title: Association analysis of UGT1A genotype and haplotype with SN-38 glucuronidation in human livers.
abstract: OBJECTIVE
  7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan, is mainly eliminated hepatically through glucuronidation by UGT1A1 and UGT1A9 enzymes. This study comprehensively investigates the effects of UGT1A1 and UGT1A9 genetic polymorphism on SN-38 glucuronidation activity.
  
  
  METHODS
  Genetic polymorphisms and combinational haplotypes of UGT1A1 and UGT1A9, SN-38 glucuronidation activities, and protein levels of UGT1A1 and UGT1A9 were determined using a set of over 45 Chinese livers.
  
  
  RESULTS
  UGT1A1 reduced function variants UGT1A1*6, *28, *60 and *1B exhibited additive effect. The number of UGT1A1 reduced function alleles was associated with decreased SN-38G formation rates and UGT1A protein levels. UGT1A9 I399C>T and UGT1A9*1b, which were highly linked, were associated with increased SN-38 glucuronidation activity and UGT1A protein levels. However, further analysis based on UGT1A9-1A1 haplotypes confirmed that their increased effect was partly due to their close linkage with UGT1A1 reduced function alleles.
  
  
  CONCLUSIONS
  UGT1A1 genetic polymorphisms have a more important function in human liver SN-38 glucuronidation activity than UGT1A9. Original submitted 7 November 2013; Revision submitted 30 January 2014.
authors.affiliation: National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, 229 North Taibai Road, Xi'an 710069, China. cchen898@nwu.edu.cn.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Wang
authors.forename: Ting
authors.initials: T
authors.lastname: Bian
authors.forename: Tianbo
authors.initials: T
authors.lastname: Jin
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Aifen
authors.initials: A
authors.lastname: Lin
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism; D008040:Genetic Linkage / Q000235:genetics; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D015810:Linkage Disequilibrium / Q000235:genetics; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme
chemical_list: D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme; C000715591:UGT1A9 protein, human
keywords: Chinese; SN-38; UGT1A1; UGT1A9; genotype; haplotype; irinotecan