UGT2B Gene Expression Analysis in Multiple Tobacco Carcinogen-Targeted Tissues

Jones, Nathan R.; Lazarus, Philip

doi:10.1124/dmd.113.054718

Cited by 29 publications

(38 citation statements)

References 53 publications

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“…However, the reported expression patterns of UGT in human brain were often incongruous with each other [3–5]. In the present study, the expressions of UGT1A1, 1A3, and 1A6 mRNAs were detected in the brain of hUGT1 mouse by RT-qPCR among the UGT1A members, which is relatively in agreement with a previous report by Court et al [4].…”

Section: Discussionsupporting

confidence: 91%

“…Court et al reported that UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A10, 2A2, 2A3, 2B7, 2B11, and 2B17 mRNAs were detected in human brain [4]. Jones et al reported that among the UGT2B family members, UGT2B4, 2B10, 2B11, 2B15, and 2B17 mRNAs were detected in the human brain [5]. These data indicate that reported UGT expression patterns in human brain were often incongruous with each other.…”

Section: Introductionmentioning

confidence: 62%

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Nicotine regulates the expression of UDP-glucuronosyltransferase (UGT) in humanized UGT1 mouse brain

Sakamoto

Itoh

Tukey

et al. 2015

Drug Metabolism and Pharmacokinetics

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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.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 62%

Nicotine regulates the expression of UDP-glucuronosyltransferase (UGT) in humanized UGT1 mouse brain

Sakamoto

Itoh

Tukey

et al. 2015

Drug Metabolism and Pharmacokinetics

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“…Given that the UGT2B gene subfamily exhibits .70% DNA sequence homology with one another (Riedy et al, 2000;Guillemette et al, 2010), they appear to have evolutionarily arisen through successive rounds of gene duplication and replication slippage. All UGT2B isoforms, excluding UGT2B28, are well expressed in the liver in addition to extrahepatic tissues involved in metabolism, including stomach, colon, small intestine, and kidney (Nakamura et al, 2008;Ohno and Nakajin, 2009;Jones and Lazarus, 2014). In addition, several UGT2B isoforms are highly expressed in extrahepatic tissues locally influenced by UGT2B substrates.…”

Section: Introductionmentioning

confidence: 99%

Regulation of UGT2B Expression and Activity by miR-216b-5p in Liver Cancer Cell Lines

Dluzen

Sutliff

Chen

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The UDP-glucuronosyltransferase (UGT) 2B enzymes are important in the detoxification of a variety of endogenous and exogenous compounds, including many hormones, drugs, and carcinogens. Identifying novel mechanisms governing their expression is important in understanding patient-specific response to drugs and cancer risk factors. In silico prediction algorithm programs were used to screen for microRNAs (miRNAs) as potential regulators of UGT2B enzymes, with miR-216b-5p identified as a potential candidate. Luciferase data suggested the presence of a functional miR-216b-5p binding motif within the 39 untranslated regions of UGTs 2B7, 2B4, and 2B10. Overexpression of miR-216b-5p mimics significantly repressed UGT2B7 (P , 0.001) and UGT2B10 (P 5 0.0018) mRNA levels in HuH-7 cells and UGT2B4 (P , 0.001) and UGT2B10 (P 5 0.018) mRNA in Hep3B cells. UGT2B7 protein levels were repressed in both HuH-7 and Hep3B cells in the presence of increasing miR-216b-5p concentrations, corresponding with significant (P , 0.001 and P 5 0.011, respectively) decreases in glucuronidation activity against the UGT2B7-specific substrate epirubicin. Inhibition of endogenous miR-216b-5p levels significantly increased UGT2B7 mRNA levels in HuH-7 (P 5 0.021) and Hep3B (P 5 0.0068) cells, and increased epirubicin glucuronidation by 85% (P 5 0.057) and 50% (P 5 0.012) for HuH-7 and Hep3B cells, respectively. UGT2B4 activity against codeine and UGT2B10 activity against nicotine were significantly decreased in both HuH-7 and Hep3B cells (P , 0.001 and P 5 0.0048, and P 5 0.017 and P 5 0.043, respectively) after overexpression of miR-216b-5p mimic. This is the first evidence that miRNAs regulate UGT 2B7, 2B4, and 2B10 expression, and that miR-216b-5p regulation of UGT2B proteins may be important in regulating the metabolism of UGT2B substrates.

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“…In another study, relatively high UGT1A6 and 2A1 were reported in human lung parenchyma, comparable to human liver expression (Somers et al, 2007). A recent study evaluated UGT2B expression in the upper respiratory tract, and reported low expression of various UGT2B isozymes (2B4, 2B7, 2B10, 2B11, 2B15, and 2B17) in the human lung (Jones and Lazarus, 2014). SULT pulmonary expression has similarly been reported, with low expression overall; SULT1E1 levels in the lung were the highest, followed by SULT1A1, 1A3, 1B1, and 2A1 (Riches et al, 2009).…”

Section: Pulmonary Metabolism Of Resveratrol: In Vitro and In Vivomentioning

confidence: 90%

“…The key P450, UGT, SULT, and drug transporters known to be expressed in the human lung are depicted (PEPT, peptide transporter; SLCO, solute carrier organic anion transporter; OATP, organic anion-transporting polypeptide). Data compiled from previously published reports (Gallagher et al, 2007;Somers et al, 2007;Bosquillon, 2010;Anttila et al, 2011;Sharan and Nagar, 2013;Jones and Lazarus, 2014).…”

Section: Pulmonary Metabolism Of Resveratrol: In Vitro and In Vivomentioning

confidence: 99%

“Target-Site” Drug Metabolism and Transport

et al. 2015

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The recent symposium on "Target-Site" Drug Metabolism and Transport that was sponsored by the American Society for Pharmacology and Experimental Therapeutics at the 2014 Experimental Biology meeting in San Diego is summarized in this report. Emerging evidence has demonstrated that drug-metabolizing enzyme and transporter activity at the site of therapeutic action can affect the efficacy, safety, and metabolic properties of a given drug, with potential outcomes including altered dosing regimens, stricter exclusion criteria, or even the failure of a new chemical entity in clinical trials. Drug metabolism within the brain, for example, can contribute to metabolic activation of therapeutic drugs such as codeine as well as the elimination of potential neurotoxins in the brain. Similarly, the activity of oxidative and conjugative drug-metabolizing enzymes in the lung can have an effect on the efficacy of compounds such as resveratrol. In addition to metabolism, the active transport of compounds into or away from the site of action can also influence the outcome of a given therapeutic regimen or disease progression. For example, organic anion transporter 3 is involved in the initiation of pancreatic b-cell dysfunction and may have a role in how uremic toxins enter pancreatic b-cells and ultimately contribute to the pathogenesis of gestational diabetes. Finally, it is likely that a combination of target-specific metabolism and cellular internalization may have a significant role in determining the pharmacokinetics and efficacy of antibody-drug conjugates, a finding which has resulted in the development of a host of new analytical methods that are now used for characterizing the metabolism and disposition of antibody-drug conjugates. Taken together, the research summarized herein can provide for an increased understanding of potential barriers to drug efficacy and allow for a more rational approach for developing safe and effective therapeutics.

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UGT2B Gene Expression Analysis in Multiple Tobacco Carcinogen-Targeted Tissues

Cited by 29 publications

References 53 publications

Nicotine regulates the expression of UDP-glucuronosyltransferase (UGT) in humanized UGT1 mouse brain

Nicotine regulates the expression of UDP-glucuronosyltransferase (UGT) in humanized UGT1 mouse brain

Regulation of UGT2B Expression and Activity by miR-216b-5p in Liver Cancer Cell Lines

“Target-Site” Drug Metabolism and Transport

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