Metabolic Activation of Gemfibrozil Mediated by Cytochrome P450 Enzymes and Sulfotransferases

Zhao, Min; Shi, Junzu; Li, Wei; Guan, Chunjing; Sun, Chen; Peng, Ying; Zheng, Jiang

doi:10.1021/acs.chemrestox.2c00054

Cited by 8 publications

(7 citation statements)

References 33 publications

(48 reference statements)

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“…aryl substructures, being risky for RM formation, which we have been able to compile should serve as an argument for increasing our limited understanding by collecting more basic quantitative data. In support of our observations, new examples (Chart 4) are being added at a steady rate: gemfibrozil forms an alkylating sulfate (Picture S11), 126 and the established drug metoprolol (154, Chart 4) was recently reported to form a methide that might explain the exceedingly rare cases of induced liver injury. 127 Several other drugs, for example zolpidem (151, Chart 4), have a structural setup for forming an arylmethanol but have not been studied so far.…”

Section: Discussionsupporting

confidence: 72%

See 1 more Smart Citation

Non-innocuous Consequences of Metabolic Oxidation of Alkyls on Arenes

Claesson¹,

Parkes²

2022

J. Med. Chem.

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Reactive metabolite (RM) formation is widely accepted as playing a pivotal role in causing adverse idiosyncratic drug reactions, with most attention paid to drug-induced liver injury. Mechanisms of RM formation are determined by the drug’s properties in relation to human enzymes transforming the drug. This Perspective focuses on enzymatic oxidation of alkyl groups on aromatics leading to quinone methides and benzylic alcohol sulfates as RMs, a topic that has not received very much attention. Unlike previous overviews, we will include in our Perspective several fulvene-like methides such as 3-methyleneindole. We also speculate that a few older drugs may form non-reported methides of this class. In addition, we report a few guiding DFT calculations of changes in free energy on going from a benzylic alcohol to the corresponding methide. Particularly facile reactions of 2-aminothiazole-5-methanol and 4-aminobenzyl alcohol are noted.

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Section: Discussionsupporting

confidence: 72%

“…As recently reported, gemfibrozil in parallel forms a benzylic alcohol, which is sulfated and forms a GSH adduct (Picture S11). 126…”

Section: Discussionmentioning

confidence: 99%

Non-innocuous Consequences of Metabolic Oxidation of Alkyls on Arenes

Claesson¹,

Parkes²

2022

J. Med. Chem.

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“…Metabolites were also analyzed by an AB SCIEX 4000 Q-trap coupled to a UPLC system. Further analyses were carried out using similar procedures, as described in our publication . In addition, a high-resolution mass spectrometer (micro Q-TOF, Bruker, Germany) was used to analyze the synthetic products (M7 and M8).…”

Section: Methodsmentioning

confidence: 99%

“…Further analyses were carried out using similar procedures, as described in our publication. 27 In addition, a high-resolution mass spectrometer (micro Q-TOF, Bruker, Germany) was used to analyze the synthetic products (M7 and M8). Data were processed using Bruker Daltonics Data Analysis 3.4 software.…”

Section: Microsomal Incubation Inhibition Experimentsmentioning

confidence: 99%

Metabolic Activation of Pesticide Isoprocarb Mediated by CYP3A4 and the Possible Correlation with Its Cytotoxicity

Guan

Zhao

Sun

et al. 2023

J. Agric. Food Chem.

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Isoprocarb (IPC), one of the most important carbamate pesticides, is used to control pests, such as rice planthoppers in crops. Studies have found that IPC induced hepatotoxicity in poultry chicken. However, the mechanisms of IPC-induced hepatotoxicity are unclear. The objectives of this study were to characterize reactive metabolites of IPC in vitro and in vivo, to identify cytochrome P450 enzymes for metabolic activation, and to define a possible correlation between the metabolic activation and cytotoxicity of IPC. In GSH- or NAC-supplemented microsomal incubations, one GSH conjugate (M6) and two NAC conjugates (M7 and M8) were detected after exposure to IPC. The corresponding GSH conjugate and NAC conjugates were found in the liver homogenates and urine of mice after IPC administration. IPC was found to be metabolized to a quinone intermediate reactive to GSH in vitro and in vivo. IPC was found to induce marked cytotoxicity in cultured mouse primary hepatocytes. Ketoconazole, a selective CYP3A4/5 enzyme inhibitor, attenuated the susceptibility of hepatocytes to IPC cytotoxicity.

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“…41 This drug is primarily used to treat individuals with Type IV and Type V hyperlipidemia who are at risk of developing cardiovascular ailments, coronary vascular issues, and other lipid-associated conditions. 38,42 Gem is ingested orally in tablet form, with a recommended dosage of approximately 20 mg/kg. 43 Each tablet contains 600 mg of Gem and is taken with water.…”

Section: Overvie W Of G Emfib Rozilmentioning

confidence: 99%

Neuroprotective effects of gemfibrozil in neurological disorders: Focus on inflammation and molecular mechanisms

Ivraghi,

Zamanian,

Gupta

et al. 2023

CNS Neurosci Ther

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BackgroundGemfibrozil (Gem) is a drug that has been shown to activate PPAR‐α, a nuclear receptor that plays a key role in regulating lipid metabolism. Gem is used to lower the levels of triglycerides and reduce the risk of coronary heart disease in patients. Experimental studies in vitro and in vivo have shown that Gem can prevent or slow the progression of neurological disorders (NDs), including cerebral ischemia (CI), Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Neuroinflammation is known to play a significant role in these disorders.MethodThe literature review for this study was conducted by searching Scopus, Science Direct, PubMed, and Google Scholar databases.ResultThe results of this study show that Gem has neuroprotective effects through several cellular and molecular mechanisms such as: (1) Gem has the ability to upregulate pro‐survival factors (PGC‐1α and TFAM), promoting the survival and function of mitochondria in the brain, (2) Gem strongly inhibits the activation of NF‐κB, AP‐1, and C/EBPβ in cytokine‐stimulated astroglial cells, which are known to increase the expression of iNOS and the production of NO in response to proinflammatory cytokines, (3) Gem protects dopamine neurons in the MPTP mouse model of PD by increasing the expression of PPARα, which in turn stimulates the production of GDNF in astrocytes, (4) Gem reduces amyloid plaque pathology, reduces the activity of glial cells, and improves memory, (5) Gem increases myelin genes expression (MBP and CNPase) via PPAR‐β, and (6) Gem increases hippocampal BDNF to counteract depression.ConclusionAccording to the study, Gem was investigated for its potential therapeutic effect in NDs. Further research is needed to fully understand the therapeutic potential of Gem in NDs.

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Metabolic Activation of Gemfibrozil Mediated by Cytochrome P450 Enzymes and Sulfotransferases

Cited by 8 publications

References 33 publications

Non-innocuous Consequences of Metabolic Oxidation of Alkyls on Arenes

Non-innocuous Consequences of Metabolic Oxidation of Alkyls on Arenes

Metabolic Activation of Pesticide Isoprocarb Mediated by CYP3A4 and the Possible Correlation with Its Cytotoxicity

Neuroprotective effects of gemfibrozil in neurological disorders: Focus on inflammation and molecular mechanisms

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