Source:http://linkedlifedata.com/resource/pubmed/id/20883830
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
1
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| pubmed:dateCreated |
2010-11-26
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| pubmed:abstractText |
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.). 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 17?-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?? 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.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Anti-Inflammatory Agents...,
http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome P-450 CYP1A1,
http://linkedlifedata.com/resource/pubmed/chemical/Estradiol,
http://linkedlifedata.com/resource/pubmed/chemical/Flavonoids,
http://linkedlifedata.com/resource/pubmed/chemical/Flavonols,
http://linkedlifedata.com/resource/pubmed/chemical/Perylene,
http://linkedlifedata.com/resource/pubmed/chemical/Phenols,
http://linkedlifedata.com/resource/pubmed/chemical/Plant Extracts,
http://linkedlifedata.com/resource/pubmed/chemical/Polyphenols,
http://linkedlifedata.com/resource/pubmed/chemical/Quercetin,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Stilbenes,
http://linkedlifedata.com/resource/pubmed/chemical/hypericin,
http://linkedlifedata.com/resource/pubmed/chemical/pseudohypericin,
http://linkedlifedata.com/resource/pubmed/chemical/resveratrol
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| pubmed:status |
MEDLINE
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| pubmed:month |
Jan
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| pubmed:issn |
0006-3002
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| pubmed:author | |
| pubmed:copyrightInfo |
Copyright © 2010 Elsevier B.V. All rights reserved.
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| pubmed:issnType |
Print
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| pubmed:volume |
1814
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
168-74
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| pubmed:dateRevised |
2011-11-17
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| pubmed:meshHeading |
pubmed-meshheading:20883830-Amino Acid Substitution,
pubmed-meshheading:20883830-Anti-Inflammatory Agents, Non-Steroidal,
pubmed-meshheading:20883830-Biocatalysis,
pubmed-meshheading:20883830-Cytochrome P-450 CYP1A1,
pubmed-meshheading:20883830-Dose-Response Relationship, Drug,
pubmed-meshheading:20883830-Estradiol,
pubmed-meshheading:20883830-Flavonoids,
pubmed-meshheading:20883830-Flavonols,
pubmed-meshheading:20883830-Genotype,
pubmed-meshheading:20883830-Humans,
pubmed-meshheading:20883830-Hydroxylation,
pubmed-meshheading:20883830-Hypericum,
pubmed-meshheading:20883830-Perylene,
pubmed-meshheading:20883830-Phenols,
pubmed-meshheading:20883830-Plant Extracts,
pubmed-meshheading:20883830-Polyphenols,
pubmed-meshheading:20883830-Quercetin,
pubmed-meshheading:20883830-Recombinant Proteins,
pubmed-meshheading:20883830-Stereoisomerism,
pubmed-meshheading:20883830-Stilbenes,
pubmed-meshheading:20883830-Substrate Specificity
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| pubmed:year |
2011
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| pubmed:articleTitle |
Inhibition of 17?-estradiol activation by CYP1A1: genotype- and regioselective inhibition by St. John's Wort and several natural polyphenols.
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| pubmed:affiliation |
Institute of Clinical Pharmacology and Toxicology, Charité, Campus Mitte, University Medicine Berlin, 10117 Berlin, Germany; Wernigeroder Str. 111, 16341 Panketal, Germany. schwarz.panketal@t-online.de
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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