REGULATION OF ADRENOCORTICAL STEROIDOGENESIS BY BENZODIAZEPINES

Benzodiazepines affect steroidogenesis in at least four ways depending on concentration and adrenocortical cell type. Firstly, at micromolar concentrations, they inhibit steroidogenic enzymes. Competition for m icrosomal 17- and 21-hydroxylase activity explains the inhibition of A CTH-stimulated aldosterone and cortisol synthesis by diazepam and mida zolam. At slightly higher concentrations, we have evidence that 11 bet a-hydroxylase activity is also inhibited. Secondly, at sub-micromolar concentrations, calcium influx is inhibited. T-type and L-type calcium channels appear to be blocked, this impairs signal response coupling and, in particular; decreases angiotensin- and K+-stimulated aldostero ne synthesis in zona glomerulosa cells. Thirdly, the mitochondrion of steroidogenic tissues is a sensitive site for the stimulatory effects of benzodiazepines. Aldosterone synthesis from added HDL-cholesterol b y cultured bovine zona glomerulosa cells is stimulated by diazepam, R0 5-4864 and PK11195. The fourth site of benzodiazepine's effect on ster oidogenesis is particular to zona glomerulosa cells. In addition to ch olesterol side chain cleavage, the final part of the aldosterone biosy nthetic pathway, the conversion from deoxycorticosterone is controlled . Although high micromolar concentrations of diazepam appear to be inh ibitory, lower nanomolar concentrations stimulate the synthesis of ald osterone from added deoxycorticosterone. In vivo, a fifth site of benz odiazepine activity may influence plasma steroid concentrations. Compe tition between steroids and benzodiazepines for hepatic clearance enzy mes may affect half lives of both drugs and hormones.