Effect of the benzodiazepines diazepam, des-N-methyldiazepam and midazolam on corticosteroid biosynthesis in bovine adrenocortical cells in vitro; location of site of action

Abstract Diazepam and midazolam inhibited cortisol and aldosterone synthesis in bovine adrenal cells in vitro . The biologically active metabolite des- N -methyldiazepam did not. Midazolam was a more potent inhibitor (IC 50 : 6μg/ml) than diazepam (IC 50 : 13μg/ml) in ACTH-stimulated cells. Both compounds inhibited steroidogenesis at several points in the biosynthetic chain; the greatest effects were on 17α hydroxylation and 21hydroxylation. Diazepam had a relatively greater effect on 17α hydroxylation; midazolam on 21hydroxylation. Both were less potent inhibitors of llβ hydroxylation and had little apparent effect on side chain cleavage. Thus microsomal hydroxylation is more vulnerable to benzodiazepines than mitrochondrial hydroxylation. It is suggested that the drugs act by competing with steroid mixed function oxidases for cytochrome P -450. The plasma concentrations required for these effects are high in relation to therapeutic levels but may be achieved, for example, during acute infusions or when they are used in combination with imidazole drugs such as cimetidine.