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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 relationship of Cytochrome P450 (CYP)3A4* 18 gene polymorphism with therapeutic efficacy and ADR of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in non-small cell lung cancer (NSCLC) patients receiving primary treatment.METHODS:A total of 46 advanced NSCLC patients receiving primary EGFR-TKI (gefitinib or edotinib) treatment until disease progression or intolerance were selected from our hospital during Jan.2013-Mar.2016,and (gefitinib of erlotinib) treatment until disease progression or intolerance.CYP3A4*18 genotype was detected by PCR and direct sequencing.Clinical efficacies,progression-free survival (PFS) and the occurrence of ADR were compared among differ ent genotypes.RESULTS:Among 46 patients,there were 17 cases of CYP3A4*18 wild-type and 29 cases of CYP3A4*18 mutation-type,with mutation frequency of 63.0％.The objective response rate (ORR) of CYP3A4*18 wild-type patients was 23.5％,and disease control rate (DCR) of them was 70.6％.For CYP3A4*18 mutation-type patients,ORR and DCR were 27.6％ and 69.0％.There was no statistical significance in the proportion of patients with partial response,stable disease or progressive dis ease,ORR or DCR among different genotypes (P＞0.05).PFS of female patients were significantly longer than male patients;those of patients without smoking history were significantly longer than those with smoking history,with statistical significance (P＜0.05).There was no correlation between patients' age,therapy drugs,Eastern Oncology Collaboration scores,EGFR mutation types,CYP3A4*18 genotypes and PFS (P＞0.05).Patients'gender and smoking history were independent prognostic factors for PFS [odds ratios were 3.438,0.205,95％ CI were(1.393,8.488),(0.088,0.481)].Among CYP3A4* 18 wild-type patients,6 patients suffered from rash (35.3％) and 3 diarrhea (17.6％).Among mutation-type patients,26 patients suffered from rash (89.7％) and 15 diarrhea (51.7％),with statistical significance (P＜0.05).There was no statistical significance in the incidence of liver function injury and interstitial dermatitis among different genotypes (P＞0.05).CONCLUSIONS:CYP3A4*18 gene polymorphism may be not associated with therapeutic efficacy of EGFR-TKI in advanced NSCLC patients receiving primary treatment,but it is correlated with the occurrence of ADR.Mutation type patients are more likely to suffered from rash,diarrhea and other ADR.
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OBJECTIVE: To investigate the interindividual variabilities of plasma concentration and lipid-regulating efficacy of atorvastatin in patients with hyperlipidemia through the genotyping of CYP3A4*18A, *18B and MDR1 C3435T genes. METHODS: One hundred and fifteen Chinese Han population with hyperlipidemia were genotyped by the PCR-RFLP (restriction fragment length polymorphism). The steady-state plasma trough concentrations of atorvastatin were measured by high performance liquid chromatography (HPLC)-UV. The levels of serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were monitored by the homogeneous enzyme method before treatment and 1 month after medication. RESULTS: The mutation frequencies of CYP3A4*18A, *18B and MDR1 C3435T were 3.48%, 23.48% and 31.74% respectively. It shows no statistically significant difference for the SNPs frequencies between the normal population reported and patients selected. Patients with CYP3A4*18B homozygous mutant (AA) showed a significantly higher plasma concentration of ATV compared with the G/A heterozygous mutat patients or the G/G wild-type homozygous (P=0.016). However, no significant difference could be shown in the patients with CYP3A4*18A and MDR1 C3435T genotypes(P>0.05). Neither CYP3A4*18A nor MDR1 C3435T could be shown a significant difference in the lipid lowering efficiency(P>0.05). Patients carrying the homozygous mutant (AA) of the CYP3A4*18B gene showed a significantly higher TC lipid-regulating effect compared with patients with the GA or GG genetic variant (P=0.02). The LDL-C change rates among the three genotype groups were significantly different, with AA group >GA group >GG group (P=0.01) and the regulation of TG and HDL-C for AA, GA or GG was compared without finding any significant difference (P>0.05). The TC changerates and plasma concentration were significantly correlated (P=0.031) before and after treatment, while there was no statistical significance in the correlation of the other three lipid change rates with plasma concentration (P>0.05). CONCLUSION: The SNPs MDR1 C3435T and CYP3A4*18A do not affect the plasma concentration and efficacy of ATV. In ATV therapy, patients with the CYP3A4*18B gene exhibit higher plasma concentrations than the non-carriers, and the lipid-lowering efficacy was more pronounced.