Ugt1a is required for the protective effect of selenium against irinotecan-induced toxicity

Abstract

Purpose Irinotecan (CPT-11) is widely used for the treatment of patients with colorectal cancer. However, the adverse effects associated with the treatment have hindered the efficacies of irinotecan. We have shown that organic selenium compounds could significantly attenuate irinotecan-associated toxicity and enhance antitumor activity in xenograft tumor models. The objective of this study is to determine the role of a specific group of uridine diphosphate glucuronosyltransferases, which is coded by UGT1A, in detoxification process of irinotecan as well as selenium-associated protective effect against irinotecan-induced toxicity. Methods In this study, the toxicities of irinotecan, docetaxel and cisplatin in the Ugta1 mutant rats and their wild-type controls were compared. The plasma concentrations of irinotecan and SN-38 were measured. The modulatory effect of a selenium compound on irinotecan-induced toxicity was analyzed in these rats. Results We demonstrated that the maximum tolerated doses of irinotecan in the homozygous mutant rats were significantly lower than those in wild-type rats, 25 mg/kg × 1 vs. 200 mg/kg × 1, and 3 mg/kg/day × 3 vs. 100 mg/kg/day × 3, respectively. The enhanced sensitivity was specific to irinotecan and was not observed with other chemotherapeutic agents, such as docetaxel and cisplatin, where Ugt1a is not required for their metabolism. Our results also showed that selective protection against irinotecan induced toxicity by 5-methylselenocysteine was achieved in the wild-type rats but not in the Ugt1a null rats. Conclusion These data support the hypothesis that expression of UGT1A is critical for 5-methylselenocysteine to exert its protective effect against irinotecan-induced toxicity.

Carboxylesterase and UDP‐glucuronosyltransferases mediated metabolism of irinotecan: In vitro and in vivo insights from quantitative ultra‐performance liquid chromatography–mass spectrometry analysis

“…It is often divided into three phases: CPT‐11 is rapidly hydrolyzed by mammalian liver carboxylesterases types 1 and 2 (CES1/2) into SN‐38 in phase I (modification); in phase II (conjugation), under the catalysis of various hepatic and extrahepatic UDP‐glucuronosyltransferase 1A (UGT1A) isozymes, SN‐38 is catalyzed to SN‐38G; and then metabolites of CPT‐11 are excreted into the intestine via biliary excretion (elimination; Chen et al, ). Some studies have suggested that UGT1A plays an important role both in metabolism and in the detoxification of CPT‐11 (Cao, Durrani, Rustum, & Yu, ). It is noteworthy that β‐ glucuronidase enzyme, which is often secreted by intestinal microbiota, especially Escherichia coil , can catalyze SN‐38G dy‐glycosylation.…”