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Titolo:
Metabolic activation of dacarbazine by human cytochromes P450: The role ofCYP1A1, CYP1A2, and CYP2E1
Autore:
Reid, JM; Kuffel, MJ; Miller, JK; Rios, R; Ames, MM;
Indirizzi:
Mayo Clin, Dept Oncol, Div Dev Oncol Res, Rochester, MN 55905 USA Mayo Clin Rochester MN USA 55905 v Dev Oncol Res, Rochester, MN 55905 USA
Titolo Testata:
CLINICAL CANCER RESEARCH
fascicolo: 8, volume: 5, anno: 1999,
pagine: 2192 - 2197
SICI:
1078-0432(199908)5:8<2192:MAODBH>2.0.ZU;2-7
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN-LIVER; DRUG-METABOLISM; N-DEMETHYLATION; BREATH TEST; MICROSOMES; ENZYMES; CANCER; PHARMACOKINETICS; INHIBITION; MELANOMA;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Citazioni:
35
Recensione:
Indirizzi per estratti:
Indirizzo: Reid, JM Mayo Clin, Dept Oncol, Div Dev Oncol Res, 200 1st St SW, Rochester, MN 55905 USA Mayo Clin 200 1st St SW Rochester MN USA 55905 ster, MN 55905 USA
Citazione:
J.M. Reid et al., "Metabolic activation of dacarbazine by human cytochromes P450: The role ofCYP1A1, CYP1A2, and CYP2E1", CLIN CANC R, 5(8), 1999, pp. 2192-2197

Abstract

Dacarbazine (DTIC), a widely used anticancer agent, is inactive until metabolized in the liver by cytochromes P450 to form the reactive N-demethylated species 5-[3-hydroxymethyl-3-methyl-triazen-1-yl]-imidazole- (HMMTIC) and5-[3-methyl-triazen-1-yl]-imidazole-4-carboxamide (MTIC). The modest activity of DTIC in the treatment of cancer patients has been attributed in partto lower activity of cytochromes P450 (P450) in humans when compared with rodents. Importantly, the particular P450 isoforms involved in the activation pathway have not been reported. We now report that the DTIC N-demethylation involved in MTIC formation by human liver microsomes is catalyzed by CYP1A1, CYP1A2, and CYP2E1, The most potent inhibitors of DTIC N-demethylation were alpha-naphthoflavone (CYP1A1 and CYP1A2), quercetin (CYP1A2), chlorzoxazone (CYP1A2 and CYP2E1), and di-sulfiram (CYP2E1). Antihuman CYP1A2 antiserum also inhibited DTIC N-demethylation, DTIC N-demethylation in a panelof 10 human liver microsome preparations was correlated with the catalyticactivities for CYP1A2 (ethoxyresorufin O-deethylation and caffeine N-3-demethylation) in the absence of alpha-naphthoflavone and with the catalytic activities for CYP2E1 (chlorzoxazone 6-hydroxylations) in the presence of cn-naphthoflavone. DTIC metabolism was catalyzed by recombinant human CYP1A1,CYP1A2, and CYP2E1. The K-m (V-max) values for metabolism of DTIC by recombinant human CYP1A1 and CYP1A2 were 595 mu M (0.684 nmol/min/mg protein) and 659 mu M (1.74 nmol/min/mg protein), respectively. The CYP2E1 K(m)value exceeded 2.8 mM. Thus, we conclude that (a) CYP1A2 is the predominant P450 that catalyzes DTIC hepatic metabolism; (b) CYP2E1 contributes to hepatic DTIC metabolism at higher substrate concentrations; and (c) CYP1A1 catalyzes extrahepatic metabolism of DTIC.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/07/20 alle ore 13:31:18