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.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:ufs/oai:etd.uovs.ac.za:etd-11202013-151617 |
| Date | 20 November 2013 |
| Creators | Thompson, Gaynor Gillian |
| Contributors | Prof CD Viljoen |
| Publisher | University of the Free State |
| Source Sets | South African National ETD Portal |
| Language | en-uk |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.uovs.ac.za//theses/available/etd-11202013-151617/restricted/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University Free State or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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