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Titolo:
N-Glucuronidation of 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) and N-hydroxy-PhIP by specific human UDP-glucuronosyltransferases
Autore:
Malfatti, MA; Felton, JS;
Indirizzi:
Univ Calif Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, Livermore, CA 94551 USA Univ Calif Lawrence Livermore Natl Lab Livermore CA USA 94551 A 94551 USA
Titolo Testata:
CARCINOGENESIS
fascicolo: 7, volume: 22, anno: 2001,
pagine: 1087 - 1093
SICI:
0143-3334(200107)22:7<1087:NO2[(>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
CDNA-EXPRESSED HUMAN; HETEROCYCLIC AMINES; LIVER-MICROSOMES; RAT-LIVER; IDENTIFICATION; 2-HYDROXYAMINO-1-METHYL-6-PHENYLIMIDAZO<4,5-B>PYRIDINE; METABOLITES; ACTIVATION; CHICKEN; 2-AMINO-3,8-DIMETHYLIMIDAZO<4,5-F>QUINOXALINE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
26
Recensione:
Indirizzi per estratti:
Indirizzo: Felton, JS Univ Calif Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, POB808,L-452, Livermore, CA 94551 USA Univ Calif Lawrence LivermoreNatl Lab POB 808,L-452 Livermore CA USA 94551
Citazione:
M.A. Malfatti e J.S. Felton, "N-Glucuronidation of 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) and N-hydroxy-PhIP by specific human UDP-glucuronosyltransferases", CARCINOGENE, 22(7), 2001, pp. 1087-1093

Abstract

Glucuronidation is a major metabolic pathway in the biotransformation of many xenobiotics, Recent studies have shown that in humans, UDP-glucuronosyltransferase (UGT)-mediated glucuronidation plays a critical role in the detoxification of food-borne carcinogenic heterocyclic amines, 2-A mino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant carcinogenic heterocyclic amine found in well-cooked meats, has been shown to be extensively glucuronidated in humans. To determine which UGT isozymes are involved in the biotransformation of PhIP and the cytochrome P4501A2-mediated reactive intermediate N-hydroxy-PhIP, microsomes expressing human UGT1A1, -1A4, -1A6 or -1A9 were incubated with PhIP and N-hydroxy-PhIP and the reaction products analyzed by HPLC and ESI-MS, Incubations containing N-hydroxy-PhIP and UGT1A1 expressing microsomes, with an apparent K-m of 4.58 muM and a V-max of 4.18 pmol/min/mg protein, had the highest capacity to convert N-hydroxy-PhIP to N-hydroxy-PhIP-N-2-glucuronide. Microsomes expressing UGT1A9 produced N-hydroxy-PhIP-N3-glucuronide at the highest rate with an apparent K, and V,, of 3.73 muM and 4.07 pmol/min/mg, respectively. A third previously undefined glucuronide accounted for 31% of the total glucuronides formed from the UGT1A4 expressing microsomes. No glucuronide conjugates were detected from microsomes expressing UGT1A6, Incubations containing PhIP as substrate formed direct PhIP-glucuronides in microsomes expressing UGT1A1, UGT1A4 and UGT1A9 but at levels averaging 53-fold lower than when N-hydroxy-PhIP was used as the substrate. Knowing the glucuronidation capacity of the specific UGT isozymes involved in PhIP and N-hydroxy-PhIP glucuronidation shouldhelp in determining the individual susceptibility to the potential cancer risk from exposure to PhIP.

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Documento generato il 03/04/20 alle ore 11:03:26