title: Nonsteroidal anti-inflammatory drugs and phenols glucuronidation in Caco-2 cells: identification of the UDP-glucuronosyltransferases UGT1A6, 1A3 and 2B7.
abstract: Glucuronidation of phenols (1-naphthol, 4-methylumbelliferone) and nonsteroidal anti-inflammatory drugs (NSAIDs) such as ketoprofen, naproxen and carprofen was investigated in human colon carcinoma Caco-2 cell clones. Glucuronidation of these substances was highly effective in microsomes of the clones PD-7 and TC-7, but much lower in the PF-11 clone. The activity increased up to a maximum after 21 days of culture. RT-PCR experiments indicated that the PD-7 and TC-7 clones expressed the UDP-glucuronosyltransferase (UGT) isoforms UGT1A6, UGT1A3 and UGT2B7, which could account for the glucuronidation of phenols and carboxylic acids observed. Beta-naphthoflavone stimulated by 2-fold the enzyme activity toward 1-naphthol in PD-7 and TC-7 clones, but not in PF-11 cells. This increase was parallel to that of the UGT1A6 mRNA level. Glucuronidation of ketoprofen was also sensitive to the inducing effect of beta-naphthoflavone. Actinomycin D and cycloheximide did not affect the induction of UGT1A6 by beta-naphthoflavone, but suppressed that of ketoprofen UGT. The UGT1A3 mRNA content was enhanced by beta-naphthoflavone; by contrast, that of UGT2B7 was insensitive to the inducer. In conclusion, several UGT isoforms of both families 1 and 2, which glucuronidate phenols and carboxylic NSAIDs, have been identified in Caco-2 cells. They are differently sensitive to beta-naphthoflavone.
authors.affiliation: Laboratoire de Pharmacologie and UMR 7561 CNRS--Université Henri Poincaré Nancy I, Faculté de Médecine, Vandoeuvre-lès-Nancy, France.
authors.forename: N
authors.initials: N
authors.lastname: Sabolovic
authors.forename: J
authors.initials: J
authors.lastname: Magdalou
authors.forename: P
authors.initials: P
authors.lastname: Netter
authors.forename: A
authors.initials: A
authors.lastname: Abid
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D018938:Caco-2 Cells; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020723:Glucuronic Acid / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010636:Phenols / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D015262:Xenobiotics / Q000378:metabolism; D019324:beta-Naphthoflavone / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D010636:Phenols; D015262:Xenobiotics; D019324:beta-Naphthoflavone; D020723:Glucuronic Acid; C122075:UDP-glucuronosyltransferase, UGT1A3; C110655:UDP-glucuronosyltransferase, UGT1A6; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase