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Titolo:
METABOLISM OF 3-METHYLINDOLE BY VACCINIA-EXPRESSED P450 ENZYMES - CORRELATION OF 3-METHYLENEINDOLENINE FORMATION AND PROTEIN-BINDING
Autore:
THORNTONMANNING J; APPLETON ML; GONZALEZ FJ; YOST GS;
Indirizzi:
UNIV UTAH,DEPT PHARMACOL & TOXICOL,112 SKAGGS HALL SALT LAKE CITY UT 84112 UNIV UTAH,DEPT PHARMACOL & TOXICOL SALT LAKE CITY UT 84112 NCI,MOLEC CARCINOGENESIS LAB BETHESDA MD 20892
Titolo Testata:
The Journal of pharmacology and experimental therapeutics
fascicolo: 1, volume: 276, anno: 1996,
pagine: 21 - 29
SICI:
0022-3565(1996)276:1<21:MO3BVP>2.0.ZU;2-H
Fonte:
ISI
Lingua:
ENG
Soggetto:
CDNA-DIRECTED EXPRESSION; COVALENT BINDING; HUMAN-LIVER; RABBIT LUNG; IDENTIFICATION; INDOLE-3-CARBINOL; INHIBITION; SEQUENCE; ADDUCT; BIOACTIVATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
67
Recensione:
Indirizzi per estratti:
Citazione:
J. Thorntonmanning et al., "METABOLISM OF 3-METHYLINDOLE BY VACCINIA-EXPRESSED P450 ENZYMES - CORRELATION OF 3-METHYLENEINDOLENINE FORMATION AND PROTEIN-BINDING", The Journal of pharmacology and experimental therapeutics, 276(1), 1996, pp. 21-29

Abstract

The toxicity of 3-methylindole (3 MI), a selective pneumotoxin, is dependent upon cytochrome P450-mediated bioactivation(3). Using vaccinia-expressed P450 enzymes, the metabolites of radiolabeled 3 MI producedby 14 individual P450s were identified and quantified by high performance liquid chromatography. Indole-3-carbinol was produced from incubations of 3 MI with only four enzymes. Although 3-methyloxindole was a product of several P450s, human 1A2 was most efficient in producing this metabolite. The toxic intermediate of 3 MI is believed to be a reactive methylene imine, 3-methyleneindolenine. In this study, this intermediate was detected as its mercapturate adduct, when N-acetylcysteinewas added to the incubations. 3-Methyleneindolenine was produced by CYP2A6 at a rate of 50.9 +/- 8.9 pmol/mg protein/hr and by CYP2F1 at a rate of 205.7 +/- 12.5 pmol/mg/hr. The mouse 1a-2 and rabbit 4B1 enzymes produced the reactive intermediate in amounts that exceeded that ofthe human 2F1 enzyme by 1.4-fold and 1.9-fold, respectively. The toxicity of 3 MI is believed to be due to covalent binding of a P450-generated intermediate to critical pulmonary proteins, Comparison of covalent binding studies to the formation of the metabolites revealed a strong correlation between the amount of the 3 MI adduct detected and covalent binding. This study showed that the methylene imine electrophile is produced by only a few P450 enzymes and is the metabolite responsible for the covalent binding and, presumably, the toxicity of 3 MI. Remarkable product preferences between the desaturation pathway to form the methyleneindolenine by CYP2F1 and the ring epoxidation pathway to form the oxindole by CYP1A2, were observed.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 03/04/20 alle ore 20:35:40