PERIPHERAL BENZODIAZEPINE RECEPTOR IN CHOLESTEROL TRANSPORT AND STEROIDOGENESIS

Steroidogenesis begins with the metabolism of cholesterol to pregnenol one by the inner mitochondrial membrane cytochrome P450 side-chain cle avage (P450scc) enzyme. The rate of steroid formation, however, depend s on the rate of cholesterol transport from intracellular stores to th e inner mitochondrial membrane and loading of P450scc with cholesterol . In previous in vitro studies, we demonstrated that a key element in the regulation of cholesterol transport is the mitochondrial periphera l-type benzodiazepine receptor (PBR). We also showed that the polypept ide diazepam binding inhibitor (DBI), an endogenous PER ligand, stimul ates cholesterol transport and promotes loading of cholesterol to P450 scc in vitro, and that its presence is vital for hCG-induced steroido- genesis by Leydig cells. Based on these data and the observations that ii the mitochondrial PER binding and topography are regulated by horm ones; ii) the 18-kDa PER protein is functionally coupled to the mitoch ondrial contact sire voltage-dependent anion channel protein; iii) the 18-kDa PER protein is a channel for cholesterol, as shown by molecula r modeling and in vitro reconstitution studies; iv) targeted disruptio n of the PER gene in steroidogenic cells dramatically reduces the abil ity of the cells to transport cholesterol in the mitochondria and prod uce steroids: v) endocrine disruptors, with known anisteroidogenic eff ect, inhibit PER ligand binding; and vi) in vivo reduction of adrenal PER expression results in reduced circulating glucocorticoid levels, w e conclude that PER is an indispensable element of the steroidogenic m achinery. (C) 1997 by Elsevier Science Inc.