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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
4
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pubmed:dateCreated |
1994-4-12
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pubmed:abstractText |
Aromatase catalyzes the conversion of androst-4-ene-3,17-dione to estrogen through sequential oxygenations at the 19-methyl group. Androst-4-ene-3,6,17-trione (AT) is a suicide substrate of aromatase, and the mechanism of inactivation of aromatase has been postulated to involve enzymatic oxygenation at the 19-position. [1 beta-3H,4-14C]-, [19-3H3,4-14C]-, and [1 beta-3H,19-14C]ATs, with high specific activities, were synthesized to study metabolic aspects and the inactivation mechanism. Incubation of the labeled AT with human placental microsomes yielded the 19-oxygenated derivatives, 19-hydroxy-AT and 19-oxo-AT, as well as the aromatization products, 6-oxoestrone and 6-oxoestradiol. A stereospecific 1 beta-proton elimination occurred during the aromatization of [1 beta-3H,4-14C]AT, and a marked tritium isotope effect was observed in the first hydroxylation at C-19 of [19-3H3,4-14C]AT. After incubation of the three double-labeled ATs, the solubilized proteins were subjected to SDS-PAGE and the 3H/14C ratio of the aromatase-bound metabolite in a 46-69 kDa fraction was analyzed. A marked decrease of the 3H/14C ratio of the metabolite was observed in the experiment using [19-3H3,4-14C]AT, compared with that of the labeled AT used, but there were no significant changes in the other experiments, indicating that the adduct retains the 1 beta-proton, the 19-carbon, and one of the three 19-methyl protons of AT. Thus, we conclude that further oxygenation of 19-oxo-AT produced by the two initial hydroxylations of AT at C-19 yields not only 6-oxoestrogen (by a mechanism similar to that involved in the aromatization of the natural substrate) but also a reactive electrophile that immediately binds to the active site in an irreversible manner, resulting in inactivation of aromatase.
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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/6-ketoestradiol,
http://linkedlifedata.com/resource/pubmed/chemical/Androstenes,
http://linkedlifedata.com/resource/pubmed/chemical/Aromatase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Carbon Radioisotopes,
http://linkedlifedata.com/resource/pubmed/chemical/Estradiol,
http://linkedlifedata.com/resource/pubmed/chemical/Formic Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Tritium,
http://linkedlifedata.com/resource/pubmed/chemical/Water,
http://linkedlifedata.com/resource/pubmed/chemical/androst-4-ene-3,6,17-trione,
http://linkedlifedata.com/resource/pubmed/chemical/formic acid
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
0006-2952
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
11
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pubmed:volume |
47
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
717-26
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:8129748-Androstenes,
pubmed-meshheading:8129748-Aromatase Inhibitors,
pubmed-meshheading:8129748-Carbon Radioisotopes,
pubmed-meshheading:8129748-Estradiol,
pubmed-meshheading:8129748-Formic Acids,
pubmed-meshheading:8129748-Humans,
pubmed-meshheading:8129748-Hydroxylation,
pubmed-meshheading:8129748-Microsomes,
pubmed-meshheading:8129748-Placenta,
pubmed-meshheading:8129748-Protein Binding,
pubmed-meshheading:8129748-Stereoisomerism,
pubmed-meshheading:8129748-Substrate Specificity,
pubmed-meshheading:8129748-Tritium,
pubmed-meshheading:8129748-Water
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pubmed:year |
1994
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pubmed:articleTitle |
Metabolic aspects of the 1 beta-proton and the 19-methyl group of androst-4-ene-3,6,17-trione during aromatization by placental microsomes and inactivation of aromatase.
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pubmed:affiliation |
Tohoku College of Pharmacy, Sendai, Japan.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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