PERIPHERAL BENZODIAZEPINE RECEPTOR LIGANDS IN RAT-LIVER MITOCHONDRIA - EFFECT ON 27-HYDROXYLATION OF CHOLESTEROL

The effect of peripheral benzodiazepine receptor ligands: PK11195 (1-( 2-chlorophenyl)-N-methyl-N-(1-methylpropyl) isoquinoline-3-carboxamide ), Ro 5-4864 (4-chlorodiazepam), hemin, N-methyl protoporphyrin IX and protoporphyrin IX on fiver mitochondrial 27-hydroxylation of choleste rol was studied by adding them together with [4-C-14]cholesterol, N-Me thyl protoporphyrin IX, PK11195 and protoporphyrin IX stimulated mitoc hondrial 27-hydroxylation of [4-C-14]cholesterol in vitro, the first t wo being the most potent (2-3-fold increase). Ro 5-4864 and hemin were not active, 27-Hydroxylation of [4-C-14]cholesterol was reduced to be low control levels (respectively 40 and 56% decrease compared to contr ol, P < 0.01) when PK11195, N-methyl protoporphyrin IX or protoporphyr in IX were allowed to equilibrate in vitro with mitochondria for 20 mi n at 37 degrees C. Hepatic protoporphyria was induced using 3,5-dietho xycarbonyl-1,4-dihydrocollidine (DDC) (100 mg/kg, i.p.) to study the e ffect of in vivo accumulation of large amounts of dicarboxylic porphyr ins, i.e. endogenous peripheral benzodiazepine receptor ligands, on ch olesterol 27-hydroxylation. DDC treatment caused an increase in total porphyrin content in liver homogenate (10-fold) and mitochondria (2-fo ld). Mitochondrial 27-hydroxylation of [4-C-14]cholesterol was depress ed after treatment (60% decrease, P < 0.01). We suggest that periphera l benzodiazepine receptor ligands act on liver mitochondrial 27-hydrox ylation of cholesterol by a mechanism coupled to these receptors and t hat the time of exposure of peripheral benzodiazepine receptors to lig ands is a major factor. The modulation of 27-hydroxycholesterol produc tion may have a physiological role in liver and possibly in other tiss ues.