title: Proficient metabolism of irinotecan by a human intestinal carboxylesterase.
abstract: Irinotecan [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11)] is metabolized by esterases to yield the potent topoisomerase I poison 7-ethyl-10-hydroxycamptothecin. One of the major side effects observed with CPT-11 is gastrointestinal toxicity, and we supposed that this might be due to local activation of CPT-11 within the gut. Carboxylesterase (CE) activity was detected in human gut biopsies, and extracts of these tissues converted CPT-11 to 7-ethyl-10-hydroxycamptothecin in vitro. Expression of a human intestinal CE cDNA in COS-7 cells produced extracts that demonstrated proficient CPT-11 activation and conferred sensitivity of cells to CPT-11. These results suggest that gut toxicity from CPT-11 may be due in part to direct drug conversion by CEs present within the small intestine.
authors.affiliation: Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: R
authors.initials: R
authors.lastname: Khanna
authors.forename: C L
authors.initials: CL
authors.lastname: Morton
authors.forename: M K
authors.initials: MK
authors.lastname: Danks
authors.forename: P M
authors.initials: PM
authors.lastname: Potter
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000493:pharmacokinetics*; D001711:Biotransformation; D019556:COS Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D002265:Carboxylic Ester Hydrolases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D018076:DNA, Complementary / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D006801:Humans; D007422:Intestines / Q000201:enzymology*; D000077146:Irinotecan; D008099:Liver / Q000201:enzymology; D008969:Molecular Sequence Data; D011817:Rabbits; D017386:Sequence Homology, Amino Acid; D014162:Transfection
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018076:DNA, Complementary; D000077146:Irinotecan; D002265:Carboxylic Ester Hydrolases; D002166:Camptothecin