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17β -Estradiol Hydroxylation Catalyzed by Human Cytochrome P450 1B1
Carrie L. Hayes, David C. Spink, Barbara C. Spink, Joan Q. Cao, Nigel J. Walker and Thomas R. Sutter
Proceedings of the National Academy of Sciences of the United States of America
Vol. 93, No. 18 (Sep. 3, 1996), pp. 9776-9781
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/39787
Page Count: 6
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The 4-hydroxy metabolite of 17β -estradiol (E2) has been implicated in the carcinogenicity of this hormone. Previous studies showed that aryl hydrocarbon-receptor agonists induced a cytochrome P450 that catalyzed the 4-hydroxylation of E2. This activity was associated with human P450 1B1. To determine the relationship of the human P450 1B1 gene product and E2 4-hydroxylation, the protein was expressed in Saccharomyces cerevisiae. Microsomes from the transformed yeast catalyzed the 4- and 2-hydroxylation of E2 with Km values of 0.71 and 0.78 μ M and turnover numbers of 1.39 and 0.27 nmol product min-1· nmol P450-1, respectively. Treatment of MCF-7 human breast cancer cells with the aryl hydrocarbon-receptor ligand indolo [3,2-b] carbazole resulted in a concentration-dependent increase in P450 1B1 and P450 1A1 mRNA levels, and caused increased rates of 2-, 4-, 6α -, and 15α -hydroxylation of E2. At an E2 concentration of 10 nM, the increased rates of 2- and 4-hydroxylation were approximately equal, emphasizing the significance of the low Km P450 1B1-component of E2 metabolism. These studies demonstrate that human P450 1B1 is a catalytically efficient E2 4-hydroxylase that is likely to participate in endocrine regulation and the toxicity of estrogens.
Proceedings of the National Academy of Sciences of the United States of America © 1996 National Academy of Sciences