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Titolo:
Catechol metabolites of polychlorinated biphenyls inhibit the catechol-O-methyltransferase-mediated metabolism of catechol estrogens
Autore:
Garner, CE; Burka, LT; Etheridge, AE; Matthews, HB;
Indirizzi:
NIEHS, Lab Pharmacol & Chem, Environm Toxicol Program, Res Triangle Pk, NC27709 USA NIEHS Res Triangle Pk NC USA 27709 Program, Res Triangle Pk, NC27709 USA Res Triangle Inst, Ctr Bioorgan Chem, Res Triangle Pk, NC 27709 USA Res Triangle Inst Res Triangle Pk NC USA 27709 Triangle Pk, NC 27709 USA
Titolo Testata:
TOXICOLOGY AND APPLIED PHARMACOLOGY
fascicolo: 2, volume: 162, anno: 2000,
pagine: 115 - 123
SICI:
0041-008X(20000115)162:2<115:CMOPBI>2.0.ZU;2-S
Fonte:
ISI
Lingua:
ENG
Soggetto:
ESTRADIOL-INDUCED TUMORIGENESIS; OXIDATIVE STRESS; TUMOR INITIATION; DNA-DAMAGE; IN-VITRO; CATECHOLESTROGENS; CANCER; ACTIVATION; ADDUCTS; KIDNEY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
44
Recensione:
Indirizzi per estratti:
Indirizzo: Garner, CE Dupont Co, Pharmaceut, Dept Drug Metab & Pharmacokinet, POB 30,Newark, DE19714 USA Dupont Co POB 30 Newark DE USA 19714 OB 30, Newark, DE19714 USA
Citazione:
C.E. Garner et al., "Catechol metabolites of polychlorinated biphenyls inhibit the catechol-O-methyltransferase-mediated metabolism of catechol estrogens", TOX APPL PH, 162(2), 2000, pp. 115-123

Abstract

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-OHE2 in 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 toward2-OHE2 and 4-OHE2, respectively. Incubation of [H-3]-beta-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 K-m'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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Documento generato il 01/12/20 alle ore 01:02:14