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-OHE(2) and 4-OHE(2), 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-OHE(2) and 2-OHE(2) 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 toward 2-OHE(2) and 4-OHE(2), respectively. Incubation of [(3)H]-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.
Garner
C E
CE
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. C.Edwin.Garner@Dupontpharma.com
Burka
L T
LT
Etheridge
A E
AE
Matthews
H B
HB
D000818:Animals; D002384:Catalysis; D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000378:metabolism* / Q000633:toxicity*; D020111:Chlorodiphenyl (54% Chlorine) / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000633:toxicity*; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism; D002393:Estrogens, Catechol / Q000378:metabolism*; D005260:Female; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008745:Methylation; D011078:Polychlorinated Biphenyls / Q000378:metabolism* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium
D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D004791:Enzyme Inhibitors; D002393:Estrogens, Catechol; D014316:Tritium; D020111:Chlorodiphenyl (54% Chlorine); D004958:Estradiol; C001390:2-hydroxyestradiol; C014036:4-hydroxyestradiol; D011078:Polychlorinated Biphenyls; D002394:Catechol O-Methyltransferase