Influence of CYP3A5 and MDR1 genetic polymorphisms on urinary 6 beta-hydroxycortisol/cortisol ratio after grapefruit juice intake in healthy Chinese.
Interindividual variability of cytochrome P450 (CYP) 3A inhibition by grapefruit juice was investigated in relation to CYP3A5 and multidrug resistance gene (MDR) 1 genetic polymorphisms in Chinese Han, Uygur, and Kazakh healthy subjects. The measurement of urinary 6 beta-hydroxycortisol/cortisol ratio was used to evaluate CYP3A activity in vivo by high-performance liquid chromatography. CYP3A5*3 and MDR1 C1236T, G2677T/A, and C3435T polymorphisms were analyzed by polymerase chain reaction restriction fragment length polymorphism. After grapefruit juice intake, urinary ratios significantly decreased in 3 Chinese ethnic groups (P < .001). Kazakh had a larger decrease of urinary ratio compared to that of Han (P < .05), and the latter had similar decrease with Uygur. Furthermore, Chinese healthy subjects carrying CYP3A5*3/*3 and MDR1(1236-2677-3435) T-T-T/T-T-T genotypes were found to have the largest reduction of urinary ratio (mean, 61.4%; 95% confidence interval, 53.4%-69.5%), whereas *1/*3 subjects carrying MDR1(1236-2677-3435) C-G-C/C-G-C genotypes had the lowest reduction (mean, 25.9%; 95% confidence interval, 3.1%-48.8%; P < .01). In conclusion, both CYP3A5*3 and MDR1 variants influenced the extent of CYP3A inhibition by grapefruit juice in Chinese healthy subjects. The genetic variations influencing the CYP3A inhibitive phenotype might be helpful to explain the individual variability of grapefruit juice-drug interactions.
Li
Dan
D
Department of Pharmacology, Basic Medical School, Beijing (Peking) University, 38 Xue-Yuan Road, Beijing, 100191, China.
Abudula
Aziguli
A
Abulahake
Muhutar
M
Zhu
An-Ping
AP
Lou
Ya-Qing
YQ
Zhang
Guo-Liang
GL
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D001628:Beverages; D002681:China; D002851:Chromatography, High Pressure Liquid; D032083:Citrus paradisi; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004247:DNA / Q000235:genetics; D005006:Ethnicity; D005260:Female; D018565:Food-Drug Interactions; D005838:Genotype; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000652:urine; D008297:Male; D010641:Phenotype; D011110:Polymorphism, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065692:Cytochrome P-450 CYP3A Inhibitors; C001380:6 beta-hydroxycortisol; D004247:DNA; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D006854:Hydrocortisone