Ile118Val genetic polymorphism of CYP3A4 and its effects on lipid-lowering efficacy of simvastatin in Chinese hyperlipidemic patients.
OBJECTIVE
To determine the frequencies of CYP3A4 alleles (CYP3A4*4,*5 and *6) in Chinese hyperlipidemic patients and to observe the impact of CYP3A4*4 (Ile118Val) genetic polymorphism on the lipid-lowering effects of simvastatin and on the activity of CYP3A4.


METHODS
From hospitalized and non-hospitalized patients, 211 unrelated hyperlipidemic patients were recruited for genotyping. CYP3A4 genotypes were determined by means of polymerase chain reaction and restriction fragment length polymorphism analysis. Of the non-hospitalized hyperlipidemic patients, 8 with CYP3A4*1/*1 and 8 with CYP3A4*1/*4 genotypes were selected to be treated with 20 mg simvastatin daily for 4 weeks. Serum triglycerides (TG), cholesterol (CHO) and low-density lipoprotein (LDL) levels were determined using an automated analyzer (Hitachi 747, Boehringer Mannheim, Mannheim, Germany). CYP3A4 activity was determined by the ratio of 6-hydroxycortisol to free cortisol (6-OHC/FC) in the morning spot urine with a high-throughput liquid chromatography-tandem mass spectrometry method.


RESULTS
Of 211 subjects, 14 (allele frequency 3.32%) were heterozygous for CYP3A4*4 (Ile118Val). Nevertheless, no subjects with a CYP3A4*5 or CYP3A4*6 allele or homozygous for CYP3A4*4 were identified. The ratio of 6beta-OHC/FC was 9.9 +/- 13.7 and 56.6 +/- 35.7 in subjects with the Ile118Val variant (n = 8) and in CYP3A4 wild-type subjects (n = 8), respectively (P = 0.0039). After oral intake of simvastatin 20 mg daily for 4 weeks, the change of serum lipids in CYP3A4*1/*1 and CYP3A4*1/*4 groups showed a significant difference, with a mean decrease in triglycerides and total cholesterol of 38.1 +/- 7.6% versus 25.1 +/- 8.3% (P = 0.034) and of 35.8 +/- 9.6% versus 22.0 +/-20.4% (P = 0.0015) (means +/- SD), respectively. We found no statistically significant difference in the reductions of LDL between subjects carrying the *1 and *4 genotypes (29.0 +/- 7.4% versus 36.8 +/- 8.8%, P = 0.0721).


CONCLUSIONS
The allele frequency of CYP3A4*4 was 3.32% among the hyperlipidemic patients from the Chinese mainland. CYP3A4*4 was an allelic variant related to a functional decrease of CYP3A4 activity, and *4 expression seemed to increase the lipid-lowering effects of simvastatin.
Wang
An
A
Department of Health Toxicology, School of Public Health, Pharmacogenetics Research Institute, Central South University, Changsha, Hunan, 410078, China.
Yu
Bang-Ning
BN
Luo
Chen-Hui
CH
Tan
Zhi-Rong
ZR
Zhou
Gan
G
Wang
Lian-Sheng
LS
Zhang
Wei
W
Li
Zhi
Z
Liu
Jie
J
Zhou
Hong-Hao
HH
D000328:Adult; D000368:Aged; D044466:Asian People; D002681:China; D002784:Cholesterol / Q000097:blood; D003348:Cortisone / Q000031:analogs & derivatives* / Q000652:urine; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D006801:Humans; D006854:Hydrocortisone / Q000652:urine; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism* / Q000627:therapeutic use; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000201:enzymology; D007532:Isoleucine / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D019821:Simvastatin / Q000378:metabolism* / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood; D014633:Valine / Q000235:genetics
C485511:6 beta-hydroxycortisone; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014280:Triglycerides; D007532:Isoleucine; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D019821:Simvastatin; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D014633:Valine; D003348:Cortisone; D006854:Hydrocortisone