Etude des polymorphismes du CYP2C9, CYP2C19 et ABCB1 (MDR1) chez les noirs subsahariens
(2005)
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- Authors
- Supervisors
- Horsmans, Yves
- Abstract
- The fundamental knowledge on drug-metabolizing enzymes or drug transporters have evolved in the last four decades. Most of human cytochromes P450 are cloned and identified. Their role, expression, regulation and distribution are well known. However, the knowledge of polymorphism distribution as well as functional relevance of these genes remains limited in the Black west sub-Saharan population. To fill in this gap, we have studied the distribution of different polymorphism of CYP2C9 and CYP2C19 among west Black African from Benin. Comparing our data with those obtained in a Caucasian population namely the Belgian population, we found that Benin population has a particular distribution with regard to allelic frequencies of the CYP2C9 tested variants. The frequencies of CYP2C9*2 and CYP2C9*3 variants within the Belgian population are higher than that of beninese population whereas the frequencies of the CYP2C9*5 and CYP2C9*11 variants within beninese population are higher than that of Belgian population. In addition, the CYP2C9*11 variant was identified and the prevalence studied for the first time in both Black and Caucasian populations. For these two populations we observed a similar distribution for the two variants of CYP2C19*2 and CYP2C19*3. Nevertheless, if the activity of enzymes CYP2C9.2 and CYP2C9.3 were well studied nothing was known about the activity of variant CYP2C9.11 and only one in vitro study was performed to evaluate CYP2C9.5 activity. To determine in vivo functional relevance of these variants, we have used the losartan/E-3174 ratio as a marker of CYP2C9 activity. The study was performed among subjects whose carriers CYP2C9*5, CYP2C9*11 alleles and subjects whose genotyped as CYP2C9*1/*1. The variant CYP2C9*5 was associated with a diminution in activity whereas the genotype CYP2C9*5/*6 was associated with a dramatic reduction in activity. These findings are relevant for Black population where alleles CYP2C9*5 and CYP2C9*6 are more present. Inherited variations in drug transport genes also likely contribute to the observed variability in drug response. However, until now, no haplotype data for ABCB1 gene are available in Black African population. Exons 2, 7, 10, 11, 12, 14, 17, 21, 26 and the surrounding intronic regions were sequenced using genomic DNA from 111 Beninese subjects to examine 19 intragenic SNPs. Twelve SNPs, including three novel ones: Exon 10, -57del A (intron 9); Exon 10, -8T>A (intron 9); 1662G>C (exon 14) were identified. The most common SNP was Exon 14, +38A>G (intron 14). Using these 12 SNPs and an expectation-maximization based program, haplotype analysis was performed and 53 haplotypes were found. The four SNPs, IVS6+139C>T, IVS9-44A>G, 1236C>T, and 3435C>T, showed close associations with each other, confirming the block concept. Black Africans from Benin may be considered as an old and homogeneous population concerning evolutionary relationships among the ABCB1 haplotypes. Finally, CYP2C9 *6, *7, *8, *9, *10, *12 alleles were studied in a Beninese population, CYP2C9 allele frequencies were: CYP2C9*6: 2.7, CYP2C9*8: 8.6% and CYP2C9*9:15.7%. CYP2C9*7, CYP2C9*10 and CYP2C9*12 were not detected in this study group. Phenytoin has been used as a probe to determine CYP2C9 phenotype by measuring the urinary excretion of its major metabolite, S-enantiomer of 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH). Phenytoin pharmacokinetic is also dependent on the activity of CYP2C19 and P-glycoprotein (ABCB1). To determine the influence of CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms on phenytoin metabolism in a Black population, 109 healthy Beninese subjects received a single 300 mg oral dose of phenytoin. Blood was drawn 4 h after drug intake and urine was collected during the first 8 hours. Plasma phenytoin and urine S- and R-enantiomers of p-HPPH were determined by high-performance liquid chromatography. Urinary excretion of (S)-p-HPPH (defined as urinary volume x (S)-p-HPPH urinary concentration) and PMR (defined as the ratio of p-HPPH in urine to 4 h phenytoin plasma concentration), markers of CYP2C9 activity, were used to determine the functional relevance of new variants of CYP2C9 (*5, *6, *8, *9 and *11) in this population. Plasma phenytoin concentration was significantly associated with ABCB1 haplotype/genotype (P=0.05, Kruskal-Wallis test) and levels increased significantly in this genotype order: wild-type, T3421A and Block-2 genotypes (P=0.015, Jonckheere-Terpstra-test) Urinary excretion of (S)-p-HPPH and PMR were significantly associated with the CYP2C9 genotype (P=0.001, ANOVA; P<0.0001, Kruskal-Wallis test; respectively) and decreased in this order: CYP2C9*1/*1, CYP2C9*1/*9, CYP2C9*9/*9, CYP2C9*1/*8, CYP2C9*8/*9, CYP2C9*9/*11, CYP2C9*1/*5, CYP2C9*6/*9, CYP2C9*1/*6, CYP2C9*8/*11, CYP2C9*5/*8, CYP2C9*5/*6 (P<0.001, Jonckheere-Terpstra-test). A combined analysis of CYP2C9, 2C19 and ABCB1 revealed that only ABCB1 predicted phenytoin concentration at 4 h and explained 8% of the variability (r2=0.8, P = 0.04). On the other hand, only CYP2C9 was predictive for the urinary excretion of (S)-p-HPPH and PMR (r2=0.21, P=0.001; r2 =0.25, P<0.001; respectively). Furthermore, significant relati ...
- Affiliations
Citations
Allabi, A. C. E. (2005). Etude des polymorphismes du CYP2C9, CYP2C19 et ABCB1 (MDR1) chez les noirs subsahariens. https://hdl.handle.net/2078.5/110670