Influence of CYP3A5 and MDR1 Genetic Polymorphisms on Urinary 6β‐Hydroxycortisol/Cortisol Ratio After Grapefruit Juice Intake in Healthy Chinese

Abstract

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.

Associations of theCYP3A5*3andCYP3A4*1Gpolymorphisms with the pharmacokinetics of oral midazolam and the urinary 6β-hydroxycortisol/cortisol ratio as markers of CYP3A activity in healthy male Chinese

“…33,34 In fact, phenotyping data on CYP3A activity obtained with different CYP3A substrates are not well correlated to each other, which may be related to the occurrence of several overlapping substrate-binding regions and the allosteric regulation of CYP3A4 enzyme activity. 4 In this study, there was no significant association between the CYP3A5*3 polymorphism and the urinary ratio of 6b-OHF to F and this is in agreement with previous studies in Chinese healthy volunteers 23 and in Chinese patients with hypercholesterolaemia receiving statin therapy. 9 The CYP3A4*1G polymorphism also showed no association with the urinary ratios of 6b-OHF to F in all subjects combined or in CYP3A5 expressers.…”

“…In this study, there was no significant association between the CYP3A5*3 polymorphism and the urinary ratio of 6β‐OHF to F and this is in agreement with previous studies in Chinese healthy volunteers and in Chinese patients with hypercholesterolaemia receiving statin therapy . The CYP3A4*1G polymorphism also showed no association with the urinary ratios of 6β‐OHF to F in all subjects combined or in CYP3A5 expressers.…”

“…CYP3A enzymes are responsible for the 6β‐hydroxylation of endogenous unconjugated cortisol (F), and both F and 6β‐hydroxycortisol (6β‐OHF) are excreted in the urine. The urinary ratio of 6β‐OHF to F has been used to evaluate CYP3A enzyme induction and inhibition in humans and to assess CYP3A activity in cross‐sectional and pharmacogenetic studies, although there is some debate about its reliability as a biomarker of CYP3A activity …”

“…20 CYP3A enzymes are responsible for the 6b-hydroxylation of endogenous unconjugated cortisol (F), and both F and 6b-hydroxycortisol (6b-OHF) are excreted in the urine. The urinary ratio of 6b-OHF to F has been used to evaluate CYP3A enzyme induction and inhibition in humans 21 and to assess CYP3A activity in cross-sectional and pharmacogenetic studies, 22,23 although there is some debate about its reliability as a biomarker of CYP3A activity. 24 This study evaluated the effect of CYP3A4*1G and CYP3A5*3 polymorphisms on the pharmacokinetics of oral midazolam and urinary ratio of 6b-OHF/F as potential markers of CYP3A activity in healthy male Chinese subjects.…”

Comparison of Endogenous 4β-Hydroxycholesterol with Midazolam as Markers for CYP3A4 Induction by Rifampicin

“…On the other hand, as described earlier, midazolam is superior to 4b-hydroxycholesterol in detecting inhibition of CYP3A4 (Table 2). Also, 6b-hydroxycortisol ratio can measure CYP3A inhibition (Li et al, 2010).…”