic step in steroidogenesis

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 (GC-S) stimulation. To assess CYP11A1 activity, pregnenolone levels were qua...

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Veröffentlicht in:Molecular and cellular endocrinology 2002-08, Vol.194 (1), p.39-50
Hauptverfasser: Drewett, James G, Adams-Hays, Robin L, Ho, Begonia Y, Hegge, David J
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Sprache:eng
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Zusammenfassung: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 (GC-S) stimulation. To assess CYP11A1 activity, pregnenolone levels were quantified in murine adrenocortical Y1 cells in the presence of the 3β-hydroxy-Δ 5-steroid dehydrogenase inhibitor, 2α-cyano-17β-hydroxy-4,4′,17α-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 22α-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 IC 50 for effects of free NO on CYP11A1 was potent and in the 0.4–2 μM range. These results support the hypothesis that NO inhibits the rate-limiting enzyme in steroidogenesis independent of GC-S activation.
ISSN:0303-7207
1872-8057
DOI:10.1016/S0303-7207(02)00214-9