Effect Of CYP3A4, CYP3A5 And MDR1 Genetic Polymorphisms On Lipid-lowering Efficacy Of Simvastatin In Chinese Hyperlipidemic Patients

Background and Objiective3-Hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase is therate-limiting enzyme of cholesterol formation in the liver and other tissues, whichplays an important role in cholesterol synthesis. Simvastatin is HMG-CoA reductaseinhibitor. It has been widely used for the treatment of hypercholesterolaemia andhypertriglyceridaemia. In vitro studies showed that SVA has affinity for CYP3A4, themetabolism of SVA in human liver microsomes is catalyzed primarily(≥80％)byCYP3A4/5.Simvastatin is also a substrate for P-glycoprotein(P-gp). P-gp is encodedby multidrug-resistance 1(MDR1). The interindividual heterogeneity in enzymaticactivity of CYP3A4 as well as CYP3A5 and P-gp in the small intestine and liver havecontributed to the variability on lipid-lowering efficacy of simvastatin in Chinesehyperlipidemic patients. Several studies showed that the lipid-lowering effect ofsimvastatin were influenced by CYP3A4, CYP3A5 and MDR1 polymorphisms.However, there are no report on the relationship of CYP3A4(CYP3A4*18B),CYP3A5(CYP3A5*3)and MDR1(MDR1C3435T)genotype with the efficacy ofsimvastatin in Chinese hyperlipidemic patients. Our research aim to determine thefrequencies of CYP3A4 alleles (CYP3A4*18B), CYP3A5 alleles (CYP3A5*3),MDR1alleles (MDR1C3435T) in Chinese hyperlipidemic patients and to observe the impactof CYP3A4*18B, CYP3A5*3, MDR1C3435T genetic polymorphism on lipid-loweringeffects of simvastatin.Materials and MethodsSubjects A group of 202 unrelated Chinese hyperlipidemic patients(triglycerides(TG)＞1.78 mmol/l or cholesterol (CHO)＞6mmol/l orlow-density lipoprotein (LDL)＞3.36mmol/l or high-density lipoprptein (HDL)＜0.82mmol/l) with a mean age 54±8.1 years were recruited from hospitalized patientsand non-hospitalized patients in the first affiliated hospital of Zhengzhou Universityand Pingdingshan first municipal people's hospital. These participants were healthy,as assessed by medical history, clinical laboratory test results of liver and kidneyfunction, blood test for human hepatitis B or C. They don't used any lipid-loweringdrug at least 2 weeks before intake of simvastatin. The study design was approved bythe Committee on Human Research of Zhengzhou University.Genotyping Genotyping of CYP3A4, CYP3A5 and MDR1 variants wasconducted by the polymerase chain reaction restriction fragment length polymorphism(PCR-RFLP) method. PCR products were detected by agarose gel electrophoresis.Alleles and genotypes were defined by fragments in agarose gel.Evaluation of therapeutic effects of simvastatin The hyperlipidemic patients weretreated with 20 mg simvastatin daily for 4 weeks. Serum triglycerides (TG), totalcholesterol (TC), low density lipoprotein (LDL) and high density lipoprotein (HDL)levels were determined using an automated analyzer(Roche 800, Japan). We observedthe impact of CYP3A4, CYP3A5 and MDR1 genetic polymorphism on thelipid-lowering effects of simvastatin. The primary effects measure at week 4 was themean percentage change in total cholesterol, triglycerides, LDL and HDL frombaseline.Statistical analysis The hyperlipidemic patients were compiled three groupsaccording to the genotype, and allele frequencies were estimated from the observednumbers of each specific allele. SPSS 10.0 software was used for statistical analyses.ANOVA was used to compare the differences on the lipid-lowering effects ofsimvastatin, LSD was used to compare the two groups. P-values＜0.05 wereconsidered statistically significant.ResultsFrequencies of CYP3A4 alleles, CYP3A5 alleles and MDR1 alleles The frequenciesof CYP3A4 alleles (CYP3A4*18B), CYP3A5 alleles(CYP3A5*3) and MDR1 alleles (MDR1C3435T) in Chinese hyperlipidemic patients were 27.4％, 67.4％, 43.0％,respectively.Effect of CYP3A4,CYP3AS,MDR1 genetic polymorphism on lipid-loweringefficacy of simvastatin After oral intake of simvastatin 20 mg daily for 4 weeks,the change of serum lipid in CYP3AS*1/*1 and CYP3A5*3/*3 groups showed asignificant difference, with a mean decrease in low density lipoprotein of23.7％±2.8％versus 28.6％±5.4％(p=0.016)(mean±SD). There is also a statisticallysignificant differences in the reduction of low density lipoprotein between subjectscarrying the CYP3A5*3/*3 and CYP3AS*1/*3 genotype (28.6％±5.4％versus26.5％±6.2％, P=0.013). We found no statistically significant differences in thereduction of low density lipoprotein between subjects carrying the CYP3A5*1/*1 andCYP3AS*1/*3 genotype (23.7％±2.8％versus 26.5％±6.2％, P=0.172). CYP3A4*18Band MDR1C3435T genetic polymorphism had not a statistically significantdifferences on the lipid-lowering effects of simvastatin.Conclusions1. The frequencies of CYP3A4 alleles (CYP3A4*18B), CYP3A5 alleles (CYP3A5*3)and MDR1 alleles (MDR1C3435T) in Chinese hyperlipidemic patients were27.4％, 67.4％, 43.0％, respectively.2. The pilot study suggests that the effect of CYP3A5 genetic polymorphismincreased the lipid-lowering effects of simvastatin.3. CYP3A4*18B genetic polymorphism may have no significant effect onsimvastatin treatment.4. MDR1C3435T genetic polymorphism may have no significant effect onsimvastatin treatment.