Objective To investigate the distribution of CYP3A4 -392A>G, SLCO1B1 388A>G and 521T>C in Bai population of Yunnan province. Methods The genotypes of CYP3A4 -392A>G, SLCO1B1 388A>G and 521T>C were detected in 94 healthy individuals of Bai by PCR-direct sequencing. Haplotypes of SLCO1B1 were inferred with the PHASE software version 2.1. Results The variant allele frequency of CYP3A4 -392A>G was zero in 94 healthy individuals of Bai. The genotype frequencies of SLCO1B1 388A>G were 3.3% (AA), 32.2% (AG), and 64.5% (GG), respectively, and the variant allele frequency was 80.6% in 90 healthy individuals of Bai. The genotype frequencies of SLCO1B1 521T>C were 91.5% (TT), 7.4% (TC) and 1.1% (CC), respectively, and the variant allele frequency was 4.8% in 94 healthy individuals of Bai. SLCO1B1*1a, *1b and *15 haplotypes were observed in Bai population, and the frequencies of them were 19.4%, 75.6% and 5.0%, respectively. Conclusion CYP3A4 -392A>G mutant is rare in Bai population of Yunnan province. The distribution of SLCO1B1 gene polymorphism is characteristic in Bai population of Yunnan province. The variant allele frequency of SLCO1B1 388A>G is very high, the variant allele frequency of SLCO1B1 521T>C is very low, and SLCO1B1*1a, *1b and *15 haplotypes can be observed.
Key words:
CYP3A4
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SLCO1B1
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population
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Gene polymorphisms
KALLIIOSKIA,NIEMIM.Impact of OATP transporters on pharmacokinetics[J].,2009,158: 693-705.
Abstract Top of page Abstract Role of transporters in pharmacokinetics Organic anion transporting polypeptides (OATPs) OATP1B1 SLCO1B1 (OATP1B1) pharmacogenetics Role of OATP1B1 in drug鈥揹rug interactions OATP1A2 OATP1B3 OATP2B1 Other OATPs Conclusion References Membrane transporters are now recognized as important determinants of the transmembrane passage of drugs. Organic anion transporting polypeptides (OATP) form a family of influx transporters expressed in various tissues important for pharmacokinetics. Of the 11 human OATP transporters, OATP1B1, OATP1B3 and OATP2B1 are expressed on the sinusoidal membrane of hepatocytes and can facilitate the liver uptake of their substrate drugs. OATP1A2 is expressed on the luminal membrane of small intestinal enterocytes and at the blood-brain barrier, potentially mediating drug transport at these sites. Several clinically used drugs have been identified as substrates of OATP transporters (e.g. many statins are substrates of OATP1B1). Some drugs may inhibit OATP transporters (e.g. cyclosporine) causing pharmacokinetic drug鈥揹rug interactions. Moreover, genetic variability in genes encoding OATP transporters can result in marked inter-individual differences in pharmacokinetics. For example, a single nucleotide polymorphism (c.521T > C, p.Val174Ala) in the SLCO1B1 gene encoding OATP1B1 decreases the ability of OATP1B1 to transport active simvastatin acid from portal circulation into the liver, resulting in markedly increased plasma concentrations of simvastatin acid and an enhanced risk of simvastatin-induced myopathy. SLCO1B1 polymorphism also affects the pharmacokinetics of many other, but not all (fluvastatin), statins and that of the antidiabetic drug repaglinide, the antihistamine fexofenadine and the endothelin A receptor antagonist atrasentan. This review compiles the current knowledge about the expression and function of human OATP transporters, their substrate and inhibitor specificities, as well as pharmacogenetics.
ZHANGW,HE YJ,GANZ,et al.OATP1B1 polymorphism is a major determinant of serum bilirubin level but not associated with rifampicin-mediated bilirubin elevation[J].,2007,34(12): 1240-1244.
1. Elevated serum bilirubin levels are caused mainly by liver diseases, haematolysis, genetic defects and drug intake. Unconjugated bilirubin (UCB) is taken up into hepatocytes by human organic anion transporting polypeptide 1B1 (OATP1B1; encoded for by the SLCO1B1 gene). The present study was performed to determine the association between SLCO1B1 gene polymorphisms and serum bilirubin levels in vivo. Moreover, the effects of administration of low-dose rifampicin on serum bilirubin levels in different SLCO1B1 genotypes was examined. 2. Serum bilirubin levels were examined in 42 healthy volunteers who had been analysed for SLCO1B1 genotype (seven, 13, 14 and eight with SLCO1B1 genotypes *1a/*1a, *1b/*1b, *1b/*15 and *15/*15, respectively). Among them, 24 subjects (seven, seven, eight and two with SLCO1B1 genotypes *1a/*1a, *1b/*1b, *1b/*15 and *15/*15, respectively) were selected to participate in an open-label, two-phase clinical trial. Each was given 450 mg rifampicin orally once daily at 2000 hours for 5 consecutive days. Serum bilirubin concentrations at 0800 hours on the 1st and 6th days were compared between the different SLCO1B1 genotypes. 3. In the 42 volunteers, the mean (+/-SD) serum UCB in both SLCO1B1*1b/*15 and *15/*15 groups was significantly higher than that in the SLCO1B1*1b/*1b group (11.07 +/- 2.31, 13.01 +/- 3.87 and 8.21 +/- 2.68 micromol/L, respectively; P = 0.009 and P < 0.001). Total bilirum (T.BIL) in both the SLCO1B1*1b/*15 and *15/*15 groups was significantly higher than that in the SLCO1B1*1b/*1b group (16.69 +/- 4.09, 20.71 +/- 5.12 and 13.06 +/- 5.12 micromol/L, respectively; P = 0.029 and P < 0.001). The direct bilirubin (D.BIL) in the SLCO1B1*15/*15 group was significantly higher than that in the SLCO1B1*1b/*1b group (7.69 +/- 1.81 vs 4.85 +/- 1.81 micromol/L, respectively; P = 0.001). Rifampicin significantly increased UCB, T.BIL and D.BIL concentrations in 24 healthy volunteers (17.68 +/- 5.96 vs 13.95 +/- 4.44 micromol/L (P = 0.040), 5.72 +/- 2.01 vs 4.35 +/- 1.50 micromol/L (P = 0.028) and 12.00 +/- 4.26 vs 9.61 +/- 3.15 micromol/L (P = 0.035), respectively). However, the extent of the increase in serum bilirubin caused by 450 mg rifampicin for 5 days was not affected by SLCO1B1 genotype. 4. Genetic polymorphism in SLCO1B1 is a major determinant of interindividual variability in the serum bilirubin level. SLCO1B1*15 carriers had higher baseline serum UCB, T.BIL and D.BIL levels compared with subjects with the SLCO1B1*1a/*1a and SLCO1B1*1b/*1b genotypes. SLCO1B1*15/*15 homozygotes are more susceptible to hyperbilirubinaemia. Serum bilirubin levels could be increased by low-dose rifampicin administration, but the extent of the increase was not associated with SLCO1B1 genotype.
OZDEMIRV,KALOWAW,TANG BK,et al.Evaluation of the genetic component of variability in CYP3A4 activity: a repeated drug administration method[J].,2000,10(5): 373-388.
The CYP3A4 enzyme contributes to the disposition of more than 60 therapeutically important drugs and displays marked person-to-person variability of the catalytic function. However, the extent of genetic contribution to variability in CYP3A4 activity remains elusive. Recently, we showed that a comparison of between- (SDb2) and within-person (SDW2) variances provides an estimate of the genetic component of variability in drug disposition. The aim of the present analysis was to assess the genetic control of CYP3A4 activity in vivo. A computerized literature search was conducted covering 1966 to September 1999 to identify studies reporting repeated administration of CYP3A4 substrates. The genetic contribution (rGC) to disposition of each CYP3A4 substrate was obtained by the formula (SDb2-SDW2)/SDb2. The rGC values approaching 1.0, point to overwhelming genetic control, whereas those close to zero suggest that environmental factors dominate. A total of 16 studies with 10 different CYP3A4 substrates were identified (n = 161 subjects). The rGC for hepatic CYP3A4 activity as measured by midazolam plasma clearance or the erythromycin breath test was 0.96 (0.92-0.98) (95% Cl) and 0.89 (0.65-0.98), respectively (P < 0.05). The point estimates of rGC for composite (hepatic + intestinal) CYP3A4 activity measured after oral administration of cyclosporine, ethinylestradiol, ethylmorphine, nifedipine and nitrendipine, ranged from 0.66-0.98 (median: 0.83) (P < 0.05). Cyclosporine data suggested a higher genetic control of CYP3A4 at night than during the day. These data indicate that further molecular genetic investigations are warranted to identify genetic variants at CYP3A4 or elsewhere in the genome which contribute to regulation of CYP3A4 activity.
DALLYH,EDLERL,JAGERB,et al.The CYP3A4*1B allele increases risk of small cell lung cancer: effect of gender and smoking dose[J].,2003,13(10): 607-618.
CYP3A isozymes are involved in carcinogen- and , and are expressed in lung tissue showing interindividual variation in expression and activity. The *1B allele has been associated with a two-fold higher promoter activity and with high-grade . The very frequent intron 3 polymorphism in the gene (*3) results in decreased levels. A case-control study was conducted in 801 Caucasian patients that included 330 adenocarcinomas, 260 squamous , 171 small (SCLC) and 432 Caucasian hospital-based controls. CYP3A-genotyping was performed by capillary polymerase chain reaction followed by fluorescence-based melting curve analysis. A significantly increased SCLC risk for *1B allele carriers [odds ratio (OR) 2.25, 95% confidence interval (CI) 1.11-4.55, P=0.02] was found. After dividing cases and controls by gender, an increased risk for *1B carriers (OR 3.04, 95% CI 0.94-9.90, P=0.06) for women but not for men (OR 1.00, 95% CI 0.56-1.81) was revealed. Heavier smoking men (> or =20 pack-years) with the *1B allele had a significant OR for of 3.42 (95% CI 1.65-7.14, P=0.001) compared to *1A/*1A carriers with lower exposure (<20 pack-years). For women, the respective OR was 8.00 (95% CI 2.12-30.30, P=0.005). Genotype frequencies were generally in Hardy-Weinberg equilibrium, except for where a greater than expected number of *1 homozygotes was observed among cases (P=0.006). In addition, we observed linkage disequilibrium of and (P<0.00001), but a non-significantly increased risk was only found for homozygous *1 allele carriers (OR 5.24, 95% CI 0.85-102.28, P=0.14) but not for heterozygotes. To confirm our observation that the *1B allele increases SCLC risk and modifies the smoking-related risk in a gender-specific manner, further studies, including CYP3A haplotype analysis, will be necessary.
DUJ,XING QH,XU LY,et al.Systematic screening for polymorphisms in the CYP3A4 gene in the Chinese population[J].,2006,7(6): 831-841.
OBJECTIVES: () is a major enzyme in the liver and intestine. It is involved in the of over 50% of all drugs currently in use. The present study was designed to determine the genetic basis of variability.: Single nucleotide polymorphism (SNP) analysis of the gene was performed on 60 healthy Chinese subjects consisting of 20 Han, 30 She and ten Dong subjects, using direct sequencing. Linkage disequilibrium, haplotype inference and Hardy-Weinberg equilibrium were also determined for these samples.: A total of 20 SNPs were found in the gene, including 11 known SNPs and nine novel SNPs. The known SNPs detected in our study were *1B, *1G, *10, *13, *14, *15, *17, *18, rs3091339, rs3091430 and rs28371761, and the novel SNPs were -658 A-->C, G27A (E10K), T48A, G14284A (G167D), A15623G (N191D), C15635A (L196I), T15656C (F203L), G14199A (intron 5) and C15566T (intron 6). The allelic frequencies found in our sample varied from 1-37%. The novel SNPs detected in the gene suggest that the Chinese population has different patterns of allele frequency compared with other populations.: Several SNPs were detected in the gene. The study of genetic variants in may have an important significance for the understanding of genotype and phenotype relationships.
SHIY,XIANGP,LIL,et al.Analysis of 50 SNPs in CYP2D6,CYP2C19,CYP2C9,CYP3A4 and CYP1A2 by MALDI-TOF mass spectrometry in Chinese Han population[J].,2011,207(1-3): 183-187.
One of the major challenges in the near future is the identification of genes that affect the metabolism of different drugs. Large scale association studies that utilise single nucleotide polymorphisms (SNPs) have been considered a valuable tool for this purpose. CYP2D6, CYP2C19, CYP2C9, CYP3A4 and CYP1A2 were found to be involved in the majority of hepatically cleared drugs. To determine the allele frequencies of some SNPs that may have great potential value in forensic science, we screened 50 SNPs in these 5 CYP genes in Chinese Han people using an accurate, high-throughput, cost-effective method. Primers were designed using the MassARRAY Assay Design software. Genomic DNA was prepared from blood samples obtained from individuals of Chinese Han origin. Multiplex PCR was performed to amplify the relevant gene fragments, and the polymorphisms were analysed by allele-specific primer extension followed by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS). A panel of genomic DNA samples previously genotyped by other methods were analysed simultaneously for quality control, and the results demonstrated that this assay was 100% accurate. A total of 17 of the analysed SNPs were polymorphic. Of these 17 SNPs, 8 (rs16947, rs28371725, rs1800754, rs4244285, rs4986893, rs12248560, rs3758580, rs2242480) had an allele frequency that was significantly different between this Chinese Han population and Caucasians (p<0.01). In addition, the frequencies of two of these SNPs (rs1800754, rs3758581) in our Chinese Han population differed significantly from the existing Chinese frequency data (p<0.01). The described method thus provides reliable results and enables the genotyping of up to thousands of samples by taking advantage of the high-throughput MALDI-TOF technology. The results herein are now included as a supplement to the P450 database.
ZHOUQ,YU XM,SHUC,et al.Analysis of CYP3A4 genetic polymorphisms in Han Chinese[J].,2011,56(6): 415-422.
Our study aimed to comprehensively investigate the genetic polymorphisms of CYP3A4 in Han Chinese. We sequenced the gene regions of CYP3A4, including its promoter, exons, surrounding introns and 3' untranslated region (3'UTR), from 100 unrelated-healthy Han Chinese individuals. We detected 11 SNPs, three of which are novel. According to in silico functional prediction of novel variants, 20148 A>G in exon 10, resulting in substitution of Tyr319 with Cys (CYP3A4*21), may induce dramatic alteration of protein conformation, and 26908 G>A in 3'UTR may disrupt post-transcriptional regulation. We identified five alleles in Han Chinese, the allele frequencies of CYP3A4*1, *5, *6, *18 and *21 are 97, 0.5, 1, 1 and 0.5%, respectively. Haplotype inference revealed 14 haplotypes, of which the major haplotype CYP3A4*1A constitutes 59% of the total chromosomes. We also examined the possible role of natural selection in shaping the variation of CYP3A4 and confirmed a trend, consistent with the action of positive selection. We systematically screened the genetic polymorphisms of CYP3A4 in Han Chinese, highlighted possible functional impairment of the novel allele and summarized the distinct allele and haplotype frequency distribution, with an emphasis on detecting the footprint of recent positive selection on the CYP3A4 gene in Han Chinese.
PASANEN MK,NEUVONEN PJ,NIEMIM.Global analysis of genetic variation in SLCO1B1[J].,2008,9(1): 19-33.
Abstract INTRODUCTION: Organic anion transporting polypeptide 1B1 (OATP1B1), encoded by the SLCO1B1 gene, mediates the hepatic uptake of endogenous compounds and xenobiotics, including drugs. The aim of this study was to investigate the diversity of the SLCO1B1 gene at the global level. MATERIALS AND METHODS: Distribution of SLCO1B1 alleles was determined in 941 individuals from 52 populations comprising Africa, the Middle East, Asia, Europe, Oceania and the Americas. DNA samples were genotyped at 12 variant sites spanning the entire gene by TaqMan 5 nuclease allelic discrimination assays. RESULTS: The frequency of the low-activity c.521T>C variant varied markedly between populations. The lowest frequencies were observed in Oceania (0.0%; 95% CI: 0.0-6.4%) and sub-Saharan Africa (1.9%; 95% CI: 0.7-4.8%), and the highest frequencies observed in American native populations (24%; 95% CI: 18-32%) and Europe (18%; 95% CI: 14-23%). Moreover, the c.521C allele (r = 0.505, p < 0.001) and the *1B (c.388G-c.521T; r = -0.405, p = 0.006) and *15 (c.388G-c.521C; r = 0.510, p < 0.001) haplotype frequencies correlated significantly with latitude in the northern hemisphere. Overall, SLCO1B1 genetic distances correlated significantly with geographic distances between populations, assuming likely routes of human migration out of Africa via five waypoints (r = 0.235, p = 0.001). SLCO1B1 diversity was generally far greater within than between populations. CONCLUSION: Functionally significant variants of SLCO1B1 are widely distributed and occur at high frequencies around the world. SLCO1B1 diversity is greater within than between populations, and genetic variation in SLCO1B1 is generally similar to that observed for other autosomal markers. However, selective pressure may have acted on SLCO1B1 during human dispersal favoring low-activity variants in the north.
HO RH,CHOIL,LEEW,et al.Effect of drug transporter genotypes on pravastatin disposition in European- and African American participants[J].,2007,17(8): 647-656.
OBJECTIVE: Our aims were to evaluate the effects of polymorphisms in the hepatic drug uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1, SLCO1B1) and efflux transporters multidrug resistance-associated protein 2 (MRP2, ABCC2), bile salt export pump (BSEP, ABCB11), and breast cancer-related protein (BCRP, ABCG2) on single-dose pravastatin pharmacokinetics in healthy European- and African-American participants. METHODS: The pharmacokinetics of a single oral 40 mg dose of pravastatin was determined in 107 participants (69 European-Americans and 38 African-Americans). Participants were genotyped for known OATP1B1, MRP2, BSEP, and BCRP polymorphisms. Baseline serum total and unconjugated plasma bilirubin concentrations were also determined. RESULTS: OATP1B1 genotypes were ethnicity-dependent with a 521C allele frequency of approximately 15% in European-Americans and approximately 1% in African-Americans. SLCO1B1 521TC genotype was associated with significantly higher pravastatin area under the curve [AUC(0-5)] (P=0.01) and Cmax values (P<0.05). When analyzed by diplotype, SLCO1B1*1a/*15 (N=8) participants exhibited 45 and 80% higher AUC values than SLCO1B1*1a/*1a (N=29) (P=0.013) and SLCO1B1*1b/*1b (N=34) (P=0.001) carriers, respectively. SLCO1B1*15/*15 (N=2) participants exhibited 92 and 149% higher AUC values than SLCO1B1*1a/*1a (P=0.017) and SLCO1B1*1b/*1b (P=0.011) carriers, respectively. European-Americans had significantly higher plasma pravastatin AUC(0-5) (P=0.01) and Cmax values (P=0.009) than African-Americans. Neither ABCC2, ABCB11, nor ABCG2 genotypes were associated with differences in pravastatin pharmacokinetics. We did not observe an effect of SLCO1B1 genotype on baseline total or unconjugated bilirubin levels. CONCLUSION: SLCO1B1 genotype, in particular the 521C allele, had a significant effect on the pharmacokinetics of pravastatin. Even when adjusted for the presence of the SLCO1B1 521C or 388G variant allele, European-Americans demonstrated significantly higher pravastatin AUC and Cmax values than African-Americans.
MORIMOTOK,UEDAS,SEKIN,et al.OATP-C(OATP1B1) *15 is associated with statin induced myopathy in hypercholesterolemic patients[J].,2005,77(2): 21-28.
ABSTRACT Background Statins are associated with muscle complaints ranging from myalgia to rhabdomyolysis. We studied the genetic contribution to the risk of the statin-induced myopathy by comparing frequencies of mutant alleles of candidate genes in case and control groups.Methods We studied ten Japanese patients with abnormal increase in plasma creatinine kinase or severe muscle complaints, in comparison with control patients (n=26) who received statins but had no myopathy. DNA samples were genotyped for 152 SNPs/mutations in eight candidate genes selected from genes responsible for inherited rhabdomyolysis and those involved in the metabolism or transport of stains.ResultsNo mutations or SNPs were detected in the genes of inherited rhabdomyolysis except for 128G>A in VLCAD, of which frequency was almost the same as that of the controls. For CYP3A4 and MRP2, one and two SNPs were detected respectively, but there was no significant difference between the groups. However, we found a significant association between OATP-C*15 and pravastatin- or atorvastatin-induced myopathy (PA in MDR1 and simvastatin- or atorvastatin-incuced myopathy was also observed (P<0.05).Conclusions The results suggest that OATP-C*15 is one of the susceptible factors for development of myopathy in patients taking pravastatin or atorvastatin.Clinical Pharmacology & Therapeutics (2005) 77, P21-P21; doi: 10.1016/j.clpt.2004.11.081