Determination of Serotonin and Dopamine Metabolites in Human Brain Microdialysis and Cerebrospinal Fluid Samples by UPLC-MS/MS: Discovery of Intact Glucuronide and Sulfate Conjugates

Suominen, Tina; Uutela, Päivi; Ketola, Raimo A.; Bergquist, Jonas; Hillered, Lars; Finel, Moshe; Zhang, Hongbo; Laakso, Aki; Kostiainen, Risto

doi:10.1371/journal.pone.0068007

Cited by 57 publications

(50 citation statements)

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“…Glucuronic acid conjugates of neurotransmitters, such as serotonin (5-HT) and dopamine (DA), were detected in cerebrospinal fluid (CSF) and microdialysis samples of humans and rats [36–38]. Glucuronic acid conjugates of steroids were also detected in the mouse brain extract [39].…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…37) Moreover, it has been reported that the glucuronide of the monoamine neurotransmitters, dopamine and serotonin, had been observed in human and rat brains. [38][39][40] Maintaining the proper concentration of a substance in a target site (specific brain region or neurons) is important to perform an effective and safe drug therapy or to maintain homeostasis. The changes in UGT expression in the target site could affect pharmacological and physiological functions owing to the alteration in the concentration of the drugs and neurotransmitters in the brain.…”

Section: )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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“…Recent work reveals that sulfoconjugates predominate among serotonin metabolites in fluids extracted from brain cortices of living humans and are major metabolites in brain-ventricle and spinal fluids (61). Studies using subsections of rat brain reveal that MAO inhibition routes dopamine metabolism substantially through the sulfonation pathway and demonstrate the interactivity of the MAO and SULT systems (62,63).…”

Section: Discussionmentioning

confidence: 99%

Tetrahydrobiopterin regulates monoamine neurotransmitter sulfonation

Cook

Wang

Leyh

2017

Proc. Natl. Acad. Sci. U.S.A.

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Monoamine neurotransmitters are among the hundreds of signaling small molecules whose target interactions are switched "on" and "off" via transfer of the sulfuryl-moiety (-SO 3 ) from PAPS (3′-phosphoadenosine 5′-phosphosulfate) to the hydroxyls and amines of their scaffolds. These transfer reactions are catalyzed by a small family of broad-specificity enzymes-the human cytosolic sulfotransferases (SULTs). The first structure of a SULT allosteric-binding site (that of SULT1A1) has recently come to light. The site is conserved among SULT1 family members and is promiscuous-it binds catechins, a naturally occurring family of flavanols. Here, the catechin-binding site of SULT1A3, which sulfonates monoamine neurotransmitters, is modeled on that of 1A1 and used to screen in silico for endogenous metabolite 1A3 allosteres. Screening predicted a single high-affinity allostere, tetrahydrobiopterin (THB), an essential cofactor in monoamine neurotransmitter biosynthesis. THB is shown to bind and inhibit SULT1A3 with high affinity, 23 (±2) nM, and to bind weakly, if at all, to the four other major SULTs found in brain and liver. The structure of the THB-bound binding site is determined and confirms that THB binds the catechin site. A structural comparison of SULT1A3 with SULT1A1 (its immediate evolutionary progenitor) reveals how SULT1A3 acquired high affinity for THB and that the majority of residue changes needed to transform 1A1 into 1A3 are clustered at the allosteric and active sites. Finally, sequence records reveal that the coevolution of these sites played an essential role in the evolution of simian neurotransmitter metabolism.sulfotransferase | tetrahydrobiopterin | neurotransmitter | allostery | evolution H uman cytosolic sulfotransferases (SULTs) regulate the activities of thousands of endogenous small-molecule metabolites and xenobiotics via transfer of the sulfuryl-moiety (-SO 3 ) to and from the hydroxyl-and amine-moieties of these acceptors. The 13 full-length SULT isoforms encoded in the human genome are expressed in tissue-and developmentally specific patterns (1-3). SULT substrate specificities are typically broad, overlapping, and centered on different areas of metabolism. The diversity of function across SULT isoforms results in a remarkably broad range of metabolic functions including potent regulation of steroids (4), thyroid (5) and peptide hormones (6), oxysterols (7), pheromones (8), selectins (9), and neurotransmitters (10, 11).Although recent work has deepened our understanding of SULT small-molecule allosteric regulation, the topic remains largely unexplored (12-16). The catechin-binding site is the most well-characterized SULT allosteric site (12). Catechins, a complex biomorphic family of SULT allosteric inhibitors, are found at high levels in tea leaves, cocoa, and coffee (17-19). The binding site is promiscuous in that it binds numerous catechins (15, 20) and related structures. The structure of the SULT1A1 catechin-binding site, the only published SULT allosteric-site structure, has recentl...

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Determination of Serotonin and Dopamine Metabolites in Human Brain Microdialysis and Cerebrospinal Fluid Samples by UPLC-MS/MS: Discovery of Intact Glucuronide and Sulfate Conjugates

Cited by 57 publications

References 50 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

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

Tetrahydrobiopterin regulates monoamine neurotransmitter sulfonation

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