Catechol Metabolites of Polychlorinated Biphenyls Inhibit the Catechol-O-methyltransferase-Mediated Metabolism of Catechol Estrogens
The catechol metabolites of estradiol, 2- and 4-hydroxyestradiol (2-OHE2 and 4-OHE2, respectively) are potent signaling molecules and are hypothesized to be central to estrogen-linked carcinogenesis. Methylation by catechol-O-methyltransferase (COMT) is the principal means of catechol estrogen (CE)...
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Published in | Toxicology and applied pharmacology Vol. 162; no. 2; pp. 115 - 123 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
San Diego, CA
Elsevier Inc
15.01.2000
Elsevier |
Subjects | |
Online Access | Get full text |
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Summary: | The catechol metabolites of estradiol, 2- and 4-hydroxyestradiol (2-OHE2 and 4-OHE2, respectively) are potent signaling molecules and are hypothesized to be central to estrogen-linked carcinogenesis. Methylation by catechol-O-methyltransferase (COMT) is the principal means of catechol estrogen (CE) deactivation in the liver and other tissues. The present studies were conducted to determine the effects of PCBs and catechol metabolites of PCBs on the COMT-mediated catabolism of 4-OHE2 and 2-OHE2in vitro and in vivo. Liver homogenates of female Sprague–Dawley rats treated with Aroclor 1254 for 21 days (5 mg/kg/day) showed a 30 and 40% reduction of COMT activity toward 2-OHE2 and 4-OHE2, respectively. Incubation of [3H]-β-estradiol with these same liver homogenates, followed by HPLC analysis, demonstrated an elevation of CEs and a nearly complete reduction in levels of methylated catechol estrogens. In classical enzyme kinetics studies, COMT was demonstrated to have a high affinity for catechol PCBs, with Km's approximately equivalent to those of CEs. Catechol PCBs were also potent inhibitors of CE O-methylation. These data suggest that PCBs may significantly alter the metabolism of catechol estrogens in vivo and that this effect may be mediated by catechol metabolites of PCBs. It is further speculated that methyltransferase inhibition by PCB catechols may contribute to PCB-mediated endocrine effects and liver carcinogenesis. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 |
ISSN: | 0041-008X 1096-0333 |
DOI: | 10.1006/taap.1999.8823 |