Pharmacogenetic and Molecular Biological Analysis of Drug Metabolizing Enzymes, in Particular, Cytochromes N502d6 (Cyp2d6) and P4502c19 (Cyp2c19) in an Ethiopia Population
| dc.contributor.advisor | K.Frederick (PhD) | |
| dc.contributor.author | Aklillu Eleni | |
| dc.date.accessioned | 2018-07-20T08:37:14Z | |
| dc.date.accessioned | 2023-11-09T16:18:20Z | |
| dc.date.available | 2018-07-20T08:37:14Z | |
| dc.date.available | 2023-11-09T16:18:20Z | |
| dc.date.issued | 1995-06 | |
| dc.description.abstract | Debrisoquine and S-mephenytoin hydroxylation polymorphism was studied in 115 healthy unrelated Ethiopian volunteers after coadministration of debrisoquine (lOmg) with S-mephenytoin (lOOmg). The ratio of the S to the R enantiomers of mephenytoin and of debrisoquine to 4-0H debrisoquine in 0-8 hr urine samples were determined using GC. Debrisoquine and S-mephenytoin are metabolized by CYP2D6 and CYP2CI9 respectively. CYP2D6 and CYP2C19 show genetic polymorphism, dividing the population into Extensive metabolizers (EMs) and Poor metabolizers (PMs). The frequency of the PM phenotype is a subject of a pronounced inter-ethnic difference. Two subjects (1.7%) are classified as a PMs (MR > 12.6) with respect to CYP2D6. The debrisoquine MRs are trimodally distributed with a greater part of the population located in the MR interval of 1 - 10. The low prevalence of PMs is due to a lower frequency of a defective CYP2D6 allele. Using a combination of RFLP, SSCP and PCR, subjects were genotyped for the known mutations in the CYP2D6 locus. Using XbaI and EcoRl RFLP, 11.5kb, 44kb and 42kb haplotypes associated with gene deletion, defective CYP2D locus and gene duplication respectively were detected. Defective CYP2D6A, CYP2D6B and exon 1 mutations were detected using PCR. SSCP and PCR were used to genotype the CYP2D6C mutations. No individual had either the CYP2D6A or the CfP2D6C allele. The allele frequencies for CYP2D6B, CYP2D6D and exon 1 mutation was 1.3%, 3% and 9.8% respectively. The allele frequency of the duplicated CYP2D6 gene (42 kb allele) is significantly higher (12.9%) among Ethiopians than in any other population studied. Furthermore, the RFLP analysis indicated the existence of alleles carrying 3, 4 and even 5 active CYP2D6 genes in tandem. For S-mephenytoin hydroxylase (CYP2CI9), six subjects (5.3%) with SIR ratio greater than 0.9 phenotyped as PMs. Three of them were homozygous (CYP2Cl9mlICYP2Cl9ml) and the rest heterozygous (CYP2Cl9mllCYP2Cl9m2) for mutated allele of CYP2C19. CYP2Cl9ml and CYP2Cl9m2 account for 75% and 25% of defective alleles respectively in PMs. These results indicate that CYP2C19 genotyping analysis for both CYP2Cl9ml and CYP2Cl9m2, enables one to apparently predict about 100% of the phenotypes. | en_US |
| dc.identifier.uri | http://etd.aau.edu.et/handle/12345678/9545 | |
| dc.language.iso | en | en_US |
| dc.publisher | Addis Ababa Universty | en_US |
| dc.subject | Cyp2d6 and P4502c19 Cyp2c19 | en_US |
| dc.title | Pharmacogenetic and Molecular Biological Analysis of Drug Metabolizing Enzymes, in Particular, Cytochromes N502d6 (Cyp2d6) and P4502c19 (Cyp2c19) in an Ethiopia Population | en_US |
| dc.type | Thesis | en_US |