Inactivation of cytochrome P-450 by the drug methoxsalen.
Administration of methoxsalen (50 mumol X kg-1 i.p.) increased 4-fold the hexobarbital sleeping time in rats; at this low dose, SKF 525-A, piperonyl butoxide and cimetidine had little or no effect. In vitro, the concentration of methoxsalen inhibiting by 50% monooxygenase activities ranged from 10 microM (for benzo(a)-pyrene and hexobarbital hydroxylases] to 25 microM for 7-ethoxy-coumarin deethylase and aminopyrine demethylase); these values were in the range of those observed with SKF 525-A (1-50 microM) or piperonyl butoxide (10-100 microM) but much lower than those for cimetidine (100-500 microM). Methoxsalen (25-1000 microM) decreased cytochrome P-450 in vitro, in the presence of EDTA; this effect required NADPH and oxygen, was decreased by piperonyl butoxide and was increased by phenobarbital pretreatment. Similarly, administration of methoxsalen (125 mumol X kg-1 i.p.) decreased cytochrome P-450 and monooxygenase activities in vivo; the decrease in cytochrome P-450 was enhanced by phenobarbital pretreatment and was prevented by piperonyl butoxide. There was no evidence for lipid peroxidation, denaturation into cytochrome P-420, formation of cytochrome P-450-metabolite complexes, destruction of heme or formation of green pigments. In contrast, a reactive metabolite of methoxsalen covalently bound to microsomal proteins; covalent binding required NADPH and oxygen, was decreased by piperonyl butoxide and was increased by phenobarbital pretreatment. We conclude that methoxsalen is activated into a metabolite which destroys cytochrome P-450.
D000818:Animals; D001711:Biotransformation; D065607:Cytochrome P-450 Enzyme Inhibitors; D004790:Enzyme Induction; D006591:Hexobarbital / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008297:Male; D008730:Methoxsalen / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012890:Sleep / Q000187:drug effects
D065607:Cytochrome P-450 Enzyme Inhibitors; D008054:Lipid Peroxides; D006591:Hexobarbital; D008730:Methoxsalen