Epicatechin gallate and epigallocatechin gallate are potent inhibitors of human arylacetamide deacetylase

Yasuda, Kaori; Watanabe, Kouichi; Fukami, Tatsuki; Nakashima, Shimon; Ikushiro, Shinichi; Nakajima, Miki; Sakaki, Toshiyuki

doi:10.1016/j.dmpk.2021.100397

Cited by 7 publications

(3 citation statements)

References 32 publications

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“…Gallic acid derivatives could also be DNA replication inhibitors as some of the green tea extracts ( López-Lázaro et al, 2011 ). Gallocatechin-3-O-gallate and Epicatechin gallate would be suppressing the production of toxic reactive metabolites ( Yasuda et al, 2021 ). These flavonoids might play a synergistic role with the upregulation of antioxidant enzymes and detoxification proteins in ROS-scavenging ( Supplementary Table 3 ).…”

Section: Discussionmentioning

confidence: 99%

Integrated transcriptome and metabolome analyses reveal the adaptation of Antarctic moss Pohlia nutans to drought stress

Fang

Zhang

et al. 2022

Front. Plant Sci.

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Most regions of the Antarctic continent are experiencing increased dryness due to global climate change. Mosses and lichens are the dominant vegetation of the ice-free areas of Antarctica. However, the molecular mechanisms of these Antarctic plants adapting to drought stress are less documented. Here, transcriptome and metabolome analyses were employed to reveal the responses of an Antarctic moss (Pohlia nutans subsp. LIU) to drought stress. We found that drought stress made the gametophytes turn yellow and curled, and enhanced the contents of malondialdehyde and proline, and the activities of antioxidant enzymes. Totally, 2,451 differentially expressed genes (DEGs) were uncovered under drought treatment. The representative DEGs are mainly involved in ROS-scavenging and detoxification, flavonoid metabolism pathway, plant hormone signaling pathway, lipids metabolism pathway, transcription factors and signal-related genes. Meanwhile, a total of 354 differentially changed metabolites (DCMs) were detected in the metabolome analysis. Flavonoids and lipids were the most abundant metabolites and they accounted for 41.53% of the significantly changed metabolites. In addition, integrated transcriptome and metabolome analyses revealed co-expression patterns of flavonoid and long-chain fatty acid biosynthesis genes and their metabolites. Finally, qPCR analysis demonstrated that the expression levels of stress-related genes were significantly increased. These genes included those involved in ABA signaling pathway (NCED3, PP2C, PYL, and SnAK2), jasmonate signaling pathway (AOC, AOS, JAZ, and OPR), flavonoid pathway (CHS, F3’,5’H, F3H, FLS, FNS, and UFGT), antioxidant and detoxifying functions (POD, GSH-Px, Prx and DTX), and transcription factors (ERF and DREB). In summary, we speculated that P. nutans were highly dependent on ABA and jasmonate signaling pathways, ROS scavenging, flavonoids and fatty acid metabolism in response to drought stress. These findings present an important knowledge for assessing the impact of coastal climate change on Antarctic basal plants.

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Section: Discussionmentioning

confidence: 99%

Integrated transcriptome and metabolome analyses reveal the adaptation of Antarctic moss Pohlia nutans to drought stress

Fang

Zhang

et al. 2022

Front. Plant Sci.

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“…In a study that screened natural compounds for their inhibitory effects on AADAC, CES1, and CES2, Yasuda et al found that curcumin and quercetin exhibited strong inhibitory effects against all three enzymes, whereas epicatechin, epicatechin gallate (ECg), and epigallocatechin gallate (EGCg) specifically inhibited AADAC (Yasuda et al, 2021). ECg and EGCg strongly inhibited AADAC-mediated rifampicin hydrolysis in human liver microsomes with IC 50 values of 2.2  1.4 µM and 1.7  0.4 µM, respectively.…”

Section: Aadac Inhibitorsmentioning

confidence: 99%

Regulation of human hydrolases and its implications in pharmacokinetics and pharmacodynamics

Jung,

Zhu

2024

Drug Metab Dispos

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Hydrolases represent an essential class of enzymes indispensable for the metabolism of various clinically essential medications. Individuals exhibit marked differences in the expression and activation of hydrolases, resulting in significant variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs metabolized by these enzymes. The regulation of hydrolase expression and activity involves both genetic polymorphisms and nongenetic factors. This review examines the current understanding of genetic and nongenetic regulators of six clinically significant hydrolases, including Carboxylesterase 1 (CES1), Carboxylesterase 2 (CES2), Arylacetamide Deacetylase (AADAC), Paraoxonase 1 (PON1), Paraoxonase 3 (PON3), and Cathepsin A (CTSA). We explore genetic variants linked to the expression and activity of the hydrolases and their effects on the PK and PD of their substrate drugs. Regarding nongenetic regulators, we focus on the inhibitors and inducers of these enzymes. Additionally, we examine the developmental expression patterns and gender differences in the hydrolases when pertinent information was available. Many genetic and nongenetic regulators were found to be associated with the expression and activity of the hydrolases and PK and PD. However, hydrolases remain generally understudied compared to other drug-metabolizing enzymes, such as cytochrome P450s. The clinical significance of genetic and nongenetic regulators has not yet been firmly established for the majority of hydrolases. Comprehending the mechanisms that underpin the regulation of these enzymes holds the potential to refine therapeutic regimens, thereby enhancing the efficacy and safety of drugs metabolized by the hydrolases.

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“…With respect to AADAC, it has been difficult to identify a specific inhibitor. However, very recently, epigallocatechin gallate appeared to be a promising AADAC inhibitor 68 .…”

Section: Substrates and Inhibitorsmentioning

confidence: 99%

Unraveling the Functions of Detoxification Enzymes and Drug Transporters

WANG¹

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Human carboxylesterase (CES) and arylacetamide deacetylase (AADAC) are two important serine esterase families expressed in liver and intestine. They can hydrolyze many carboxylester, amide, and thioester bonds in both endogenous molecules and xenobiotic compounds. Thus, they are involved in the activation or detoxification of many (pro-)drugs, influencing the absorption, distribution, metabolism and excretion (ADME) profiles for these drugs. Considering that CES and AADAC are abundant in both intestine and liver, they will play important roles in intestinal and subsequent liver metabolism of oral drugs (first-pass metabolism). This can profoundly influence the overall exposure, the efficacy, and the safety of specific ester (pro-)drugs.From this perspective, it is important to systematically understand the specific roles of each esterase, especially the hepatic and intestinal esterases, such as CES and AADAC. Such improved understanding will benefit rational drug design, development of new drugs and optimization of clinical drug regimens. In this review, we discuss the three different main hepatic and intestinal esterases (CES1, CES2 and AADAC), their specific substrates and inhibitors, their polymorphisms, and their hepatic or intestinal pharmacological roles in drug metabolism. We further discuss related pre-clinical mouse models that may help to meet currently unmet research needs on these esterases.

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Epicatechin gallate and epigallocatechin gallate are potent inhibitors of human arylacetamide deacetylase

Cited by 7 publications

References 32 publications

Integrated transcriptome and metabolome analyses reveal the adaptation of Antarctic moss Pohlia nutans to drought stress

Integrated transcriptome and metabolome analyses reveal the adaptation of Antarctic moss Pohlia nutans to drought stress

Regulation of human hydrolases and its implications in pharmacokinetics and pharmacodynamics

Unraveling the Functions of Detoxification Enzymes and Drug Transporters

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