Association of Plasma Concentration of 4 beta-Hydroxycholesterol with CYP3A5 Polymorphism and Plasma Concentration of Indoxyl Sulfate in Stable Kidney Transplant Recipients

作者：Suzuki Yosuke^*; Itoh Hiroki; Fujioka Takashi; Sato Fuminori; Kawasaki Kanako; Sato Yukie; Sato Yuhki; Ohno Keiko; Mimata Hiromitsu; Kishino Satoshi

来源：Drug Metabolism and Disposition, 2014, 42(1): 105-110.

DOI：10.1124/dmd.113.054171

Several studies have shown that renal failure decreases CYP3A activity and that uremic toxins may play a role via transcriptional or translational modifications of cytochrome P450 (P450) enzymes and direct inhibition of P450-mediated metabolism. In this study, we evaluated the relationship between CYP3A activity (using plasma concentration of 4 beta-hydroxycholesterol as a biomarker) and clinical characteristics including plasma concentrations of indoxyl sulfate (3-INDS) and indole-3-acetic acid (3-IAA) in stable kidney transplant recipients. Forty-five Japanese kidney transplant recipients who underwent transplantation more than 90 days prior to the study were included. Morning blood samples were collected and plasma concentrations of 4b-hydroxycholesterol, 3-INDS, and 3-IAA were measured. Plasma concentrations of 4b-hydroxycholesterol were 57.1 +/- 11.2, 42.1 +/- 11.8, and 34.5 +/- 7.3 ng/ml in recipients with CYP3A5*11 (n = 5), *13 (n = 15), and *33 (n = 25) genotypes, respectively, with significant differences between three genotypes. A significant correlation was observed between plasma concentrations of 4b-hydroxycholesterol and 3-INDS but not 3-IAA. Multiple regression analysis identified the number of CYP3A5*3 alleles in genotype, plasma concentration of 3-INDS, and body weight as independent variables associated with plasma concentration of 4b-hydroxycholesterol. In conclusion, these results suggest that CYP3A5 polymorphism and plasma concentration of 3-INDS may account for the interindividual variability of CYP3A activity, and that plasma concentration of 3-INDS may partially explain the gap in CYP3A activity that cannot be explained by genetic contribution in patients with renal failure.

• 出版日期2014-1