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Association of CYP1A1 polymorphisms with differential metabolic activation of 17beta-estradiol and estrone

Item Type:Article
Title:Association of CYP1A1 polymorphisms with differential metabolic activation of 17beta-estradiol and estrone
Creators Name:Kisselev, P. and Schunck, W.H. and Roots, I. and Schwarz, D.
Abstract:Several epidemiologic studies associate certain CYP1A1 genotypes, alone or in combination, with an increased risk of estrogen-related cancers. To answer the question of whether genotype-dependent activation of estrogens by CYP1A1 could be the underlying mechanism, we studied the hydroxylation activity of the most common allelic variants of human CYP1A1 towards both endogenously occurring estrogens, 17{beta}-estradiol (E2) and estrone (E1). We expressed and purified CYP1A1.1 (wild-type), CYP1A1.2 (Ile 462Val), and CYP1A1.4 (Thr 461Asn) and did enzymatic assays of NADPH-dependent estrogen hydroxylation in reconstituted CYP1A1 systems. All CYP1A1 variants catalyzed the formation of 2-, 4-, 6{alpha}-, and 15{alpha}-hydroxylated estrogen metabolites from E2 and E1, yet with varying catalytic efficiency and distinct regiospecificity. Whereas the variant CYP1A1.2 (Ile 462Val) had a significant higher catalytic activity for all hydroxylation sites and both substrates, it was most pronounced for 2-hydroxylation. Catalytic efficiencies for the formation of the major metabolites, 2-OH-E2 and 2-OH-E1, by CYP1A1.2 were 5.7- and 12-fold higher, respectively, compared with the wild-type enzyme. The catalytic efficiencies for hydroxylations catalyzed by CYP1A1.4 were roughly comparable with those of the wild-type enzyme. Enzyme kinetics showed that the superior activity of CYP1A1.2 (Ile 462Val) is mainly caused by a higher V max) whereas K m values of all variants were similar. The data suggest that risk of estrogen-induced cancers and cardiovascular diseases might be - at least partially - determined by the CYP1A1 genotype.
Keywords:Binding Sites, Biotransformation, Cytochrome P-450 CYP1A1, Estradiol, Estrone, Genetic Polymorphism, Hydroxylation, Kinetics, Recombinant Proteins, Substrate Specificity, Animals
Source:Cancer Research
Publisher:American Association for Cancer Research
Page Range:2972-2978
Date:1 January 2005
Official Publication:https://doi.org/10.1158/0008-5472.CAN-04-3543
PubMed:View item in PubMed

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