Inactivation of cytochrome P-450 by the drug methoxsalen.

摘要: 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, concentration inhibiting by 50% monooxygenase activities ranged from 10 microM (for benzo(a)-pyrene hydroxylases] to 25 for 7-ethoxy-coumarin deethylase aminopyrine demethylase); these values were range those observed with 525-A (1-50 microM) (10-100 but much lower than (100-500 microM). Methoxsalen (25-1000 decreased cytochrome P-450 presence EDTA; effect required NADPH oxygen, was phenobarbital pretreatment. Similarly, administration (125 vivo; decrease enhanced pretreatment prevented butoxide. There evidence lipid peroxidation, denaturation into P-420, formation P-450-metabolite complexes, destruction heme green pigments. contrast, a reactive metabolite covalently bound microsomal proteins; covalent binding We conclude that is activated which destroys P-450.