title: Intestinal glucuronidation protects against chemotherapy-induced toxicity by irinotecan (CPT-11).
abstract: Camptothecin (CPT)-11 (irinotecan) has been used widely for cancer treatment, particularly metastatic colorectal cancer. However, up to 40% of treated patients suffer from severe late diarrhea, which prevents CPT-11 dose intensification and efficacy. CPT-11 is a prodrug that is hydrolyzed by hepatic and intestinal carboxylesterase to form SN-38, which in turn is detoxified primarily through UDP-glucuronosyltransferase 1A1 (UGT1A1)-catalyzed glucuronidation. To better understand the mechanism associated with toxicity, we generated tissue-specific Ugt1 locus conditional knockout mouse models and examined the role of glucuronidation in protecting against irinotecan-induced toxicity. We targeted the deletion of the Ugt1 locus and the Ugt1a1 gene specifically in the liver (Ugt1(ΔHep)) and the intestine (Ugt1(ΔGI)). Control (Ugt1(F/F)), Ugt1(ΔHep), and Ugt1(ΔGI) adult male mice were treated with different concentrations of CPT-11 daily for four consecutive days. Toxicities were evaluated with regard to tissue glucuronidation potential. CPT-11-treated Ugt1(ΔHep) mice showed a similar lethality rate to the CPT-11-treated Ugt1(F/F) mice. However, Ugt1(ΔGI) mice were highly susceptible to CPT-11-induced diarrhea, developing severe and lethal mucositis at much lower CPT-11 doses, a result of the proliferative cell loss and inflammation in the intestinal tract. Comparative expression levels of UGT1A1 in intestinal tumors and normal surrounding tissue are dramatically different, providing for the opportunity to improve therapy by differential gene regulation. Intestinal expression of the UGT1A proteins is critical toward the detoxification of SN-38, whereas induction of the UGT1A1 gene may serve to limit toxicity and improve the efficacy associated with CPT-11 treatment.
authors.affiliation: Laboratory of Environmental Toxicology, Departments of Chemistry and Biochemistry and Pharmacology, and Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, La Jolla, CA 92023.
authors.forename: Shujuan
authors.initials: S
authors.lastname: Chen
authors.forename: Mei-Fei
authors.initials: MF
authors.lastname: Yueh
authors.forename: Cyril
authors.initials: C
authors.lastname: Bigo
authors.forename: Olivier
authors.initials: O
authors.lastname: Barbier
authors.forename: Kepeng
authors.initials: K
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Nghia
authors.initials: N
authors.lastname: Nguyen
authors.forename: Robert H
authors.initials: RH
authors.lastname: Tukey
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020723:Glucuronic Acid / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006652:Histological Techniques; D015151:Immunoblotting; D007413:Intestinal Mucosa / Q000378:metabolism*; D000077146:Irinotecan; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099148:UGT1A1 Enzyme
chemical_list: D002166:Camptothecin; D020723:Glucuronic Acid; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme