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@#CYP3A4 and CYP3A5 are metabolizing enzymes abundantly expressed in liver and involved in the metabolism of xenobiotics as well as clinically used drugs. Genetic polymorphisms in CYP3A4 and CYP3A5 may alter the metabolic ability of individuals. Thus, CYP3A4 and CYP3A5 might play an important role in the aetiology of chronic myeloid leukaemia (CML) and as modulators of cancer therapy response. In this study, the impact of two single nucleotide polymorphisms (SNPs) CYP3A4*18 (878T>C) and CYP3A5*3 (6986A>G) on CML susceptibility risk was investigated. This case-control study involved a total of 520 study subjects comprising 270 CML patients and 250 normal healthy controls. Genotyping of CYP3A4*18 and CYP3A5*3 was performed by polymerase chain reaction – restriction fragment length polymorphism (PCR-RFLP) technique. The association between allelic variants and CML susceptibility risk was assessed by logistic regression analysis, deriving odds ratio (OR) with 95% confident intervals. The results showed that heterozygous (*1/*1*8) genotype of CYP3A4*18 was significantly associated with CML susceptibility risk (OR 3.387; 95% CI: 1.433–8.007, p = 0.005). No homozygous variant (*18/*18) genotype was detected in this study. On the contrary, homozygous variant (*3/*3) and heterozygous (*1/*3) genotypes of CYP3A5*3 were associated with significantly lower risk for CML susceptibility (OR 0.140; 95% CI: 0.079–0.246’ p < 0.001 and OR 0.310; 95% CI: 0.180–0.535, p < 0.001, respectively). The results prompt us to conclude that genetic variation in CYP3A4*18 may contribute to a higher risk whereas CYP3A5*3 polymorphism confers a lower susceptibility risk in Malaysian CML patients.
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OBJECTIVE:To investigate the influence of CYP3A5*3 (rs776746) genetic polymorphism on blood concentration of tacmlimus (TAC) and renal function in renal transplant recipients during the stable period.METHODS:A total of 98 renal transplant recipients during the stable period receiving TAC-based triple anti-rejection scheme (TAC + sodium mycophenol +predrnisone acetate) after surgery and regular follow-up were selected from our hospital during Jan.1995-Dec.2014.The follow-up information during Jan.-Dec.2016 was also collected.Trough concentration of TAC in renal transplant recipients was determined by chemiluminescence microparticle immuno assay.Standard blood concentration (C/D) was calculated after corrected with body weight and daily dose.Scr level was detected with dry chemistry method.CYP3A5*3 genotype was detected by PCR-RFLP and direct sequencing.The relationship of CYP3A5*3 genetic polymorphism with TAC C/D value and Scr level was determined by Kruskal Wallis H or Mann-Whitney U assay.RESULTS:Among 98 renal transplant recipients,there were 9 cases of CYP3A5*3 *1/*1(AA) genotype,37 cases of *1/*3 (AG) genotype and 52 cases of *3/*3 (GG)genotype.The gene frequencies were 9.18％,37.76％,53.06％,which were all in line with Hardy-Weinberg equilibrium (P＞0.05).There was no statistical significance in trough concentration of TAC among different genotypes (P＞0.05).There was statistical significance in TAC dose and C/D value among different genotypes (P＞0.05).TAC dose of CYP3A5*3 *3/*3 genotype recipients was significantly lower than those of *1/*3 and *1/*1 genotype recipients;that of *1/*3 genotype recipients was significantly lower than that of *1/*1 genotype recipients.C/D value of *3/*3 genotype recipients was significantly higher than those of *1/*3 and *1/*1 genotype recipients;that of *1/*3 genotype recipients was significantly higher than that of *1/*1 genotype recipients,with statistical significance (P＜0.05).There was no statistical significance in Scr levels among different genotypes (P＞0.05).CONCLUSIONS:CYP3A5*3 genetic polymorphism significantly influences blood concentration of TAC in renal transplant recipients during the stable period,and *3 allele carriers have higher C/D values and need smaller TAC daily dose.CYP3AS*3 genetic polymorphism may be not associated with Scr level.
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OBJECTIVE:To investigate the association of synergistic effects of Wuzhi capsules on tacrolimus with CYP3A5*3 (6986A>G,rs776746) gene polymorphisms. METHODS:One hundred and severty patients underwent renal transplantation receiving tacrolimus maintenance therapy after surgery were selected from our hospital during Jan. 1997-Dec. 2015,and then divided into Wuzhi capsules(+)group(74 cases)and Wuzhi capsules(-)group(96 cases)according to the use of Wuzhi capsules. Both groups received tacrolimus+mycophenolate mofetil+prednisone;Wuzhi capsules (+)group was additionally given Wuzhi capsules,one capsule each time,bid,for more than 12 months. Trough concentration of tacrolimus was detected by CMIA 0,1,3,6,12 months after medica-tion,and the blood concentrations(C0/D)were calculated at different time points after correcting daily dose. CYP3A5*3 gene polymor-phisms was detected by PCR-RFLP. The association of C0/D value with gene polymorphism was investigated by analysis of covariance. RESULTS:Among 170 patients,there were 65 cases of CYP3A5 GG genotype,83 cases of AG genotype and 22 cases of AA geno-type;genotype frequencies were 38.2%,48.8% and 12.9%,which was in line with Hardy-Weinberg balance (P>0.05). There was statistical significance in the distribution frequencies of GG,AG+AA genotype between Wuzhi capsules(+)group and Wuzhi capsules (-)group (P0.05). CON-CLUSIONS:Wuzhi capsules can increase C0/D of tacrolimus in CYP3A5*3 AG+AA genotype,but have no significant effect on C0/D of tacrolimus in GG genotype;CYP3A5*3 genotype should be considered when using Wuzhi capsules as synergist of tacrolimus.
ABSTRACT
The cytochrome P450 (CYP) 3A subfamily is estimated to participate in the biotransformation of 50% of the currently prescribed drugs. Four members of the CYP3A subfamily have been identified in humans: CYP3A4, CYP3A5, CYP3A7, and CYP3A43. Initial data suggested that CYP3A5 accounts for only a small proportion of the total hepatic CYP3A in about 20% of samples, but it was later revealed that CYP3A5 represents more than 50% of the total CYP3A amount in some individuals. Several genetic variants have been described for the CYP3A5 gene, of which the CYP3A5*3 allele (gA6986G), the most common form and leading to the loss of CYP3A5 activity, has been extensively investigated in the aspect of pharmacokinetics and disease risk. This review summarized the molecular characteristics of the CYP3A5 gene, and discusses the association of the CYP3A5*3 polymorphism with disease risks such as cancer and hypertension, along with its role in the pharmacokinetics of CYP3A substrates.