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Titolo:
Reaction of trichloroethylene and trichloroethylene oxide with cytochrome P450 enzymes: Inactivation and sites of modification
Autore:
Cai, HL; Guengerich, FP;
Indirizzi:
Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA VanderbiltUniv Nashville TN USA 37232 t Biochem, Nashville, TN 37232 USA Vanderbilt Univ, Sch Med, Ctr Mol Toxicol, Nashville, TN 37232 USA Vanderbilt Univ Nashville TN USA 37232 l Toxicol, Nashville, TN 37232 USA
Titolo Testata:
CHEMICAL RESEARCH IN TOXICOLOGY
fascicolo: 4, volume: 14, anno: 2001,
pagine: 451 - 458
SICI:
0893-228X(200104)14:4<451:ROTATO>2.0.ZU;2-L
Fonte:
ISI
Lingua:
ENG
Soggetto:
LIVER MICROSOMAL CYTOCHROME-P-450; PERFORMANCE LIQUID-CHROMATOGRAPHY; RAT-LIVER; COVALENT BINDING; ESCHERICHIA-COLI; PROTEIN ADDUCTS; DRUG-METABOLISM; DRINKING-WATER; ACTIVE-SITE; MICE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
57
Recensione:
Indirizzi per estratti:
Indirizzo: Guengerich, FP Vanderbilt Univ, Sch Med, Dept Biochem, 23rd & Pierce Ave,638 Med Res Bldg1, Nashville, TN 37232 USA Vanderbilt Univ 23rd & Pierce Ave,638 Med Res Bldg 1 Nashville TN USA 37232
Citazione:
H.L. Cai e F.P. Guengerich, "Reaction of trichloroethylene and trichloroethylene oxide with cytochrome P450 enzymes: Inactivation and sites of modification", CHEM RES T, 14(4), 2001, pp. 451-458

Abstract

Trichloroethylene (TCE) has been shown to be toxic to experimental animalsand humans. TCE oxide is a reactive electrophile formed during TCE oxidation and rearranges to acylating intermediates [Cai, H., and Guengerich, F. P. (1999) J. Am. Chem. Sec. 121, 11656-11663], which may be related to the toxicity. Mice treated with TCE have been reported to contain N-6-dichloroacetylLys residues in P450 2E1, as detected by immunochemical methods. TCE can be oxidized by both P450 2E1 and (rat) 2B1. In this work, direct reactionof TCE oxide with either human P450 2E1, P450 2B1, or NADPH-P450 reductasewas shown to lead to enzyme inactivation, and no recovery of the activity of either enzyme occurred, consistent with the view of inactivation reactions with Lys groups and not hydroxyls or Cys. Furthermore, Lys adducts were detected in the reaction of TCE oxide with both P450 2E1 and NADPH-P450 reductase, with a larger amount of N-6-formylLys observed compared to N-6-dichloroacetylLys in both cases. Inactivation of P450 2E1 during NADPH-dependent TCE oxidation was not observed, compared to control experiments. However,inactivation of P450 2B1 during NADPH-dependent TCE oxidation was detected. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry of tryptic peptides indicated that the direct reaction of TCE oxide with human P450 2E1 resulted in the modification of peptides containing Lys87 (AVKEALLDYK), Lys251 (VKEHHQSLDPNCPR), and Lys487 (YKLCVIPR), with either aformyl or dichloroacetyl group attached. Lys87 and Lys487 of human P450 2E1 appear to be modified during the oxidation of TCE, using the same approach. The results are considered in the context of comparison of species and P450s.

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Documento generato il 10/04/20 alle ore 01:43:26