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Titolo:
Metabolism of 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline in human hepatocytes: 2-Amino-3-methylimidazo [4,5-f]quinoxaline-8-carboxylic acid is a major detoxication pathway catalyzed by cytochrome P450 1A2
Autore:
Langouet, S; Welti, DH; Kerriguy, N; Fay, LB; Huynh-Ba, T; Markovic, J; Guengerich, FP; Guillouzo, A; Turesky, RJ;
Indirizzi:
Univ Rennes 1, INSERM U456, Fac Pharm, F-35043 Rennes, France Univ Rennes 1 Rennes France F-35043 6, Fac Pharm, F-35043 Rennes, France Vanderbilt Univ, Dept Biochem, Sch Med, Nashville, TN 37232 USA VanderbiltUniv Nashville TN USA 37232 , Sch Med, Nashville, TN 37232 USA Vanderbilt Univ, Ctr Mol Toxicol, Sch Med, Nashville, TN 37232 USA Vanderbilt Univ Nashville TN USA 37232 , Sch Med, Nashville, TN 37232 USA Nestec Ltd, Nestle Res Ctr, CH-1000 Lausanne 26, Switzerland Nestec Ltd Lausanne Switzerland 26 Ctr, CH-1000 Lausanne 26, Switzerland
Titolo Testata:
CHEMICAL RESEARCH IN TOXICOLOGY
fascicolo: 2, volume: 14, anno: 2001,
pagine: 211 - 221
SICI:
0893-228X(200102)14:2<211:MO2QIH>2.0.ZU;2-M
Fonte:
ISI
Lingua:
ENG
Soggetto:
HETEROCYCLIC AROMATIC-AMINES; FOOD-BORNE CARCINOGEN; HUMAN-LIVER; 2-AMINO-1-METHYL-6-PHENYLIMIDAZO<4,5-B>PYRIDINE PHIP; NONHUMAN-PRIMATES; COOKED FOODS; MUTAGEN 2-AMINO-3,8-DIMETHYLIMIDAZO<4,5-F>QUINOXALINE; BACTERIAL METABOLITE; COLORECTAL-CANCER; RAT HEPATOCYTES;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
60
Recensione:
Indirizzi per estratti:
Indirizzo: Langouet, S Fac Sci Pharmaceut & Biol, INSERM U456, 2 Ave Prof L Bernard, F-35043 Rennes, France Fac Sci Pharmaceut & Biol 2 Ave Prof L Bernard Rennes France F-35043
Citazione:
S. Langouet et al., "Metabolism of 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline in human hepatocytes: 2-Amino-3-methylimidazo [4,5-f]quinoxaline-8-carboxylic acid is a major detoxication pathway catalyzed by cytochrome P450 1A2", CHEM RES T, 14(2), 2001, pp. 211-221

Abstract

Metabolic pathways of the mutagen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxa (MeIQx) remain incompletely characterized in humans. In this study, the metabolism of MeIQx was investigated in primary human hepatocytes. Six metabolites were characterized by UV and mass spectroscopy. Novel metabolites were additionally characterized by H-1 NMR spectroscopy. The carcinogenic metabolite, 2-(hydroxyamino)-3, 8-dimethylimidazo[4,5-f]quinoxaline, which is formed by cytochrome P450 1A2 (P450 1A2), was found to be transformed into the N-2-glucuronide conjugate, N-2-(beta -1-glucosiduronyl)-2-(hydroxyamino) f]quinoxaline. The phase II conjugates N-2-(3,8-dimethylimidazo[4,5-flquinoxalinacid and N-2-(beta -1-glucosiduronyl)-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, as well as the 7-oxo derivatives of MeIQx and N-desmethyl-MeIQx, 2-amino-3,8-dimethyl-6-hydro-7H-imidazo[4,5-f]quinoxalin-7-one (7-oxo-MeIQx), and 2-amino-6-hydro-8-methyl-7H-imidazo[4,5-f]quinoxalin-7-one (N-desmethyl-7-oxo-MeIQx), thought to be formed exclusively by the intestinalflora, were also identified. A novel metabolite was characterized as 2-amino-3-methylimidazo-[4,5-f]quinoxaline-8-carboxylic acid (IQx-8-COOH), and it was the predominant metabolite formed in hepatocytes exposed to MeIQx at levels approaching human exposure. IQx-8-COOH formation is catalyzed by P450 1A2, This metabolite is a detoxication product and does not induce umuC gene expression in Salmonella typhimurium strain NM2009. IQx-8-COOH is also the principal oxidation product of MeIQx excreted in human urine [Turesky, R., et al. (1998) Chem. Res. Toxicol. 11, 217-225]. Thus, P450 1A2 is involved in both the metabolic activation and detoxication of this procarcinogenin humans. Analogous metabolism experiments were conducted with hepatocytes of untreated rats and rats pretreated with the P450 inducer 3-methycholanthrene. Unlike human hepatocytes, the rat cell preparations did not produceIQx-8-COOH but catalyzed the formation of 2-amino-3,8-dimethyl-5-hydroxyimidazo[4,5-f]quinoxaline as a major P450-mediated detoxication product. In conclusion, our results provide evidence of a novel MeIQx metabolism pathwayin humans through P450 1A2-mediated C-8-oxidation of MeIQx to form IQx-8-COOH. This biotransformation pathway has not been detected in experimental animal species. Considerable interspecies differences exist in the metabolism of MeIQx by P450s, which may affect the biological activity of this mutagen and must be considered when assessing human health risk.

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Documento generato il 22/01/20 alle ore 12:16:46