Evaluation of effects of indoxyl sulfate and parathyroid hormone on CYP3A activity considering the influence of CYP3A5 gene polymorphisms

Aims: Indoxyl sulfate and parathyroid hormone (PTH), which accumulate in chronic kidney disease (CKD), have been reported to reduce cytochrome P450(CYP)3A activity. Homozygotes of the CYP3A5*3 allele have reduced CYP3A5 activity compared to carriers of at least one CYP3A5*1 allele. 4 beta-Hydroxycholesterol (4 beta-OHC) has been established as an endogenous substrate reflecting CYP3A activity. 4 beta-OHC is produced through hydroxylation by CYP3A4 and CYP3A5 and by autoxidation of cholesterol, whereas 4 alpha-hydroxycholesterol (4 alpha-OHC) is produced solely by autoxidation of cholesterol. This study focused on CKD patients and evaluated the effects of plasma indoxyl sulfate and intact-PTH concentrations on plasma 4 beta-OHC concentration, 4 beta-OHC/total cholesterol ratio and 4 beta-OHC-4 alpha-OHC, with consideration of the influence of CYP3A5 polymorphism. Methods: Sixty-three CKD patients were analysed and divided into CYP3A5 carrier group (n = 26) and non-carrier group (n = 37). Results: Plasma indoxyl sulfate significantly correlated inversely with 4 beta-OHC concentration and with 4 beta-OHC-4 alpha-OHC in both the CYP3A5*1 carrier group (r = -0.42, P =.034; r = -0.39, P =.050, respectively) and the non-carrier group (r = -0.45, P =.0054; r = -0.39, P =.019, respectively). However, multiple regression analysis did not identify plasma indoxyl sulfate concentration as a significant independent factor associated with any of the CYP3A activity indices. There was no significant correlation between plasma intact-PTH concentration and any of the CYP3A activity indices. Conclusions: The present results suggest that plasma indoxyl sulfate and intact-PTH concentrations do not have clinically significant effects on CYP3A activity in patients with CKD.