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Target organ-specific inactivation of drug metabolizing enzymes in kidney of hamsters treated with estradiol

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Abstract

Chronic treatment of hamsters with estradiol for several months has previously been shown to decrease the specific content of cytochrome P450 in the kidney, a target of hormonal carcinogenesis, but not in liver. The reason for this decrease in metabolic enzyme activity is unknown and has been examined in this investigation. We now report that the decrease in specific content of renal cytochrome P450 by 73% in response to estradiol was not affected by co-treatment with tamoxifen for 1 month. The subcutaneous infusion of 250 µg/day estradiol for 7 days lowered renal cytochrome P450 by 71% from control values and was therefore used for further mechanistic studies. This treatment decreased renal activities of estradiol 2- or 4-hydroxylase by 77 to 80%, of 7-ethoxycoumarin-O-deethylase by 66% of control values, respectively, and completely eliminated aryl hydrocarbon hydroxylase activities, whereas liver enzymes remained unaffected. After 7 days of infusion of estradiol, fluorescent products of lipid peroxidation were more than doubled in hamster kidney but remained unchanged in liver. The possibility of enzyme destruction by binding of estradiol 2,3-quinone to metabolizing enzymes was investigatedin vitro. In the presence of 2-hydroxyestradiol, cumene hydroperoxide, and microsomes, conditions known to favor the oxidation of the steroid to quinone, the binding of catechol estrogen metabolite to microsomal protein increased 60 fold over control values in the absence of cofactor. Purified rat liver cytochrome P450c also oxidized 2-hydroxyestradiol to 2,3-estradiol quinone. The rate of oxidation was linear for the first 2–3 min, but thereafter decreased with time. Under these incubation conditions, irreversible binding of catechol estrogen metabolite to cytochrome P450c increased for the first 2–3 min and then remained at this plateau level. It was concluded that enzyme destruction by a reactive estrogen metabolite or by lipid peroxides may be a major reason for the organ-specific decrease in cytochrome P450 enzymes in kidneys of estrogen-treated hamsters.

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Abbreviations

E2 :

17β-Estradiol

2-OH-E2 :

2-Hydroxy-17β-Estradiol

DES:

Diethylstilbestrol

DES Q:

Diethylstilbestrol-4′, 4″-quinone

CuOOH:

Cumene Hydroperoxide

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  1. Department of Pharmacology and Toxicology, The University of Texas Medical Branch, 77550-2782, Galveston, TX, USA

    Deodutta Roy & Joachim G. Liehr

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  1. Deodutta Roy
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  2. Joachim G. Liehr
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Roy, D., Liehr, J.G. Target organ-specific inactivation of drug metabolizing enzymes in kidney of hamsters treated with estradiol. Mol Cell Biochem 110, 31–39 (1992). https://doi.org/10.1007/BF02385003

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  • DOI: https://doi.org/10.1007/BF02385003

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