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Titolo:
Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos
Autore:
Dai, D; Tang, J; Rose, R; Hodgson, E; Bienstock, RJ; Mohrenweiser, HW; Goldstein, JA;
Indirizzi:
NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA NIEHS ResTriangle Pk NC USA 27709 em, NIH, Res Triangle Pk, NC 27709 USA N Carolina State Univ, Dept Toxicol, Raleigh, NC 27695 USA N Carolina State Univ Raleigh NC USA 27695 Toxicol, Raleigh, NC 27695 USA Lawrence Livermore Natl Lab, Livermore, CA USA Lawrence Livermore Natl Lab Livermore CA USA Natl Lab, Livermore, CA USA
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 3, volume: 299, anno: 2001,
pagine: 825 - 831
SICI:
0022-3565(200112)299:3<825:IOVOCA>2.0.ZU;2-9
Fonte:
ISI
Lingua:
ENG
Soggetto:
ADULT HUMAN-LIVER; AMINO-ACID; GENETIC VARIANT; CLINICAL PRESENTATION; CYTOCHROME-P450 3A4; PROSTATE TUMORS; SMALL-BOWEL; BIOTRANSFORMATION; SUBSTITUTIONS; POLYMORPHISM;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
41
Recensione:
Indirizzi per estratti:
Indirizzo: Goldstein, JA NIEHS, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA NIEHS POB 12233 Res Triangle Pk NC USA 27709 k, NC 27709 USA
Citazione:
D. Dai et al., "Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos", J PHARM EXP, 299(3), 2001, pp. 825-831

Abstract

CYP3A4 is the most abundant isoform of cytochrome P450 (CYP) in adult human liver. It metabolizes numerous clinically, physiologically, and toxicologically important compounds. The expression of CYP3A4 varies 40-fold in individual human livers, and metabolism of CYP3A4 substrates varies at least 10-fold in vivo. Single nucleotide polymorphisms (SNPs) in CYP3A4 were identified by direct sequencing of genomic DNA in 72 individuals from three different ethnic groups, including Caucasians, Blacks (African-Americans and African pygmies), and Asians. A total of 28 SNPs were identified, including five which produced coding changes M445T (CYP3A4*3), R162Q (CYP3A4*15), F189S(CYP3A4*17), L293P (CYP3A4*18), and P467S (CYP3A4*19). The latter four represent new alleic variants. Racial variability was observed for the frequency of individual SNPs. CYP3A R162Q was identified only in Black populationswith an allelic frequency of 4%. CYP3A4 F189S and CYP3A4 M445T were identified in Caucasians with allelic frequencies 2% and 4%, respectively. L293P and P467S were only observed in Asians at allelic frequencies of 2%. The cDNAs for the F189S, L293P, M445T, and P467S mutant alleles were constructed by site-directed mutagenesis and expressed in an Escherichia coli expression system. Testosterone and the insecticide chlorpyrifos were used to assessthe catalytic activities of the most common CYP3A4 allele (CYP3A4*1) and its allelic variants. CYP3A4 F189S exhibited lower turnover numbers for testosterone and chlorpyrifos, while CYP3A4 L293P had higher turnover numbers for both substrates. The turnover numbers of the CYP3A4 M445T and P467S alleles to metabolize these compounds were not significantly different from those of wild-type CYP3A4.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/01/20 alle ore 22:17:34