Navigating genetic polymorphisms of CYPZC8 using denaturing high performance liquid chromatography (DHPLC) / Mohd Khairi Zahri @ Johari

Cytochrome P450 2C8 (CYPZC8), which was reported to be polymorphic, plays an important role in the metabolism of several therapeutically important drugs and endogenous substances. The large inter - subjects pharmacokinetics variations were therefore under the great influence of genetic polymorphism...

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Main Author:	Zahri @ Johari, Mohd Khairi
Format:	Thesis
Language:	English
Published:	2009
Subjects:	RS Pharmacy and materia medica
Online Access:	https://ir.uitm.edu.my/id/eprint/39731/1/39731.pdf
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id	my-uitm-ir.39731
record_format	uketd_dc
spelling	my-uitm-ir.397312020-12-27T15:04:53Z Navigating genetic polymorphisms of CYPZC8 using denaturing high performance liquid chromatography (DHPLC) / Mohd Khairi Zahri @ Johari 2009 Zahri @ Johari, Mohd Khairi RS Pharmacy and materia medica Cytochrome P450 2C8 (CYPZC8), which was reported to be polymorphic, plays an important role in the metabolism of several therapeutically important drugs and endogenous substances. The large inter - subjects pharmacokinetics variations were therefore under the great influence of genetic polymorphism of CYP2C8. However, the inability to detect the genetic variation despite well known inter - subjects pharmacokinetics variabilities of CYPZC8, suggested that new variants may exist in the population or the current detection methods are not sensitive enough to detect new variants. The ability to identify the genetic variations is important to help predict the different responses in different individuals and maximise clinical drug safety. The aim of the study was to develop and validate a higher throughput screening method for detection of CYP2C8 polymorphisms. The method would then be used to determine the genetic variations in healthy volunteers and cardiovascular patients in Malaysia. Whole blood was obtained and DNA was extracted from 200 subjects; 100 of healthy volunteers and 100 of cardiovascular patients Each DNA sample was screened for variations using the PCR and DHPLC method developed. The method was compared with other existing method (allele specific PCR) and validated by direct sequencing. Six variants were detected using the method developed. Two of the variants were found to be novel. In comparison with healthy volunteers and cardiovascular patients (CVS), the frequency of IVS9-24 (C35322T) was lower in healthy volunteers which was 18% compared to 48.5% in CVS patients with a P value of <0.001. Meanwhile in exon 8 of CYP2C8, variant A13410 (C33468T) was only detected in CVS patients with a frequency of 3%. In conclusion, we had successfully developed a higher throughput and automated method for the population study of CYP2C8 in Malaysia. The presence of significantly higher frequencies of variant IVS -24 among the CVS patients suggests possible risk factor to CVS. However, further studies are required to confirm this finding. 2009 Thesis https://ir.uitm.edu.my/id/eprint/39731/ https://ir.uitm.edu.my/id/eprint/39731/1/39731.pdf text en public masters Universiti Teknologi MARA Faculty of Pharmacy
institution	Universiti Teknologi MARA
collection	UiTM Institutional Repository
language	English
topic	RS Pharmacy and materia medica
spellingShingle	RS Pharmacy and materia medica Zahri @ Johari, Mohd Khairi Navigating genetic polymorphisms of CYPZC8 using denaturing high performance liquid chromatography (DHPLC) / Mohd Khairi Zahri @ Johari
description	Cytochrome P450 2C8 (CYPZC8), which was reported to be polymorphic, plays an important role in the metabolism of several therapeutically important drugs and endogenous substances. The large inter - subjects pharmacokinetics variations were therefore under the great influence of genetic polymorphism of CYP2C8. However, the inability to detect the genetic variation despite well known inter - subjects pharmacokinetics variabilities of CYPZC8, suggested that new variants may exist in the population or the current detection methods are not sensitive enough to detect new variants. The ability to identify the genetic variations is important to help predict the different responses in different individuals and maximise clinical drug safety. The aim of the study was to develop and validate a higher throughput screening method for detection of CYP2C8 polymorphisms. The method would then be used to determine the genetic variations in healthy volunteers and cardiovascular patients in Malaysia. Whole blood was obtained and DNA was extracted from 200 subjects; 100 of healthy volunteers and 100 of cardiovascular patients Each DNA sample was screened for variations using the PCR and DHPLC method developed. The method was compared with other existing method (allele specific PCR) and validated by direct sequencing. Six variants were detected using the method developed. Two of the variants were found to be novel. In comparison with healthy volunteers and cardiovascular patients (CVS), the frequency of IVS9-24 (C35322T) was lower in healthy volunteers which was 18% compared to 48.5% in CVS patients with a P value of <0.001. Meanwhile in exon 8 of CYP2C8, variant A13410 (C33468T) was only detected in CVS patients with a frequency of 3%. In conclusion, we had successfully developed a higher throughput and automated method for the population study of CYP2C8 in Malaysia. The presence of significantly higher frequencies of variant IVS -24 among the CVS patients suggests possible risk factor to CVS. However, further studies are required to confirm this finding.
format	Thesis
qualification_level	Master's degree
author	Zahri @ Johari, Mohd Khairi
author_facet	Zahri @ Johari, Mohd Khairi
author_sort	Zahri @ Johari, Mohd Khairi
title	Navigating genetic polymorphisms of CYPZC8 using denaturing high performance liquid chromatography (DHPLC) / Mohd Khairi Zahri @ Johari
title_short	Navigating genetic polymorphisms of CYPZC8 using denaturing high performance liquid chromatography (DHPLC) / Mohd Khairi Zahri @ Johari
title_full	Navigating genetic polymorphisms of CYPZC8 using denaturing high performance liquid chromatography (DHPLC) / Mohd Khairi Zahri @ Johari
title_fullStr	Navigating genetic polymorphisms of CYPZC8 using denaturing high performance liquid chromatography (DHPLC) / Mohd Khairi Zahri @ Johari
title_full_unstemmed	Navigating genetic polymorphisms of CYPZC8 using denaturing high performance liquid chromatography (DHPLC) / Mohd Khairi Zahri @ Johari
title_sort	navigating genetic polymorphisms of cypzc8 using denaturing high performance liquid chromatography (dhplc) / mohd khairi zahri @ johari
granting_institution	Universiti Teknologi MARA
granting_department	Faculty of Pharmacy
publishDate	2009
url	https://ir.uitm.edu.my/id/eprint/39731/1/39731.pdf
_version_	1783734531486908416

Navigating genetic polymorphisms of CYPZC8 using denaturing high performance liquid chromatography (DHPLC) / Mohd Khairi Zahri @ Johari

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