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  • Title: Inactivation and induction of cytochrome P-450 by various psoralen derivatives in rats.
    Author: Letteron P, Descatoire V, Larrey D, Tinel M, Geneve J, Pessayre D.
    Journal: J Pharmacol Exp Ther; 1986 Aug; 238(2):685-92. PubMed ID: 3735138.
    Abstract:
    8-Methoxypsoralen has been shown to both inactivate and induce microsomal enzymes. We report here the effects of other psoralen derivatives in rats. CO-binding cytochrome P-450 decreased when hepatic microsomes were incubated for 10 min with an NADPH-generating system and 8-methoxypsoralen, 5-methoxypsoralen or psoralen (400 microM), but remained unchanged with trioxsalen (400 microM). The destruction of cytochrome P-450 with the former derivatives required NADPH. It was greater with microsomes from phenobarbital-pretreated rats. Monooxygenase activities were decreased by 30 to 60% when 8-methoxypsoralen, 5-methoxypsoralen or psoralen (10 or 25 microM) were added to the incubation mixtures, but remained unchanged upon addition of trioxsalen (10 or 25 microM). In vivo, monooxygenase activities were decreased 4 hr after the administration of a single dose of 8-methoxypsoralen, 5-methoxypsoralen or psoralen (125 mumol X kg-1 p.o.) but remained unchanged after trioxsalen (125 mumol X kg-1 p.o.). During repeated administration of 8-methoxypsoralen or 5-methoxypsoralen (125 mumol X kg-1 p.o. for 3 or 4 days), there was evidence for both induction and inactivation of drug-metabolizing enzymes; monooxygenase activities were high or normal late after a preceding dose, but fell again to normal or low values, respectively, early after a further dose. With psoralen, there was only inactivation, and monooxygenase activities tended to remain low throughout. Monooxygenase activities remained normal with trioxsalen. We conclude that 5-methoxypsoralen, like 8-methoxypsoralen, both inactivates and induces microsomal enzymes. In contrast, psoralen only inactivates them, whereas trioxsalen shows little effects.(ABSTRACT TRUNCATED AT 250 WORDS)
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