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-carboxamid e), Ro 5-4864 (4-chlorodiazepam), hemin, N-methyl protoporphyrin IX and protoporphyrin IX on liver mitochondrial 27-hydroxylation of cholesterol was studied by adding them together with [4-14C]cholesterol. N-Methyl protoporphyrin IX, PK11195 and protoporphyrin IX stimulated mitochondrial 27-hydroxylation of [4-14C] cholesterol in vitro, the first two being the most potent (2-3-fold increase). Ro 5-4864 and hemin were not active. 27-Hydroxylation of [4-14C]cholesterol was reduced to below control levels (respectively 40 and 56% decrease compared to control, P < 0.01) when PK11195, N-methyl protoporphyrin IX or protoporphyrin IX were allowed to equilibrate in vitro with mitochondria for 20 min at 37 degrees C. Hepatic protoporphyria was induced using 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) (100 mg/kg, i.p.) to study the effect of in vivo accumulation of large amounts of dicarboxylic porphyrins, i.e. endogenous peripheral benzodiazepine receptor ligands, on cholesterol 27-hydroxylation. DDC treatment caused an increase in total porphyrin content in liver homogenate (10-fold) and mitochondria (2-fold). Mitochondrial 27-hydroxylation of [4-14C]cholesterol was depressed after treatment (60% decrease, P < 0.01). We suggest that peripheral benzodiazepine receptor ligands act on liver mitochondrial 27-hydroxylation of cholesterol by a mechanism coupled to these receptors and that the time of exposure of peripheral benzodiazepine receptors to ligands is a major factor. The modulation of 27-hydroxycholesterol production may have a physiological role in liver and possibly in other tissues.
Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
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Tsankova
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Cantoni
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Carelli
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Tacconi
D000818:Animals; D003997:Dicarbethoxydihydrocollidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006888:Hydroxycholesterols / Q000378:metabolism*; D007546:Isoquinolines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*
D006888:Hydroxycholesterols; D007546:Isoquinolines; D011524:Protoporphyrins; D011963:Receptors, GABA-A; D003997:Dicarbethoxydihydrocollidine; C076996:27-hydroxycholesterol; C028842:N-methylprotoporphyrin IX; C028025:protoporphyrin IX; C037850:PK 11195