title: Impact of cytochrome P450 3A5 polymorphism in graft livers on the frequency of acute cellular rejection in living-donor liver transplantation.
abstract: OBJECTIVE
  We investigated whether the cytochrome P450 3A5*3 (CYP3A5*3) genotype affects tacrolimus pharmacokinetics and the risk of acute cellular rejection in living-donor liver transplant patients in Japan.
  
  
  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 CYP3A5*1 allele vs. 7.4% for CYP3A5*3/*3; P=0.2643), although the concentration/dose ratio of tacrolimus was significantly higher in patients with the intestinal CYP3A5*3/*3 genotype than in those with the CYP3A5*1 allele for 5 post-transplant weeks. However, patients who received a graft liver with the CYP3A5*1 allele showed a higher rate of acute cellular rejection than those who received a graft liver with the CYP3A5*3/*3 genotype (14.5 vs. 5.7%; P=0.0134). The relative risk for acute cellular rejection associated with the CYP3A5*1 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.
authors.affiliation: aDepartment of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Faculty of Medicine bDepartment of Surgery and Pediatric Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Uesugi
authors.forename: Mio
authors.initials: M
authors.lastname: Kikuchi
authors.forename: Haruka
authors.initials: H
authors.lastname: Shinke
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Omura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yonezawa
authors.forename: Kazuo
authors.initials: K
authors.lastname: Matsubara
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Fujimoto
authors.forename: Shinya
authors.initials: S
authors.lastname: Okamoto
authors.forename: Toshimi
authors.initials: T
authors.lastname: Kaido
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
authors.forename: Satohiro
authors.initials: S
authors.lastname: Masuda
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007223:Infant; D007413:Intestinal Mucosa / Q000473:pathology; D007564:Japan; D017093:Liver Failure / Q000628:therapy*; D016031:Liver Transplantation / Q000379:methods*; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012307:Risk Factors; D016559:Tacrolimus / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus