Comparison of Serotonin Glucuronidation Activity of UDP-glucuronosyltransferase 1a6a (Ugt1a6a) and Ugt1a6b: Evidence for the Preferential Expression of Ugt1a6a in the Mouse Brain

Uchihashi, Shinsuke; Nishikawa, Miyu; Sakaki, Toshiyuki; Ikushiro, Shinichi

doi:10.2133/dmpk.dmpk-12-nt-091

Cited by 9 publications

(12 citation statements)

References 28 publications

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“…Although historically a source of significant debate (36,44,48,49), recent reports have shown that serotonin can potentiate GIIS through autocrine activation of serotonin receptor 3a following secretion (30,31,42) or receptor-independent intracellular protein serotonylation (44). Serotonin is also the only endogenous metabolite in the pathway that mouse UGT1A6A is known to target (4,54). It is unlikely that the products of serotonin metabolism downstream of AANAT activity (N-acetylserotonin, melatonin, and 6-hydroxymelatonin) are involved, as Aanat expression in our model was nearly undetectable.…”

Section: Discussionmentioning

confidence: 99%

Arsenic modifies serotonin metabolism through glucuronidation in pancreatic β-cells

Carmean

Yokoi

Takahashi

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

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In arsenic-endemic regions of the world, arsenic exposure correlates with diabetes mellitus. Multiple animal models of inorganic arsenic (iAs, as As3+) exposure have revealed that iAs-induced glucose intolerance manifests as a result of pancreatic β-cell dysfunction. To define the mechanisms responsible for this β-cell defect, the MIN6-K8 mouse β-cell line was exposed to environmentally relevant doses of iAs. Exposure to 0.1–1 µM iAs for 3 days significantly decreased glucose-induced insulin secretion (GIIS). Serotonin and its precursor, 5-hydroxytryptophan (5-HTP), were both decreased. Supplementation with 5-HTP, which loads the system with bioavailable 5-HTP and serotonin, rescued GIIS, suggesting that recovery of this pathway was sufficient to restore function. Exposure to iAs was accompanied by an increase in mRNA expression of UDP-glucuronosyltransferase 1 family, polypeptide a6a ( Ugt1a6a), a phase-II detoxification enzyme that facilitates the disposal of cyclic amines, including serotonin, via glucuronidation. Elevated Ugt1a6a and UGT1A6 expression levels were observed in mouse and human islets, respectively, following 3 days of iAs exposure. Consistent with this finding, the enzymatic rate of serotonin glucuronidation was increased in iAs-exposed cells. Knockdown by siRNA of Ugt1a6a during iAs exposure restored GIIS in MIN6-K8 cells. This effect was prevented by blockade of serotonin biosynthesis, suggesting that the observed iAs-induced increase in Ugt1a6a affects GIIS by targeting serotonin or serotonin-related metabolites. Although it is not yet clear exactly which element(s) of the serotonin pathway is/are most responsible for iAs-induced GIIS dysfunction, this study provides evidence that UGT1A6A, acting on the serotonin pathway, regulates GIIS under both normal and pathological conditions.

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Section: Discussionmentioning

confidence: 99%

Arsenic modifies serotonin metabolism through glucuronidation in pancreatic β-cells

Carmean

Yokoi

Takahashi

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

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“…UGT2B7 also exhibited very low activity towards this substrate (King et al, 1999 ). The recombinant mouse Ugt1a6a and Ugt1a6b isoforms were able to glucuronidate 5-HT with approximately same efficiencies (Uchihashi et al, 2013 ). Since Ugt1a6a was predominantly expressed in mouse brain, especially in the hippocampus, it was proposed that this isoform is involved in the glucuronidation 5-HT in mouse brain.…”

Section: Role Of Glucuronidation In the Metabolism Of Neurotransmittementioning

confidence: 99%

The UDP-glucuronosyltransferases of the blood-brain barrier: their role in drug metabolism and detoxication

Ouzzine

Gulberti

Ramalanjaona

et al. 2014

Front. Cell. Neurosci.

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UDP-glucuronosyltransferases (UGTs) form a multigenic family of membrane-bound enzymes expressed in various tissues, including brain. They catalyze the formation of β-D-glucuronides from structurally unrelated substances (drugs, other xenobiotics, as well as endogenous compounds) by the linkage of glucuronic acid from the high energy donor, UDP-α-D-glucuronic acid. In brain, UGTs actively participate to the overall protection of the tissue against the intrusion of potentially harmful lipophilic substances that are metabolized as hydrophilic glucuronides. These metabolites are generally inactive, except for important pharmacologically glucuronides such as morphine-6-glucuronide. UGTs are mainly expressed in endothelial cells and astrocytes of the blood brain barrier (BBB). They are also associated to brain interfaces devoid of BBB, such as circumventricular organ, pineal gland, pituitary gland and neuro-olfactory tissues. Beside their key-role as a detoxication barrier, UGTs play a role in the steady-state of endogenous compounds, like steroids or dopamine (DA) that participate to the function of the brain. UGT isoforms of family 1A, 2A, 2B and 3A are expressed in brain tissues to various levels and are known to present distinct but overlapping substrate specificity. The importance of these enzyme species with regard to the formation of toxic, pharmacologically or physiologically relevant glucuronides in the brain will be discussed.

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“…1) A few studies have also reported the presence of UGT isoforms in brain tissue, neurons, and astrocytes. [2][3][4] Therefore, it is expected that UGT1As would be involved in the metabolism of several drugs that have pharmacological effects in the brain, such as acetaminophen, 5) amitriptyline, 6) and valproic acid. 7) UGT1As also have potential to catalyze the glucuronidation of neurotransmitters and neurosteroids, such as serotonin, 8) dopamine, 9) and estradiol.…”

mentioning

confidence: 99%

Effects of β-Naphthoflavone on Ugt1a6 and Ugt1a7 Expression in Rat Brain

Sakakibara

Katoh

Kondo

et al. 2016

Biological & Pharmaceutical Bulletin

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Uridine 5′-diphosphate-glucuronosyltransferase (UGT) catalyzes a major phase II reaction in a drugmetabolizing enzyme system. Although the UGT1A subfamily is expressed mainly in the liver, it is also expressed in the brain. The purpose of the present study was to elucidate the effect of β-naphthoflavone (BNF), one of the major inducers of drug-metabolizing enzymes, on Ugt1a6 and Ugt1a7 mRNA expression and their glucuronidation in the rat brain. Eight-week-old male Sprague-Dawley rats were treated intraperitoneally with BNF (80 mg/kg), once daily for 7 d. Ugt1a6 and Ugt1a7 mRNA expression increased in the cerebellum and hippocampus (Ugt1a6: 2.1-and 2.3-fold, respectively; Ugt1a7: 1.7-and 2.8-fold, respectively); acetaminophen glucuronidation also increased in the same regions by 4.1-and 2.7-fold, respectively. BNF induced Ugt1a6 and Ugt1a7 mRNA expression and their glucuronidation, and the degree of induction differed among 9 regions. BNF also upregulated CYP1A1, CYP1A2, and CYP1B1 mRNAs in the rat brain. Since the aryl hydrocarbon receptor signaling pathway was activated by BNF, it is indicated that Ugt1a6 and Ugt1a7 were induced via AhR in the rat brain. This study clarified that Ugt1a6 and Ugt1a7 mRNA expression and their enzyme activities were altered by BNF, suggesting that these changes may lead to alteration in the pharmacokinetics of UGT substrate in rat brain.

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Comparison of Serotonin Glucuronidation Activity of UDP-glucuronosyltransferase 1a6a (Ugt1a6a) and Ugt1a6b: Evidence for the Preferential Expression of Ugt1a6a in the Mouse Brain

Cited by 9 publications

References 28 publications

Arsenic modifies serotonin metabolism through glucuronidation in pancreatic β-cells

Arsenic modifies serotonin metabolism through glucuronidation in pancreatic β-cells

The UDP-glucuronosyltransferases of the blood-brain barrier: their role in drug metabolism and detoxication

Effects of β-Naphthoflavone on Ugt1a6 and Ugt1a7 Expression in Rat Brain

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