Distribution, properties, and inhibitor sensitivity of zebrafish catechol-O-methyl transferases (COMT)

Semenova, Svetlana; Rozov, Stanislav; Panula, Pertti

doi:10.1016/j.bcp.2017.08.017

Cited by 9 publications

(5 citation statements)

References 71 publications

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“…Quercetin 3-O-glucuronide is one of the most common quercetin metabolites produced by phase II biotransformation in small intestine and liver cells, besides sulfated and methylated derivatives [27]. Once in the kidney, the entry of quercetin metabolites in tubular cells takes place mainly through influx transporters in the basolateral membrane and transporters in the apical membrane via tubular reabsorption [28]. It has been reported that glucuronide conjugates, such as quercetin 3'-O-glucuronide, have a high affinity for OAT3, whereas quercetin 3-O-glucuronide and quercetin 7-O-glucuronide are weak substrates of OAT1 and OAT3 [29].…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Quercetin 3-O-Glucuronide against Cisplatin Cytotoxicity in Renal Tubular Cells

et al. 2022

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Quercetin, a flavonoid with promising therapeutic potential, has been shown to protect from cisplatin nephrotoxicity in rats following intraperitoneal injection, but its low bioavailability curtails its prospective clinical utility in oral therapy. We recently developed a micellar formulation (P-quercetin) with enhanced solubility and bioavailability, and identical nephroprotective properties. As a first aim, we herein evaluated the oral treatment with P-quercetin in rats, which displayed no nephroprotection. In order to unravel this discrepancy, quercetin and its main metabolites were measured by HPLC in the blood and urine after intraperitoneal and oral administrations. Whilst quercetin was absorbed similarly, the profile of its metabolites was different, which led us to hypothesize that nephroprotection might be exerted in vivo by a metabolic derivate. Consequently, we then aimed to evaluate the cytoprotective capacity of quercetin and its main metabolites (quercetin 3-O-glucoside, rutin, tamarixetin, isorhamnetin and quercetin 3-O-glucuronide) against cisplatin toxicity, in HK-2 and NRK-52E tubular cell lines. Cells were incubated for 6 h with quercetin, its metabolites or vehicle (pretreatment), and subsequently 18 h in cotreatment with 10–300 μM cisplatin. Immediately after treatment, cell cultures were subject to the MTT technique as an index of cytotoxicity and photographed under light microscopy for phenotypic assessment. Quercetin afforded no direct cytoprotection and quercetin-3-O-glucuronide was the only metabolite partially preventing the effect of cisplatin in cultured tubule cells. Our results identify a metabolic derivative of quercetin contributing to its nephroprotection and prompt to further explore exogenous quercetin-3-O-glucuronide in the prophylaxis of tubular nephrotoxicity.

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Section: Discussionmentioning

confidence: 99%

Protective Effect of Quercetin 3-O-Glucuronide against Cisplatin Cytotoxicity in Renal Tubular Cells

et al. 2022

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“…Renal cells also show COMT activity [41]. These enzymes carry out efficient methylation of quercetin aglycones to form methylated derivatives in kidney cells.…”

Section: Quercetin Metabolism In Tubular Cellsmentioning

confidence: 99%

Transit and Metabolic Pathways of Quercetin in Tubular Cells: Involvement of Its Antioxidant Properties in the Kidney

2021

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Quercetin is a flavonoid with antioxidant, antiviral, antimicrobial, and anti-inflammatory properties. Therefore, it has been postulated as a molecule with great therapeutic potential. The renoprotective capacity of quercetin against various toxins that produce oxidative stress, in both in vivo and in vitro models, has been shown. However, it is not clear whether quercetin itself or any of its metabolites are responsible for the protective effects on the kidney. Although the pharmacokinetics of quercetin have been widely studied and the complexity of its transit throughout the body is well known, the metabolic processes that occur in the kidney are less known. Because of that, the objective of this review was to delve into the molecular and cellular events triggered by quercetin and/or its metabolites in the tubular cells, which could explain some of the protective properties of this flavonoid against oxidative stress produced by toxin administration. Thus, the following are analyzed: (1) the transit of quercetin to the kidney; (2) the uptake mechanisms of quercetin and its metabolites from plasma to the tubular cells; (3) the metabolic processes triggered in those cells, which affect the accumulation of metabolites in the intracellular space; and (4) the efflux mechanisms of these compounds and their subsequent elimination through urine. Finally, it is discussed whether those processes that are mediated in the tubular cells and that give rise to different metabolites are related to the antioxidant and renoprotective properties observed after the administration of quercetin.

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“…The role of COMT in metabolizing dopamine in zebrafish is not well understood, but suggested that the presence of 3MT, the product of dopamine methylation, is evidence of the role of COMT in metabolizing dopamine. Another study showed that comta mRNA expression was abundant in the gut, gills, and spleen, while comtb mRNA expression was abundant in the liver and brain, highlighting that comtb is more relevant to central nervous system than comta [9]. Although COMT inhibition did not result in an increased level of dopamine in larval zebrafish, an increase in DOPAC was observed, indicating activation of oxidative metabolism [9].…”

Section: Dopamine Signaling In Zebrafishmentioning

confidence: 99%

“…Another study showed that comta mRNA expression was abundant in the gut, gills, and spleen, while comtb mRNA expression was abundant in the liver and brain, highlighting that comtb is more relevant to central nervous system than comta [9]. Although COMT inhibition did not result in an increased level of dopamine in larval zebrafish, an increase in DOPAC was observed, indicating activation of oxidative metabolism [9]. D2 autoreceptor plays a role in inhibiting neurotransmission by a negative feedback mechanism.…”

Section: Dopamine Signaling In Zebrafishmentioning

confidence: 99%

“…The rhombencephalon has CA in the preoptic area (PO), locus coeruleus (LC), medulla oblongata (MO), and area postrema (AP). classified CA populations into 17 populations (populations [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. The midbrain of zebrafish does not have any DA neurons, in contrast to the mammalian brain.…”

Section: Distribution Of Dopaminergic Neurons In the Zebrafish Brainmentioning

confidence: 99%

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Chemical and Genetic Zebrafish Models to Define Mechanisms of and Treatments for Dopaminergic Neurodegeneration

Wasel

Freeman

2020

IJMS

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The zebrafish (Danio rerio) is routinely used in biological studies as a vertebrate model system that provides unique strengths allowing applications in studies of neurodevelopmental and neurodegenerative diseases. One specific advantage is that the neurotransmitter systems are highly conserved throughout vertebrate evolution, including between zebrafish and humans. Disruption of the dopaminergic signaling pathway is linked to multiple neurological disorders. One of the most common is Parkinson’s disease, a neurodegenerative disease associated with the loss of dopaminergic neurons, among other neuropathological characteristics. In this review, the development of the zebrafish’s dopaminergic system, focusing on genetic control of the dopaminergic system, is detailed. Second, neurotoxicant models used to study dopaminergic neuronal loss, including 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the pesticides paraquat and rotenone, and 6-hydroxydopamine (6-OHDA), are described. Next, zebrafish genetic knockdown models of dj1, pink1, and prkn established for investigating mechanisms of Parkinson’s disease are discussed. Chemical modulators of the dopaminergic system are also highlighted to showcase the applicability of the zebrafish to identify mechanisms and treatments for neurodegenerative diseases such as Parkinson’s disease associated with the dopaminergic system.

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Distribution, properties, and inhibitor sensitivity of zebrafish catechol-O-methyl transferases (COMT)

Cited by 9 publications

References 71 publications

Protective Effect of Quercetin 3-O-Glucuronide against Cisplatin Cytotoxicity in Renal Tubular Cells

Protective Effect of Quercetin 3-O-Glucuronide against Cisplatin Cytotoxicity in Renal Tubular Cells

Transit and Metabolic Pathways of Quercetin in Tubular Cells: Involvement of Its Antioxidant Properties in the Kidney

Chemical and Genetic Zebrafish Models to Define Mechanisms of and Treatments for Dopaminergic Neurodegeneration

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