Molecular Pharmacology, Vol 13, 415-425, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

Effects of Linoleic Acid Hydroperoxide on the Hepatic Monooxygenase Systems of Microsomes from Untreated, Phenobarbital-Treated, and 3-Methylcholanthrene-Treated Rats

¹ Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455

Increasing concentrations of linoleic acid hydroperoxide (10-250 µM) destroyed increasing amounts of P-450 hemoprotein in hepatic microsomes from untreated, phenobarbital-treated, and 3-methylcholanthrene-treated rats. Loss of P-450 hemoprotein in microsomes from untreated and phenobarbital-treated rats was biphasic; 50% was destroyed at low concentrations of linoleic acid hydroperoxide (50 µM or less), and only about half the remainder was destroyed at relatively high concentrations (150 µM or more). The labile population of P-450 hemoprotein was designated P-450_(ll), and the stable, P-450_(ls). The loss of P-450 hemoprotein in microsomes from 3-methylcholanthrene-treated rats was not biphasic, and most of the hemoprotein was in the stable form. Almost all of the monooxygenase activity (ethylmorphine N-demethylase, aniline hydroxylase) and type I binding (hexobarbital) was associated with P-45O_(ll). Microsomal NADPH-cytochrome c reductase activities and cytochrome b₅ levels were not affected by linoleic acid hydroperoxide until high concentrations were reached (150 µM or more). NADH-cytochrome c reductase activity was similarly unaffected by linoleic acid hydroperoxide in microsomes from untreated rats, was slightly elevated in microsomes from 3-methylcholanthrene-treated rats, and was greatly elevated in microsomes from phenobarbital-treated rats. NADPH oxidase activity was unaffected by linoleic acid hydroperoxide in microsomes from untreated and 3-methylcholanthrene-treated rats, but was decreased slightly in microsomes from phenobarbital-treated animals. These results led to the conclusion that P-450_(ll) functions in the oxidation of exogenous substrates, that P-450_(ls) functions in the oxidation of endogenous substrates, and that the two functions are essentially independent of each other.

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