Genetic polymorphism of cytochrome P450 3A5 in Chinese.
The CYP3A subfamily enzymes are the most abundant and important drug-metabolizing enzymes. Wide variation in the CYP3A5 expression was well known. Recently, G(-44) to A of CYP3AP1 was found to segregate with CYP3A5*3 defective allele. The homozygous A(-44) subjects showed low expression of CYP3A5. In Caucasian, only 9.2% of CYP3AP1 alleles were with G(-44) and associated with the wild-type CYP3A5*1 allele, which expressed CYP3A5 significantly. By using polymerase chain reaction and FauI endonuclease digestion, we found that 28% of CYP3AP1 alleles are G(-44) in 110 Chinese subjects. The frequency is 3 times higher in Chinese than in Caucasian, implying more Chinese subjects are probably extensive CYP3A5 metabolizers. In two Chinese subjects, we also found a heterozygous G(13048)gt-to-G(13048)gc mutation at the intron 5 splicing donor site, leading to a splicing defect. A 6478-base pair minigene, including intron 4 to intron 7, was used for in vitro transcription. Both the wild-type and the mutated minigenes produced splicing variants. The wild-type minigene used Ggt(13050) as the splicing donor. The mutant minigene used gt(8504) in intron 4 or gt(13112) in intron 5 as the splicing donor for various splicing acceptors. The splicing defect may result in a shorter peptide or cause the frame shift. In the other two Chinese subjects, we found A(14763)-to-G mutation in exon 7, resulting in the Q200R amino acid change. The consequence of the polymorphism site has not been known. In Caucasian, there is a reported T398N polymorphism. In these Chinese subjects, we did not find polymorphism at this site.
Chou
F C
FC
Department of Pharmacology, College of Medicine, National Cheng Kung University, Medical Center, 1 University Road, Tainan 70101, Taiwan.
Tzeng
S J
SJ
Huang
J D
JD
D002681:China; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D006801:Humans; D007438:Introns; D009154:Mutation; D011110:Polymorphism, Genetic
D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A