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

Abstract

Aims It has been reported that cytochrome P450 (CYP)3A activity increases significantly in patients with end stage renal disease (ESRD) after kidney transplantation, with wide interindividual variability in the degree of increase. The aim of this study was to evaluate the influence of CYP3A5 polymorphism on the increase in CYP3A activity after living kidney transplantation, by measuring the plasma concentration of 4β‐hydroxycholesterol. Methods This prospective study recruited 22 patients with ESRD who underwent a first living kidney allograft transplantation, comprising 12 patients with CYP3A5*1 allele (CYP3A5*1/*1 or *1/*3) and 10 patients without CYP3A5*1 allele (CYP3A5*3/*3). Results No significant difference in estimated glomerular filtration rate over time was observed between patients with the CYP3A5*1 allele and patients without the CYP3A5*1 allele, suggesting that the degrees of recovery in renal function after living kidney transplantation were similar in the two groups. However, plasma concentrations of 4β‐hydroxycholesterol on days 90 (57.1 ± 13.4 vs. 39.5 ± 10.8 ng ml−1) and 180 (55.0 ± 14.5 vs. 42.4 ± 12.6 ng ml−1) after living kidney transplantation were significantly higher in the presence of the CYP3A5*1 allele than in the absence of the CYP3A5*1 allele [P = 0.0034 (95% confidence interval of difference 6.55, 28.6) and P = 0.043 (95% confidence interval of difference 0.47, 24.8), respectively], suggesting that CYP3A activity may increase markedly associated with recovery of renal function in patients with the CYP3A5*1 allele. Conclusions These findings suggest that the presence of the CYP3A5*1 allele contributes to marked elevation of CYP3A activity associated with recovery of renal function after kidney transplantation.

Sensitive UHPLC-MS/MS quantification method for 4β- and 4α-hydroxycholesterol in plasma for accurate CYP3A phenotyping

“…The validated UHPLC-MS/MS method was used to measure plasma 4β-OHC and 4α-OHC concentrations in healthy volunteers and CKD patients. Plasma 4β-OHC concentrations in this study were similar to previously reported values in healthy volunteers ( 11 , 22 , 23 , 27 ), stage 3–5 CKD patients ( 18 , 21 ), and stage 5D CKD patients ( 17 , 19 ). Plasma 4α-OHC concentrations in healthy volunteers in this study were also similar to previous reports ( 11 , 22 , 27 ).…”

“…4β-OHC is slowly metabolized by CYP7A1 ( 14 ), and CYP7A1 activity is not affected by kidney failure ( 15 ). Therefore, plasma 4β-OHC concentration is a suitable probe for CYP3A phenotyping in infants, elderly people, and patients with kidney failure or liver diseases including cirrhosis ( 16 , 17 , 18 , 19 , 20 , 21 ).…”

Association of CYP3A5 polymorphisms and parathyroid hormone with blood level of tacrolimus in patients with end‐stage renal disease

“…In general, it is not possible to prove to what extent the reduced CYP3A activity observed in animal studies is attributed to the relative expression levels of CYP3A4 and CYP3A5 in humans. Suzuki et al 29 suggested that CYP3A activity may increase markedly with recovery of renal function in patients with the CYP3A5*1 allele, or that CYP3A activity may not decrease remarkably during renal failure in patients without the CYP3A5*1 allele. Thus, we speculate that CYP3A activity in CYP3A5 nonexpressors is not affected by uremic toxins accumulated in renal failure.…”

CYP3A5 Gene-Guided Tacrolimus Treatment of Living-Donor Egyptian Kidney Transplanted Patients

“…CYP3A5*3 allele results in alternative spicing of the mRNA which leads to absence of CYP3A5 protein activity and is associated with reduced tacrolimus dose requirement ( Ferraris et al., 2011 ). The presence of the wild-type allele ( CYP3A5*1 ) contributes significantly to the increase of CYP3A activity associated with recovery of renal function after transplantation ( Suzuki et al., 2015 ). Two more variant alleles, CYP3A5*6 and CYP3A5*7 , result also at loss of expression of the functional protein in homozygotes ( Birdwell et al., 2015 ).…”