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 4b-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 6 11.2, 42.1 6 11.8, and 34.5 6 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 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.

CYP3A5 Polymorphism affects the increase in CYP3A activity after living Kidney transplantation in patients with end stage renal disease

“…To the best of our knowledge, this is the first report of the association of a genetic factor with change in CYP3A activity accompanying renal failure. On the other hand, no significant correlation was observed between eGFR and plasma concentration of 4β-hydroxycholesterol on day 90 after living kidney Figure 3 Plasma concentrations of 4β-hydroxycholesterol in patients with the CYP3A5*1 allele and patients without the CYP3A5*1 allele (A) and correlation between eGFR and plasma concentration of 4β-hydroxycholesterol (B) on day 90 after living kidney transplantation transplantation, supporting the finding in stable kidney transplant recipients reported previously [22].…”

“…On the other hand, plasma 4β-hydroxycholesterol concentrations were significantly elevated on days 90 and 180 after living kidney transplantation, indicating recovery of CYP3A activity with improvement in renal function in ESRD patients after living kidney transplantation. Plasma 4β-hydroxycholesterol concentrations 180 days after kidney transplantation were slightly higher compared with the concentrations in stable kidney transplant recipients reported previously (39.5 ± 11.7 ng ml À1 ), which may be due to the change in renal function over time after kidney transplantation (180 vs. 1398 ± 1315 days) [22]. Furthermore, plasma concentrations of 4β-hydroxycholesterol on days 90 and 180 after living kidney transplantation were significantly higher in patients with the CYP3A5*1 allele than in patients without the CYP3A5*1 allele.…”

“…Thus, it is important to identify the factors that account for this variability in order to support individualized drug therapy based on CYP3A activity after kidney transplantation. We have previously reported that CYP3A5 polymorphism and, to a lesser extent, accumulation of uraemic toxins, influence CYP3A activity in stable kidney transplant recipients [22]. Then, wide interindividual variability in the degree of increase in CYP3A activity after kidney transplantation may be explained by CYP3A5 polymorphism.…”

Elevated 4β‐hydroxycholesterol/cholesterol ratio in anorexia nervosa patients

“…Genotyping of CYP3A4 and CYP3A5 would also have been of interest. Expression of the CYP3A5*1 allele has been associated with elevated 4βOHC levels, although a larger study did not find any association between 4βOHC levels and CYP3A5*3 or CYP3A4*22 polymorphisms . Other potential sources of inter‐individual variation in 4βOHC levels are ethnicity and inflammation …”

Microbiota-derived uremic retention solutes: perpetrators of altered nonrenal drug clearance in kidney disease

“…Indoxyl sulfate also inhibits CYP3A4 activity in human hepatocytes and microsomes, animal models and potentially in kidney disease patients [54–56]. Indoxyl sulfate plasma concentrations are inversely related to CYP3A4 activity measured by endogenous 4β-hydroxycholesterol formation in stable renal transplant patients [57]. Conversely, some reports suggest that indoxyl sulfate or other microbial toxins have no interactions with CYP3A4 activity or expression [53,58].…”