title: Gilbert's Syndrome and irinotecan toxicity: combination with UDP-glucuronosyltransferase 1A7 variants increases risk.
abstract: BACKGROUND
  Gilbert's syndrome is characterized by a functional promoter single nucleotide polymorphism (SNP) of the UDP-glucuronosyltransferase (UGT) 1A1 gene and represents a pharmacogenetic risk factor for irinotecan toxicity, but study data remain controversial. The active CPT-11 metabolite 7-ethyl-10-hydroxycamptothecin is detoxified by several UGT1A proteins, which include UGT1A7 with a high specific activity that may contribute to the risk of irinotecan toxicity in Gilbert's syndrome patients.
  
  
  METHODS
  Genotyping of the UGT1A1*28, UGT1A7 N129K/R131K, and UGT1A7-57T/G variants was done in 105 irinotecan-treated patients with metastatic colorectal cancer; adverse events were documented during all 297 treatment cycles and analyzed by Cochran-Mantel-Haenszel, Mann-Whitney, and chi2 tests.
  
  
  RESULTS
  The presence of UGT1A7 but not UGT1A1 variants was associated with at least one adverse event. In patients combining all three variants, thrombocytopenia and leukopenia were significantly more frequent. The overall incidence of adverse events was significantly higher (P = 0.0035) in carriers of the UGT1A risk alleles, who also had significantly higher rate of dose reductions.
  
  
  CONCLUSIONS
  Irinotecan toxicity is more likely in patients with Gilbert's syndrome carrying the UGT1A1*28 allele combined with reduced function UGT1A7 N129K/R131K and UGT1A7-57T/G SNP. Based on the ability of UGT1A7 to metabolize and eliminate the active irinotecan metabolite 7-ethyl-10-hydroxycamptothecin, the UGT1A1/UGT1A7 SNP combination haplotype appears to be a superior risk predictor than Gilbert's syndrome alone.
authors: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors: Tim O
authors: TO
authors: Lankisch
authors: Christoph
authors: C
authors: Schulz
authors: Thomas
authors: T
authors: Zwingers
authors: Thomas J
authors: TJ
authors: Erichsen
authors: Michael P
authors: MP
authors: Manns
authors: Volker
authors: V
authors: Heinemann
authors: Christian P
authors: CP
authors: Strassburg
mesh_terms: D000483:Alleles; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000633:toxicity; D016009:Chi-Square Distribution; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005878:Gilbert Disease / Q000201:enzymology* / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D018709:Statistics, Nonparametric
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D014453:Glucuronosyltransferase; D002166:Camptothecin