Peripheral-type benzodiazepine receptors are involved in the regulation of cholesterol side chain cleavage in adrenocortical mitochondria.
In an attempt to elucidate the physiological relevance of the peripheral type of benzodiazepine receptor in adrenocortical mitochondria, we examined the effect of three different benzodiazepines (diazepam, Ro5-4864, and chlordiazepoxide) on the conversion of cholesterol to pregnenolone, the rate-limiting step in steroidogenesis, by using cholesterol-loaded mitochondria from bovine adrenal zona fasciculata. These benzodiazepines, except chlordiazepoxide, caused a dose-dependent stimulation of the cholesterol side chain cleavage in the mitochondria. The stimulatory effect of Ro5-4864 was approximately 10 times more potent than that of diazepam. No inhibitory effect of YM-684 (Ro15-1788), a potent antagonist to central-type benzodiazepine receptors, was observed in the stimulation induced by diazepam and Ro5-4864. Both external calcium ion and voltage-dependent calcium channel blocker, (+)-PN200-110, were without effect on the diazepam-induced steroidogenesis. By contrast, pretreatment of mitochondria with digitonin abolished the stimulatory effect of diazepam on the mitochondrial steroidogenesis. The present results indicate that the peripheral-type benzodiazepine receptor of adrenocortical mitochondria plays an essential role in regulating cholesterol side chain cleavage without any change of calcium channels.
Yanagibashi
K
K
Department of Pharmacology I, Jikei University School of Medicine, Tokyo.
Ohno
Y
Y
Nakamichi
N
N
Matsui
T
T
Hayashida
K
K
Takamura
M
M
Yamada
K
K
Tou
S
S
Kawamura
M
M
D000302:Adrenal Cortex / Q000648:ultrastructure*; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002417:Cattle; D002784:Cholesterol / Q000378:metabolism*; D003975:Diazepam / Q000494:pharmacology; D004072:Digitonin / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism*; D011284:Pregnenolone / Q000096:biosynthesis; D011963:Receptors, GABA-A / Q000378:metabolism*; D013256:Steroids / Q000096:biosynthesis
D011963:Receptors, GABA-A; D013256:Steroids; D001569:Benzodiazepines; D011284:Pregnenolone; D002784:Cholesterol; D004072:Digitonin; D003975:Diazepam; D002118:Calcium