Genotypic and expression analysis of CYP3A4 and CYP3A5 in patients with chronic myeloid leukaemia
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Date
2013-01
Authors
Thompson, Gaynor Gillian
Journal Title
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Publisher
University of the Free State
Abstract
Chronic myeloid leukaemia (CML) is a haematological malignancy characterised by the BCR-ABL fusion oncogene which encodes for a constitutively active tyrosine kinase. Imatinib mesylate is a tyrosine kinase inhibitor that has effectively been used in the treatment of CML. However, some individuals experience adverse drugs reactions (ADRs) to imatinib. One of the reasons for varied treatment response among individuals may be as a result of inter-individual differences in the metabolism of imatinib. Imatinib is metabolised by the drug metabolizing enzymes CYP3A4 and CYP3A5. Single nucleotide polymorphisms (SNPs) in CYP3A4 and CYP3A5 have been described, some of which have been associated with altered catalytic activity of these enzymes. SNPs in CYP3A4 and CYP3A5 may also impact the expression of these genes and result in a less favourable response to imatinib treatment. Patients with a decrease in catalytic activity of CYP3A4 and CYP3A5 may experience ADRs due to prolonged exposure to imatinib. On the other hand an increase in activity may lead to ineffective treatment as a result of increased clearance of the drug. Thus the aim of this study was to screen CYP3A4 and CYP3A5 for SNPs using high resolution melting curve analysis (HRM) and determine the impact of these SNPs on gene expression in CML patients treated with imatinib. A total of ten SNPs were detected in CYP3A4, of which two SNPs, namely A15619G and A15649T have not been previously described in literature. A15619G was a synonymous SNP while A15649T resulted in a change in amino acid from glutamine to a histidine. A total of four SNPs were detected in CYP3A5, of which one SNP namely, G7226A, had not previously been reported in literature and did not result in an amino acid change. Out of all the detected SNPs in CYP3A4, the G20338A SNP was statistically associated with the occurrence of ADRs but not with mRNA expression. The I369V SNP was statistically associated with increased CYP3A4 mRNA expression. None of the SNPs detected in CYP3A5 significantly affected mRNA expression. Expression of CYP3A4 and CYP3A5 was not dependent on ethnicity or gender, with the exception of CYP3A5 which showed a statistically significant difference between males and females. Currently a limited amount of literature exists regarding SNPs in CYP3A4 and CYP3A5 and CML treatment. Given the potential impact that SNPs can have on the CYP3A4 and CYP3A5 enzymes and therefore imatinib treatment, it is an important issue that needs to be investigated. Determining the potential impact of SNPs and differential gene expression of CYP3A4 and CYP3A5 is important as it may allow for more effective imatinib treatment.
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Keywords
Dissertation (M.Med.Sc. (Haematology and Cell Biology))--University of the Free State, 2013, Chronic myeloid leukemia -- Genetic aspects, Chronic myeloid leukemia -- Treatment, Gene expression, Chronic myeloid leukemia -- Diagnosis, Imatinib, Aromatase, BCRABL, Imatinib mesylate, mRNA expression, CYP3A4, Single nucleotide polymorphism (SNP), CYP3A5, Cytochrome P450