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 antiin-flammatory 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.

Expression ofUDP-Glucuronosyltransferase 1(UGT1) and Glucuronidation Activity toward Endogenous Substances in HumanizedUGT1Mouse Brain

“…In the hUGT1 mice, UGT1A1, 1A3, 1A6, and 1A10 were expressed in the brain (Fig. 1B), which was in agreement with our previous study (Sakamoto et al, 2015). The expression pattern of UGT1As in the brain was very similar between human and hUGT1 mice (Fig.…”

Bioaccessibility and bioavailability of phenolic compounds

“…Herein, genistein-7-glucoside has a higher affinity for β-glucosidase than quercetin-4′-glucoside thus the former shows a higher deglycosylation rate, whereas some other glycosides such as quercetin-3,4′-diglucoside, quercetin-3-glucoside, kaempferol-3-glucoside, quercetin-3-rhamnoglucoside, and naringenin-7-rhamnoglucoside prefer to remain unchanged (Day et al, 1998). This intracellular reaction is regarded as a vital way to expose hydroxyl group of xenobiotics for further conjugation Cheng et al (1999), Margaillan et al (2015), Wong et al (2009), Finel et al (2005), King et al (1999), Mostaghel et al (2016), King et al (2000), Teubner et al (2007), Cheng et al (1998), Cheng et al (1999), Barbier et al (2000), Knights et al (2013), Chimalakonda et al (2011), Riches et al (2009), Ghosh et al (2013), Sakamoto et al (2015), Lu et al (2015), Guidry et al (2017), Kurogi et al (2017),…”

Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans

“…Subsequently, it was demonstrated that treatments of hUGT1 mice with TCDD, PCN, phenytoin, and fatty acids caused induction of human UGT1A1 in the liver, indicating that the promoter region of human UGT1A1 in hUGT1 mice is responsive to AhR, PXR, and PPAR activations as well [11,34,52]. It was also shown that human UGT1A isoforms expressed in extrahepatic tissues such as small intestine, skin, and brain were inducible by xenobiotics in hUGT1 mice [53–55]. hUGT1 mice were also useful to understand the transcriptional regulation of human UGT1A isoforms in the liver during pregnancy [56].…”