Recombinant CYP3A4*17 is defective in metabolizing the hypertensive drug nifedipine, and the CYP3A4*17 allele may occur on the same chromosome as CYP3A5*3, representing a new putative defective CYP3A haplotype.
Genetic variation in CYP3A activity may influence the rate of the metabolism and elimination of CYP3A substrates in humans. We previously reported four new CYP3A4 coding variants in three different racial groups. In the present study, we examined metabolism of nifedipine by the recombinant forms of these allelic variants. Metabolism of nifedipine by the L293P (CYP3A4*18), M445T (CYP3A4*3), and P467S (CYP3A4*19) allelic variants was not significantly different from wild-type CYP3A4*1. However, F189S (CYP3A4*17) exhibited a >99% decrease in both V(max) and CL(max) of nifedipine compared with CYP3A4*1. Of 72 racially diverse individuals, CYP3A4*17 was identified in 1 of 24 Caucasian samples [1:5 Eastern European (Adygei ethnic group)]. Genotyping of an extended set of 276 genomic DNAs of Caucasians (100 from the Coriell Repository and an additional 176 from the United States) for CYP3A4*17 detected no additional individuals containing the CYP3A4*17 allele. However, additional genotyping of four more Adygei samples available from Coriell detected an additional individual carrying the CYP3A4*17 allele. New specific polymerase chain reaction-restriction fragment length polymorphism genotyping procedures were developed for the major splice variant of CYP3A5 (CYP3A5*3) and CYP3A4*17. Genotyping revealed that the two individuals carrying CYP3A4*17 were either homozygous or heterozygous for the more frequent CYP3A5*3 allele, suggesting that the two alleles may exist on the same chromosome as a new putative CYP3A poor metabolizer haplotype. We predict that individuals who are homozygous for defective alleles of both of these genes would metabolize CYP3A substrates poorly. The new genetic tests will be useful in future clinical studies to investigate genotype/phenotype associations.
Lee
Su-Jun
SJ
Human Metabolism Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Bell
Douglas A
DA
Coulter
Sherry J
SJ
Ghanayem
Burhan
B
Goldstein
Joyce A
JA
D000465:Algorithms; D000483:Alleles; D000595:Amino Acid Sequence; D002121:Calcium Channel Blockers / Q000378:metabolism*; D002875:Chromosomes / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D009543:Nifedipine / Q000378:metabolism*; D010084:Oxidation-Reduction; D012150:Polymorphism, Restriction Fragment Length; D018807:Polymorphism, Single-Stranded Conformational; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D002121:Calcium Channel Blockers; D011994:Recombinant Proteins; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009543:Nifedipine