Mirghani Rajaa A, Sayi Jane, Aklillu Eleni, Allqvist Annika, Jande Mary, Wennerholm Agneta, Eriksen Jaran, Herben Virginie M M, Jones Barry C, Gustafsson Lars L, Bertilsson Leif
Department of Clinical Toxicology, Central Laboratories & Blood Bank, King Fahad Medical City, Riyadh 11525, Kingdom of Saudi Arabia.
Pharmacogenet Genomics. 2006 Sep;16(9):637-45. doi: 10.1097/01.fpc.0000230411.89973.1b.
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.
研究坦桑尼亚黑人与瑞典高加索人CYP3A5基因多态性与奎宁3-羟化之间的相关性，并探讨两群体间CYP3A活性的种族差异。
给予坦桑尼亚（n = 144）和瑞典（n = 136）健康受试者单次口服250mg盐酸奎宁，并于给药后16小时采集血样。采用高效液相色谱法测定血浆中奎宁/3-羟基奎宁的代谢率。对所有受试者进行与各自群体相关的CYP3A5已知突变的基因分型。研究奎宁代谢率与CYP3A5基因多态性之间的相关性以及两群体间CYP3A活性的种族差异。
坦桑尼亚人的平均奎宁代谢率（9.5±3.5）显著高于瑞典人（7.6±3.1）（P < 0.0001）。正如预期的那样，坦桑尼亚人高CYP3A5表达等位基因的频率（51%）高于瑞典人（7%）。CYP3A5低表达基因纯合的坦桑尼亚人的平均±标准差奎宁代谢率（10.7±3.9）显著高于CYP3A5高表达等位基因杂合（9.5±3.3；P = 0.02）或纯合（8.1±3.1；P = 0.002）的受试者的相应平均代谢率。观察到CYP3A5低表达等位基因的瑞典人比具有一个或两个高表达等位基因的瑞典人有更高奎宁代谢率的趋势。CYP3A5低表达基因纯合的坦桑尼亚人（即仅表达CYP3A4）的奎宁代谢率（10.7±3.9）显著高于相应的瑞典人（7.7±3.1）（P < 0.0001）。
坦桑尼亚人和瑞典人之间观察到明显的CYP3A活性种族差异。在坦桑尼亚人中，CYP3A5基因多态性与奎宁3-羟化之间存在显著关联，表明CYP3A5对总3A活性有显著贡献。坦桑尼亚人中CYP3A4催化的奎宁羟化作用（两个CYP3A5低表达等位基因）低于瑞典人。
