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Titolo:
Metabolism of methyl tert-butyl ether and other gasoline ethers by human liver microsomes and heterologously expressed human cytochromes P450: Identification of CYP2A6 as a major catalyst
Autore:
Hong, JY; Wang, YY; Bondoc, FY; Lee, M; Yang, CS; Hu, WY; Pan, JM;
Indirizzi:
Rutgers State Univ, Coll Pharm, Canc Res Lab, Piscataway, NJ 08854 USA Rutgers State Univ Piscataway NJ USA 08854 Lab, Piscataway, NJ 08854 USA Rutgers State Univ, Coll Pharm, Dept Biol Chem, Piscataway, NJ 08854 USA Rutgers State Univ Piscataway NJ USA 08854 Chem, Piscataway, NJ 08854 USA
Titolo Testata:
TOXICOLOGY AND APPLIED PHARMACOLOGY
fascicolo: 1, volume: 160, anno: 1999,
pagine: 43 - 48
SICI:
0041-008X(19991001)160:1<43:MOMTEA>2.0.ZU;2-P
Fonte:
ISI
Lingua:
ENG
Soggetto:
COUMARIN 7-HYDROXYLATION; INTERINDIVIDUAL VARIABILITY; NITROSAMINE METABOLISM; GENETIC-POLYMORPHISM; EXPOSURE; 2A6; INDIVIDUALS; ACTIVATION; SEQUENCE; MTBE;
Keywords:
methyl tert-butyl Ether; gasoline oxygenate; metabolism; human liver microsomes; cytochromes P450;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
31
Recensione:
Indirizzi per estratti:
Indirizzo: Hong, JY Rutgers State Univ, Coll Pharm, Canc Res Lab, 164 Frelinghuysen Rd, Piscataway, NJ 08854 USA Rutgers State Univ 164 Frelinghuysen Rd Piscataway NJ USA 08854 A
Citazione:
J.Y. Hong et al., "Metabolism of methyl tert-butyl ether and other gasoline ethers by human liver microsomes and heterologously expressed human cytochromes P450: Identification of CYP2A6 as a major catalyst", TOX APPL PH, 160(1), 1999, pp. 43-48

Abstract

To reduce the production of carbon monoxide and other pollutants in motor vehicle exhaust, methyl tert-butyl ether (MTBE), ethyl tert-butyl ether (ETBE), and tert-amyl methyl ether (TAME) are added to gasoline as oxygenates for more complete combustion. Previously, we demonstrated that human liver is active in metabolizing MTBE to tert-butyl alcohol (TBA) and that cytochrome P450 (CYP) enzymes play a critical role in the metabolism of MTBE. The present study demonstrates that human liver is also active in the oxidativemetabolism of ETBE and TAME. A large interindividual variation in metabolizing these gasoline ethers was observed in 15 human liver microsomal samples. The microsomal activities in metabolizing MTBE, ETBE, and TAME were highly correlated among each other (r, 0.91-0.96), suggesting that these ethersare metabolized by the same enzyme(s). Correlation analysis of the ether-metabolizing activities with individual CYP enzyme activities in the liver microsomes showed that the highest degree of correlation was with human CYP2A6 (r, 0.90-0.95), which is constitutively expressed in human Livers and known to be polymorphic. CYP2A6 displayed the highest turnover number in metabolizing gasoline ethers among a battery of human CYP enzymes expressed in human B-lymphoblastoid cells. Kinetic studies on MTBE metabolism with threehuman liver microsomes exhibited apparent K-m values that ranged from 28 to 89 mu M and the V-max values from 215 to 783 pmol/min/mg, with similar catalytic efficiency values (7.7 to 8.8 mu l/min/mg protein). Metabolism of MTBE, ETBE, and TAME by human liver microsomes was inhibited by coumarin, a known substrate of human CYP2A6, in a concentration-dependent manner. Monoclonal antibody against human CYP2A6 caused a significant inhibition (75% to95%) of the metabolism of MTBE, ETBE, and TAME in human liver microsomes. Taken together, these results clearly indicate that in human liver, CYP2A6 is the major enzyme responsible for the metabolism of MTBE, ETBE, and TAME. (C) 1999 Academic Press.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 15/07/20 alle ore 14:37:22