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Titolo:
Phenolphthalein metabolite inhibits catechol-O-methyltransferase-mediated metabolism of catechol estrogens: A possible mechanism for carcinogenicity
Autore:
Garner, CE; Matthews, HB; Burka, LT;
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
Titolo Testata:
TOXICOLOGY AND APPLIED PHARMACOLOGY
fascicolo: 2, volume: 162, anno: 2000,
pagine: 124 - 131
SICI:
0041-008X(20000115)162:2<124:PMICM>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
ESTRADIOL-INDUCED TUMORIGENESIS; TUMOR INITIATION; SYRIAN-HAMSTER; CANCER-CELLS; IN-VITRO; 2-METHOXYESTRADIOL; CATECHOLESTROGENS; INDUCTION; ACTIVATION; APOPTOSIS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
42
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., "Phenolphthalein metabolite inhibits catechol-O-methyltransferase-mediated metabolism of catechol estrogens: A possible mechanism for carcinogenicity", TOX APPL PH, 162(2), 2000, pp. 124-131

Abstract

Phenolphthalein (PT), used in over-the-counter laxatives, has recently been identified as a multisite carcinogen in rodents, but the molecular species responsible for the carcinogenicity is not known. A catechol metabolite of PT, hydroxyphenolphthalein (PT-CAT), was recently identified and may be the molecular species responsible for at least part of the toxicity/carcinogenicity of PT. We hypothesize that PT-CAT inhibits the enzyme catechol-O-methyltransferase (COMT) and therefore potentiates genotoxicity by either PT-CAT itself or the endogenous catechol estrogens (CEs) in susceptible tissues. The present studies were conducted to determine the effects of PT treatment and PT-CAT itself on the COMT-mediated metabolism of 4- and 2-hydroxyestradiol both in vitro and in vivo. Female mice were treated with PT (50 mg/kg/d) for 21 days and then euthanized. PT-CAT concentration in urine reached plateau levels by 7 days of exposure. An O-methylated metabolite of PT-CAT was detected in feces. In vitro experiments demonstrated that PT treatment resulted in an increase in free CEs, which are normally cleared by COMT and a concurrent decrease in the capacity of hepatic catechol clearance by COMT, In vitro, PT-CAT was a substrate of COMT, with kinetic properties within the range measured with endogenous substrates. PT-CAT was an extremely potent mixed-type inhibitor of the O-methylation of the catechol estrogens, with 90-300 nM IC50s. The above data, when taken together, suggest that chronic administration of PT may enhance metabolic redox cycling of both PT-CAT and the catechol estrogens and this, in turn, may contribute to PT-induced tumorigenesis.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/11/20 alle ore 18:47:42