title: Association of plasma concentration of 4β-hydroxycholesterol with CYP3A5 polymorphism and plasma concentration of indoxyl sulfate in stable kidney transplant recipients.
abstract: 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 4β-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 4β-hydroxycholesterol, 3-INDS, and 3-IAA were measured. Plasma concentrations of 4β-hydroxycholesterol were 57.1 ± 11.2, 42.1 ± 11.8, and 34.5 ± 7.3 ng/ml in recipients with CYP3A5*1/*1 (n = 5), *1/*3 (n = 15), and *3/*3 (n = 25) genotypes, respectively, with significant differences between three genotypes. A significant correlation was observed between plasma concentrations of 4β-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 4β-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.
authors.affiliation: Department of Clinical Pharmacy, Oita University Hospital, Hasama-machi, Oita, Japan (Y.S., H.I., T.F., K.K., Y.S., Y.S.); Department of Urology, Faculty of Medicine, Oita University, Hasama-machi, Oita, Japan (F.S., H.M.); and Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan (K.O., S.K.).
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Itoh
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujioka
authors.forename: Fuminori
authors.initials: F
authors.lastname: Sato
authors.forename: Kanako
authors.initials: K
authors.lastname: Kawasaki
authors.forename: Yukie
authors.initials: Y
authors.lastname: Sato
authors.forename: Yuhki
authors.initials: Y
authors.lastname: Sato
authors.forename: Keiko
authors.initials: K
authors.lastname: Ohno
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Mimata
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kishino
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D044466:Asian People / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood*; D007200:Indican / Q000097:blood*; D007210:Indoleacetic Acids / Q000097:blood; D007668:Kidney / Q000378:metabolism; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D006888:Hydroxycholesterols; D007210:Indoleacetic Acids; C099828:cholest-5-ene-3,4-diol; C030737:indoleacetic acid; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D007200:Indican