title: Nicotine regulates the expression of UDP-glucuronosyltransferase (UGT) in humanized UGT1 mouse brain.
abstract: UDP-glucuronosyltransferase (UGT) is a family of enzymes that catalyze the glucuronidation of various compounds, and thereby has an important role in metabolism and detoxification of a large number of xenobiotic and endogenous compounds. UGTs are present highly in the liver and small intestine, while several investigations on quantification of UGT mRNA reported that UGTs were also expressed in the brain. However, reported expression patterns of UGT isoforms in human brain were often incongruous with each other. In the present study, therefore, we investigated UGT mRNA expressions in brains of humanized UGT1 (hUGT1) mice. We found that among the human UGT1 members, UGT1A1, 1A3, and 1A6 were expressed in the brain. We further observed that nicotine (3 mg/kg) induced the expression of UGT1A3 mRNA in the brain, but not liver. While it was not statistically significant, the nicotine treatment resulted in an increase in the chenodeoxycholic acid glucuronide-formation activity in the brain microsomes. UGT1A3 is involved in metabolism of various antidepressants and non-steroidal antiinflammatory drugs, which exhibit their pharmacological effects in the brain. Therefore, nicotine-treated hUGT1 mice might be useful to investigate the role of brain UGT1A3 in the regulation of local levels of these drugs and their response.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Sakamoto
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Itoh
authors.affiliation: Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Tukey
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. Electronic address: fujiwarar@pharm.kitasato-u.ac.jp.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000378:metabolism*; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D009538:Nicotine / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D020719:Glucuronides; D012333:RNA, Messenger; D009538:Nicotine; D014453:Glucuronosyltransferase
keywords: Brain; Humanized animal model; Nicotine; Tissue-specific regulation; UDP-glucuronosyltransferase (UGT)