CYP3A5 genotype has significant effect on quinine 3-hydroxylation in Tanzanians, who have lower total CYP3A activity than a Swedish population

Abstract

To study the correlation between CYP3A5 genotype and quinine 3-hydroxylation in black Tanzanian and Swedish Caucasians as well as to investigate the interethnic differences in CYP3A activity between the two populations. Tanzanian (n=144) and Swedish (n=136) healthy study participants were given a single oral 250 mg dose of quinine hydrochloride and a 16-h post-dose blood sample was collected. The metabolic ratio of quinine/3-hydroxyquinine was determined in plasma by high-performance liquid chromatography. All the participants were genotyped for the known mutations of CYP3A5, which are relevant for the respective population. Correlation between quinine metabolic ratio and CYP3A5 genotype as well as the interethnic difference in CYP3A activity between the two populations was studied. Tanzanians had significantly higher (P<0.0001) mean quinine metabolic ratio (9.5+/-3.5) than Swedes (7.6+/-3.1). As expected, the frequency of high CYP3A5 expression alleles was higher in Tanzanians (51%) than in Swedes (7%). The mean+/-SD quinine metabolic ratio (10.7+/-3.9) in Tanzanians homozygous for low CYP3A5 expression gene was significantly higher than the corresponding mean metabolic ratio in participants heterozygous (9.5+/-3.3; P=0.02) or homozygous (8.1+/-3.1; P=0.002) for high expression CYP3A5 alleles, respectively. A tendency to higher quinine metabolic ratio in Swedes with low expression alleles compared with those with one or two high expression alleles was observed. Tanzanians homozygous for low CYP3A5 expression gene (i.e. only CYP3A4 is expressed) had significantly (P<0.0001) higher quinine metabolic ratio (10.7+/-3.9) than corresponding Swedes (7.7+/-3.1). Clear interethnic differences were observed in the activity of CYP3A between Tanzanians and Swedes. A significant association is noted between CYP3A5 genotype and quinine 3-hydroxylation in Tanzanians, indicating a significant contribution of CYP3A5 to total 3A activity. The CYP3A4 catalyzed hydroxylation of quinine (two low CYP3A5 expression alleles) was lower in Tanzanians than in Swedes.