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W Levin

Publications and source records attributed to W Levin.

365 records · Page 21Linked to original sources
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Reconstituted liver microsomal enzyme system that hydroxylates drugs, other foreign compounds, and endogenous substrates. IX. The formation of a 455-nm metabolite-cytochrome P-450 complex.

The reconstituted liver microsomal hydroxylation system was used to study the formation of a metabolite-cytochrome P-450 complex absorbing maximally at 455 nm, with benzphetamine and N-hydroxyamphetamine as substrates. Complex formation required the presence of NADPH, substrate, NADPH-cytochrome c reductase, lipid, and cytochrome P-450, indicating that metabolism of the substrate is essential. In the presence of fixed amounts of lipid and NADPH-cytochrome c reductase, the rate of complex formation with cytochrome P-450 isolated from phenobarbital-treated rats was much greater than that observed with cytochrome P-48 from 3-methylcholanthrene-treated rats or rabbits. These results are consistent with recent studies indicating that different forms of cytochrome P-450 with distinct spectral, catalytic, and immunological properties exist in liver microsomes.

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Effects of three recombinant human leukocyte interferons on drug metabolism in mice.

Three recombinant human leukocyte interferons (IFLrA, IFLrD, and a hybrid IFLrA/D) that differ markedly in their antiviral activity in murine L cells were examined for their effects on hepatic microsomal drug metabolism in adult female CD-1 mice. When administered for 1 or 3 consecutive days, IFLrA/D, which exhibited the highest antiviral activity in murine L cells, caused a dose-dependent decrease in cytochrome P-450 content and in the rate of metabolism in vitro of benzo[a]pyrene, hexobarbital, 7-ethoxycoumarin, benzphetamine, and zoxazolamine. The concentration of cytochrome b and the activity of NADPH-cytochrome c reductase were also depressed when IFLrA/D was administered for 3 days. Similar but somewhat smaller changes were observed following treatment of mice with IFLrD, which possessed approximately 1% of the antiviral activity of IFLrA/D in murine L cells. In contrast, IFLrA, which was essentially devoid of antiviral activity in the mouse cell line, failed to depress cytochrome P-450 levels and in vitro drug metabolism activity in a consistent or dose-dependent manner. Cytochrome P-450 content and the in vitro rate of metabolism of benzphetamine and zoxazolamine were maximally depressed 8-24 hr after a single intraperitoneal injection of 1.5 micrograms of interferon per mouse; at this time the interferons were no longer detectable in serum. Near-normal levels of cytochrome P-450 and in vitro drug metabolism activity were restored by 48 hr after a single injection of interferon. Treatment of mice with 1.5 micrograms of IFLrA/D once daily for 3 days prolonged hexobarbital sleeping time but not zoxazolamine paralysis time, whereas neither of these was influenced by treatment with IFLrA or D. The results indicate that an interferon-dependent process reduces the level of microsomal cytochrome P-450 in liver and potentiates the pharmacological actions of certain drugs in mice.

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Immunohistochemical localization of cytochrome P-450a in liver sections from untreated rats and rats treated with phenobarbital or 3-methylcholanthrene.

Antibodies against cytochrome P-450a purified from hepatic microsomes of Long-Evans rats were used for indirect immunofluorescent localization of cytochrome P-450a within the livers of untreated, phenobarbital-treated, and 3-methylcholanthrene-treated mature and immature male and female rats. Immunohistochemical localization of cytochrome P-450a in liver sections from untreated mature male rats revealed fluorescence primarily in the central and midzonal regions, and moderate fluorescence in the periportal region. This pattern of fluorescence was not significantly altered in liver sections from mature male rats treated with phenobarbital or 3-methylcholanthrene. Liver sections from untreated mature female and immature male and female rats were primarily fluorescent in the central region with weak fluorescence in the midzonal and periportal regions of the lobule. Phenobarbital or 3-methylcholanthrene treatment markedly enhanced the intensity and lobular distribution of the fluorescence in liver sections from mature female and immature male and female rats. The apparent induction of cytochrome P-450a in the mature female and immature male and female rats, but not in mature males, is consistent with our previous immunochemical studies on the quantity of cytochrome P-450a in hepatic microsomes from untreated and treated rats. In addition, this study demonstrates that the lobular distribution of cytochrome P-450a in untreated mature male rats is different from the distribution of cytochrome P-450a in untreated female or immature rats.

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