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Titolo:
Identification of the human liver cytochrome P450 isoenzyme responsible for the 6-methylhydroxylation of the novel anticancer drug 5,6-dimethylxanthenone-4-acetic acid
Autore:
Zhou, SF; Paxton, JW; Tingle, MD; Kestell, P;
Indirizzi:
Univ Auckland, Sch Med, Dept Pharmacol & Clin Pharmacol, Auckland, New Zealand Univ Auckland Auckland New Zealand lin Pharmacol, Auckland, New Zealand Univ Auckland, Auckland Canc Soc Res Ctr, Auckland, New Zealand Univ Auckland Auckland New Zealand c Soc Res Ctr, Auckland, New Zealand
Titolo Testata:
DRUG METABOLISM AND DISPOSITION
fascicolo: 12, volume: 28, anno: 2000,
pagine: 1449 - 1456
SICI:
0090-9556(200012)28:12<1449:IOTHLC>2.0.ZU;2-C
Fonte:
ISI
Lingua:
ENG
Soggetto:
FLAVONE-8-ACETIC ACID; IN-VIVO; METABOLISM; MICROSOMES; OXIDATION; FURAFYLLINE; ELIMINATION; SPECIFICITY; PREDICTION; INHIBITORS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
39
Recensione:
Indirizzi per estratti:
Indirizzo: Paxton, JW Univ Auckland, Sch Med, Dept Pharmacol & Clin Pharmacol, Auckland, New Zealand Univ Auckland Auckland New Zealand ol, Auckland, New Zealand
Citazione:
S.F. Zhou et al., "Identification of the human liver cytochrome P450 isoenzyme responsible for the 6-methylhydroxylation of the novel anticancer drug 5,6-dimethylxanthenone-4-acetic acid", DRUG META D, 28(12), 2000, pp. 1449-1456

Abstract

In vitro studies were conducted to identify the hepatic cytochrome P450 (CYP) isoenzyme involved in the 6-methylhydroxylation of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by using a human liver library (n = 14). The metabolite 6-hydroxymethyl-5-methylxanthenone-4-acetic acid (6-OH-MXAA) was determined by HPLC with fluorescence detection. The metabolite formed in human liver microsomes and by cDNA-expressed CYP isoform was identified by liquidchromatography mass spectrometry as 6-OH-MXAA. In human liver microsomes (n = 14), 6-methylhydroxylation of DMXAA followed monophasic Michaelis-Menten kinetics, with a mean apparent K-m of 21 +/- 5 muM and V-max of 0.043 +/-0.019 nmol/min/mg. An approximate 10-fold interindividual variation in theintrinsic clearance (V-max /K-m) of DMXAA 6-methylhydroxylation in human liver microsomes was observed. The involvement of CYP1A2 in DMXAA metabolismby human livers was demonstrated by the following: 1) the potent inhibition of DMXAA metabolism by furafylline (k(inact) = 0.23 +/- 0.04 min(-1), K'(app) = 15.6 +/- 6.7 muM) and alpha -naphthoflavone (K-i = 0.036 muM), but not by cimetidine, ketoconazole, tolbutamide, quinidine, chlorzoxazone, diethyldithiocarbamate, troleandomycin, and sulfaphenazole; 2) when incubated with human lymphoblastoid cell microsomes containing cDNA-expressed CYP isoenzymes, DMXAA was metabolized only by CYP1A2, with an apparent K-m of 6.2 +/- 1.5 muM and V-max of 0.014 +/- 0.001 nmol/min/mg, but not by CYP2A6, CYP2B6, CYP2C9 (Arg(144)), CYP2C19, CYP2D6 (Val(374)), CYP2E1, and CYP3A4; 3) a significant correlation (r = 0.90; P < .001) between 6-methylhydroxylation of DMXAA and 7-ethoxyresorufin O-deethylation; and 4) a significant correlation (r = 0.75; P < .01) between the CYP1A protein level determined by Western blots and DMXAA 6-methylhydroxylation.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 04/07/20 alle ore 05:22:30