The screening for single nucleotide polymorphisms of CYP3A4 in chronic myelogenous leukemia patients receiving imatinib

[摘要] English: Chronic myelogenous leukaemia (CML) is a malignant clonal disorder that results in the uncontrolled production of white blood cells. This disease is a result of a reciprocal translocation of the long arms of chromosome 9 and 22 resulting in a shortened chromosome 22, harbouring the BCR-ABL fusion gene, known as the Philadelphia chromosome. The BCR-ABL oncogene encodes for a constitutively activated tyrosine kinase that interferes with normal cell differentiation and apoptosis. CML can be effectively treated with tyrosine kinase inhibitors, such as imatinib mesylate (GleevecÒ). However, some CML patients experience adverse drugs reactions (ADRs) to imatinib and cannot be treated at the recommended dose. There is a concern that lowering the dose of imatinib to reduce the side effects can result in the development of resistant cancer cells, and thus a cessation in treatment is rather recommended. Imatinib is metabolized by the cytochrome P450 enzyme, CYP3A4. However, if the ADRs were a result of decreased metabolic effect of CYP3A4, it would be possible to reduce the dose of imatinib without effecting efficacy. It is hypothesised that single nucleotide polymorphisms (SNPs) can alter the catalytic activity of the CYP3A4 enzyme. Thus a decrease in metabolic rate can result in ADRs due an increased exposure to the drug. Therefore, the aim of this study was to determine whether SNPs in the CYP3A4 gene are associated with ADRs from imatinib treatment. In this study, the DNA sequence of the CYP3A4 gene from 25 CML patients treated with imatinib were compared to a reference DNA sequence obtained from Genbank. The SNPs identified during this study was statistically analysed, and their association with the presence of ADRs was determined using the online statistics package, SNPator. A total of six SNPs were detected, I193I, T15871G, CYP3A4*1G, C23187T, I369V and G73239A. Of these, I369V and G73239A are novel and not described previously in literature. It was found that I369V resulted in an amino acid change, involving a substitution of isoleucine with valine. The remaining SNPs identified in this study were located in intron regions, with the exception of I193I which is a synonymous SNP. There is little information available on the frequency of SNPs located in introns, since these SNPs are generally regarded to have no impact on the expression or activity of a protein. However, in this study an SNP located in intron 10 was significantly associated with the presence ADRs. Current hypothesises suggest that intron SNPs could affect the expression levels of a protein by influencing the splicing efficiency of mRNA and subsequently translation efficacy. Future research needs to elaborate on the role of CYP3A4*1G on CYP3A4 expression as well as on the prevalence of other alleles identified in this study in South African populations.

[发布机构] University of the Free State