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 CochranMantel-Haenszel, Mann-Whitney, and C 2 tests.

Prevalence of Clinically Relevant UGT1A Alleles and Haplotypes in African Populations

“…For drugs, such as irinotecan, a combination of (TA) 7 and functional SNPs in other UGT1A isoforms, such as UGT1A7, has been proposed to be a better predictor of drug toxicity (Lankisch et al, 2008), but these coexist on the same haplotype (CA7) so that the whole haplotype is predictive of risk, and it is hard to separate the effects of the TATA box variation from that of other functional SNPs. In the African populations studied here the situation is quite different and recombination has separated the low-activity alleles.…”

Genetic and biochemical study of dual hereditary jaundice: Dubin–Johnson and Gilbert’s syndromes. Haplotyping and founder effect of deletion in ABCC2

“…Certain drug precautions should be taken in advance of pharmacotherapy in patients with dual hereditary jaundice including irinotecan, atazanavir, cisplatin, vincristine or doxorubicin to prevent its toxicity or sensitivity. 28,29 Coproporphyrin Urinary excretion of coproporphyrin reflects the heme degradation and excreted isomers are presented as isomers I-IV with the most significant isomers I and III. The proportion of coproporphyrin isomer III in urine samples of healthy adults is 70-80%, compared with~20-30% in DJS patients, who excrete about 80-97% of coproporphyrin I.…”

Shared Regulation of UGT1A7 by Hepatocyte Nuclear Factor (HNF) 1α and HNF4α

“…UGT1A7 is of interest because of its ability to detoxify environmental carcinogens, such as hydroxylated benzo [a]pyrenes and N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (Nowell et al, 1998;Bock et al, 1999;Strassburg et al, 1999). Low-activity variants of UGT1A7 have been linked to cancer (reviewed in Nagar and Remmel, 2006) and drug side effects (Lankisch et al, 2008b;Cecchin et al, 2009). An elucidation of the underlying molecular mechanisms for tissuespecific expression, transcriptional control, and interindividual variability is required to appreciate the potential impact of UGT1A7 on susceptibility to cancer and drug toxicity (Urquhart et al, 2007;Gardner-Stephen and Mackenzie, 2008).…”