Mitochondrial benzodiazepine receptors regulate steroid biosynthesis.

Abstract

Recent observations on the steroid synthetic capability within the brain open the possibility that benzodiazepines may influence steroid synthesis in nervous tissue through interactions with peripheral-type benzodiazepine recognition sites, which are highly expressed in steroidogenic cells and associated with the outer mitochondrial membrane. To examine this possibility nine molecules that exhibit a greater than 10,000-fold difference in their affinities for peripheral-type benzodiazepine binding sites were tested for their effects on a well-established steroidogenic model system, the Y-1 mouse adrenal tumor cell line. 4'-Chlorodiazepam, PK 11195, and PK 14067 stimulated steroid production by 2-fold in Y-1 cells, whereas diazepam, flunitrazepam, zolpidem, and PK 14068 displayed a lower (1.2- to 1.5-fold) maximal stimulation. In contrast, clonazepam and flumazenil did not stimulate steroid synthesis. The potencies of these compounds to inhibit 3H-labeled PK 11195 binding to peripheral-type benzodiazepine recognition sites correlated (r = 0.985) with their potencies to stimulate steroid production. Similar findings were observed in bovine and rat adrenocortical cell preparations. These results suggest that ligands of the peripheral-type benzodiazepine recognition site acting on this mitochondrial receptor can enhance steroid production. This action may contribute specificity to the pharmacological profile of drugs preferentially acting on the benzodiazepine recognition site associated with the outer membrane of certain mitochondrial populations.

Unconventional Secretion of AcbA in Dictyostelium discoideum through a Vesicular Intermediate

“…DBI can displace diazepam bound to the GABA A receptor and was named the diazepam binding inhibitor for this property (11,12). In a wide variety of tissues, DBI binds to the peripheral receptor localized on mitochondria, where it modulates steroid synthesis, leading to the processing of cholesterol into pregnenolone, the precursor of all steroids (27,33). Although DBI clearly acts as an intercellular signal, it is not clear how it or its precursor is released since neither one possesses a signal sequence that would direct it to the conventional endoplasmic reticulum-Golgi pathway.…”

Current status and future perspectives: TSPO in steroid neuroendocrinology

“…As recently speculated (Midzak & Papadopoulos 2014), it may be possible that drugs that bind TSPO could induce a conformational change resulting in a decreased cholesterol affinity, making more molecules available for steroid synthesis. This mechanism could explain the transient steroidogenic effect observed with different TSPO-binding drugs (Mukhin et al 1989). However, it does not explain how PK11195 could induce steroidogenesis in cells that are deficient in TSPO (Tu et al 2015), and it is unclear if such a transient production would have physiological and/or therapeutic effect.…”

“…Before the discovery of STAR, it was observed that chemicals capable of binding to the peripheral benzodiazepine receptor (PBR, the previous name for TSPO), which is present in the OMM (Anholt et al 1986), could stimulate modest amounts of steroid synthesis in adrenal tumor cells (Mukhin et al 1989) and Leydig tumor cells . Although TSPO was not a product of rapid de novo synthesis during steroid production, it was reported that TSPO knockdown could decrease steroid synthesis (Hauet et al 2005).…”

“…In 1989, testing the effect of TSPO-binding chemicals (including the isoquinolone carboxamide PK11195 and chlorodiazepam Ro5-4864) on the Y1 adrenocortical cell line and the MA-10 Leydig cell line resulted in the induction of progesterone production (Mukhin et al 1989). However, these effects were extremely modest and transient compared with physiological induction (80-fold lower response, and hormone levels plateauing within 40 min with no progressive accumulation as observed with physiological stimulation of these same cells).…”

Histological Changes of the Ovary of Adult Mice Exposed Prenatally to Flunitrazepam

“…BDZs are agonist ligands of the central benzodiazepinic receptor (CBR), located in the chlorine channels contacting the central nervous system, they are also ligands of the ubiquitous peripheral benzodiazepine receptor (PBR) (Parola et al, 1993;Zisterer &Willians, 1997). The steroidogenic ovary, testes, and adrenal glands contain PBRs involved in the metabolism and/or transport of cholesterol (Mukhin et al, 1989;Papadopoulos et al, 1991Papadopoulos et al, , 1997.…”