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  • Title: Influence of the oral contraceptive, menstranol, on drug-metabolizing enzymes of female rats in thiamin-supplemented and deficiency states.
    Author: Wade AE, Evans JL, Seitz A.
    Journal: Pharmacology; 1976; 14(2):104-14. PubMed ID: 822434.
    Abstract:
    The administration of a diet deficient in thiamin results in elevated hepatic microsomal activity of aniline hydroxylase, ethylmorphone demethylase, NADPH cytochrome c reductase and cytochrome P-450 when compared to similar female rats fed diets supplemented with thiamin. Accompanying these differences in enzyme activity are increased concentrations of microsomal docosahexaenoic acid and arachidonic acid. Binding of aniline to microsomes from rats fed high levels of thiamin is decreased due to a decrease in cytochrome P-450. On the other hand, the binding of ethylmorphine to P-450 is decreased by feeding high levels of thiamin. The daily administration of mestranol enhanced ethylmorphine and aniline metabolism to a greater extent in rats fed thiamin-rich diet than in rats fed thiamin-deficient diet or laboratory chow. This treatment did not increase cytochrome P-450 cytochrome c reductase or microsomal protein nor does it appear to affect the binding of aniline to cytochrome P-450. Ethylmorphine binding is generally decreased by this treatment. Alterations in the Michaelis constants for these reactions were limited to an increase in the Ks for aniline in pair-fed animals and in the Ks for ethylmorphine in thiamin-deficient rats receiving 1.0 mg mestranol per day. The effect of mestranol on drug-metabolizing enzymes was studied in female rats receiving either deficient or thiamin-supplemented diets. Rats on the deficient diet showed increased hepatic microsomal activity of aniline hydroxylase, ethylmorphine demethylase, NADPH cytochrome c reductase, and cytochrome P-450. There were also increased concentrations of microsomal docosahexaenoic acid and arachidinic acid. Rats on the thiamin-supplemented diet showed decreased binding of aniline to microsomes, which was due to decreased levels of cytochrome P-450. However, high levels of thiamin decreased the binding of ethylmorphine to P-450. Mestranol increased ethylmorphine and aniline metabolism to a greater degree in animals receiving the thiamin-supplemented diet than those receiving the deficient diet or laboratory feed. However, levels of cytochrome P-450, cytochrome c reductase, or microsomal proteins were not increased, and the binding of aniline to cytochrome P-450 was not affected. Generally, treatment with mestranol decreased the binding of ethylmorphine. It appears that mestranol alters the Type I binding site on cytochrome P-450, but has no effect on the Type II binding site.
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