Impact of cytochrome P450 3A5 polymorphism in graft livers on the frequency of acute cellular rejection in living-donor liver transplantation.

OBJECTIVE

We investigated whether the cytochrome P450 3A53 (CYP3A53) genotype affects tacrolimus pharmacokinetics and the risk of acute cellular rejection in living-donor liver transplant patients in Japan.

MATERIALS AND METHODS

Between July 2004 and June 2011, we enrolled 410 living-donor liver transplant patients receiving tacrolimus. Biopsy specimens of intestinal mucosa and graft liver at surgery were obtained to examine the mRNA expression of CYP3A subfamilies as well as the genotyping of CYP3A5*3 polymorphism.

RESULTS

The CYP3A5 genotype in the native intestine had no significant effect on the occurrence of acute cellular rejection between postoperative days 14 and 23 in cases with identical or compatible ABO blood types (11.5% for the CYP3A51 allele vs. 7.4% for CYP3A53/3; P=0.2643), although the concentration/dose ratio of tacrolimus was significantly higher in patients with the intestinal CYP3A53/3 genotype than in those with the CYP3A51 allele for 5 post-transplant weeks. However, patients who received a graft liver with the CYP3A51 allele showed a higher rate of acute cellular rejection than those who received a graft liver with the CYP3A53/3 genotype (14.5 vs. 5.7%; P=0.0134). The relative risk for acute cellular rejection associated with the CYP3A51 liver allele was 2.629 (P=0.018, Cox regression model). Consequently, graft liver CYP3A5*1 genotype might increase the risk for acute cellular rejection after living-donor liver transplantation, possibly by associating with the local hepatic tacrolimus concentration.

CONCLUSIONS

The target level of tacrolimus may be affected by the CYP3A5*3 genotype of the liver, rather than by that of the small intestine, after postoperative day 14.