Inhibition of 17beta-estradiol activation by CYP1A1: Genotype- and regioselective inhibition by St. John's wort and several natural polyphenols

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Item Type:	Article
Title:	Inhibition of 17beta-estradiol activation by CYP1A1: Genotype- and regioselective inhibition by St. John's wort and several natural polyphenols
Creators Name:	Schwarz, D., Kisselev, P., Schunck, W.H. and Roots, I.
Abstract:	Several epidemiological studies associate certain CYP1A1 genotypes, alone or in combination, with an increased risk of estrogen-related cancers. Previously we demonstrated that metabolic activation of estrogens by CYP1A1 is a genotype-dependent reaction with the CYP1A1.2 (Ile462Val) variant being the most efficient catalyst (Kisselev et al., Cancer Res. 2005;65:2972-2978). To answer the question whether genotype-dependent inhibition of activation of estrogens by CYP1A1 could also contribute, we studied the inhibition of hydroxylation activity of the most common allelic variants of human CYP1A1 towards 17beta-estradiol. We expressed and purified CYP1A1.1 (wild-type), CYP1A1.2 (Ile462Val), and CYP1A1.4 (Thr461Asn) and performed inhibition assays by natural polyphenols of our diet and drugs of NADPH-dependent estradiol hydroxylation in reconstituted CYP1A1 systems. From the polyphenols studied, a St. John's wort (Hypericum perforatum) extract, some of its main single constituents hypericin, pseudohypericin, and quercetin, as well as the flavonols kaempferol, myricetin and the phytoestrogens resveratrol and tetramethyl-stilbene exhibited strong inhibition. For the St. John's wort extract and its single constituents hypericin, pseudohypericin, and quercetin, inhibition exhibited a remarkable dependency on the CYP1A1 genotype. Whereas (wild-type) CYP1A1.1 was most inhibited by the whole crude extract, the variant CYP1A1.2 (Ile462Val) was significantly stronger inhibited by the constituents in its pure form: IC(50) values for 2-hydroxylation was more than two times lower compared with the wild-type enzyme and the variant CYP1A1.4 (Thr461Asn). Besides this, the inhibition exhibited a remarkable regioselectivity. The data suggest that risk of estrogen-mediated diseases might be not only influenced by CYP1A1 genotype-dependent activation but also its inhibition by natural polyphenols of our diet and drugs.
Keywords:	CYP1A1, Estradiol, Metabolic Activation, Inhibition, Polymorphism
Source:	Biochimica et Biophysica Acta - Proteins and Proteomics
ISSN:	1570-9639
Publisher:	Elsevier
Volume:	1814
Number:	1
Page Range:	168-174
Date:	January 2011
Official Publication:	https://doi.org/10.1016/j.bbapap.2010.09.014
PubMed:	View item in PubMed

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