Abstract
BackgroundTacrolimus is the first-line immunosuppressant after organ transplantation. It is mainly metabolized by cytochrome P450, family 3, subfamily A (CYP3A) enzymes, but there are large individual differences in metabolism. Interleukin 6 (IL6) has been shown to cause a pan-suppression of mRNA levels of ten major CYP enzymes in human hepatocyte cultures. IL6 has been shown to provide hepatoprotection in various models of liver injury. Rs1800796 is a locus in the IL6 gene promoter region which regulates cytokine production. We speculated that IL6 rs1800796 polymorphisms may lead to individual differences in tacrolimus metabolism by affecting CYP3A enzymes levels and liver function after liver transplantation.Methodology/Principal FindingsNinety-six liver transplant patients receiving tacrolimus were enrolled in the study. Two single nucleotide polymorphisms (SNP), CYP3A5 rs776746 and IL6 rs1800796, were genotyped in both donors and recipients. The effects of SNPs on tacrolimus concentration/dose (C/D ratio) at four weeks after transplantation were studied, as well as the effects of donor IL6 rs1800796 polymorphisms on liver function. Both donor and recipient CYP3A5 rs776746 allele A showed association with lower C/D ratios, while donor IL6 rs1800796 allele G showed an association with higher C/D ratios. Donor CYP3A5 rs776746 allele A, IL6 rs1800796 allele C, and recipient CYP3A5 rs776746 allele A were associated with fast tacrolimus metabolism. With increasing numbers of these alleles, patients were found to have increasingly lower tacrolimus C/D ratios at time points after transplantation. Donor IL6 rs1800796 allele G carriers showed an association with higher glutamic-pyruvic transaminase (GPT) levels.ConclusionsCombined analysis of donor CYP3A5 rs776746, IL6 rs1800796, and recipient CYP3A5 rs776746 polymorphisms may distinguish tacrolimus metabolism better than CYP3A5 rs776746 alone. IL6 may lead to individual differences in tacrolimus metabolism mainly by affecting liver function.
Highlights
Tacrolimus is the first-line immunosuppressant after organ transplantation, reducing rejection and improving graft and recipient survival
Interleukin 6 (IL6) may lead to individual differences in tacrolimus metabolism mainly by affecting liver function
In a study by Birdwell et al, eight single nucleotide polymorphisms (SNP) in the CYP3A4 gene and one in the CYP3A7 gene were found to be associated with tacrolimus metabolism, but these SNPs were in linkage disequilibrium with CYP3A5 rs776746 [12]
Summary
Tacrolimus is the first-line immunosuppressant after organ transplantation, reducing rejection and improving graft and recipient survival. It is characterized by a narrow therapeutic window, and large individual differences in metabolism [1,2]. It is difficult to institute individualized medicine in the early postoperative period Genetic factors such as polymorphisms can be closely related to drug metabolism. Pharmacogenomics research on tacrolimus could contribute to individualized medication in the early postoperative period of liver transplantation. Tacrolimus is the first-line immunosuppressant after organ transplantation It is mainly metabolized by cytochrome P450, family 3, subfamily A (CYP3A) enzymes, but there are large individual differences in metabolism. We speculated that IL6 rs1800796 polymorphisms may lead to individual differences in tacrolimus metabolism by affecting CYP3A enzymes levels and liver function after liver transplantation
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