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Vol. 299, Issue 3, 825-831, December 2001
National Institute of Environmental Health Sciences, National
Institutes of Health, Research Triangle Park, North Carolina (D.D.,
R.J.B., J.A.G.); Department of Toxicology, North Carolina State
University, Raleigh, North Carolina (J.T., R.R., E. H.); and
Lawrence Livermore National Laboratory, Livermore, California (H.W.M.)
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 populations with 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 assess the 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 .
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