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. 4β‐Hydroxycholesterol (4β‐OHC) has been established as an endogenous substrate reflecting CYP3A activity. 4β‐OHC is produced through hydroxylation by CYP3A4 and CYP3A5 and by autoxidation of cholesterol, whereas 4α‐hydroxycholesterol (4α‐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 4β‐OHC concentration, 4β‐OHC/total cholesterol ratio and 4β‐OHC–4α‐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 4β‐OHC concentration and with 4β‐OHC–4α‐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. [ABSTRACT FROM AUTHOR]