Interaction between 3,4‑dichlorophenyl‑propenoyl‑sec.‑butylamine (3,4‑DCPB), an antiepileptic drug, and cytochrome P450 in rat liver microsomes and recombinant human enzymes in vitro

Cheng, Hui G.; Lu, Yingyuan; Wang, Xin; Ren, Hongqiang; Li, Qiang; Wang, Shumei; Ding, Yu; Lou, Ya-Qing; Zhang, Guoliang

doi:10.1016/j.ejps.2018.07.018

Cited by 5 publications

(3 citation statements)

References 35 publications

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“…CYP450 enzymes in the body are found mainly in the endoplasmic reticulum and mitochondria of the liver, and the structural and functional integrity of the liver determines to some extent the body's ability to metabolize drugs [35]. CYP450 contains the detoxi cation system, which is the rst enzyme defense against exogenous substances, and the oxidation reaction catalyzed by this enzyme is the main pathway of drug metabolism in the body.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Lipid Peroxidation and Microsomal Drug-metabolizing Enzyme Activity of Rat Hepatotoxicity under Heavy Metals from Slag Waste Exposure

Wan²,

Kuang

et al. 2023

Cell Biochem Biophys

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Heavy metals from slag waste (HMSWs) have been a long-term concern around the world, posing serious environmental and visceral toxicity, especially hepatotoxicity. Investigating the leaching behavior and hepatotoxicity of HMSWs is of great signi cance. Based on the toxicogenomic analysis, the targets and related signaling pathways of heavy metal-induced liver injury were predicted, and the effects of different HMSWs on mitochondrial lipid peroxidation injury and microsomal drug-metabolizing enzyme activities in rats were experimentally explored. The results showed that different heavy metals might have the function of interfering with physiological processes such as oxidative stress, cell death, and energy metabolism regulation in vivo, and participate in the regulation of HIF-1 signaling pathway, peroxisomes, drug metabolism-cytochrome P450, ferroptosis, and other signaling pathways. HMSWs exposure caused weight loss, and signi cantly increased lactate dehydrogenase (LDH), malondialdehyde (MDA), alanine transaminase (ALT), and aspartate transaminase (AST) in different groups of rat liver, suggesting the presence of mitochondrial lipid peroxidation damage. Meanwhile, the activities of superoxide dismutase (SOD) and mitochondrial membrane potential (MMP) in the liver were signi cantly decreased, and microsomal Cytochrome P450 1A2 (CYP1A2) and 3A1 (CYP3A1) enzyme activities were induced, predicting the involvement of the microsomal drug-metabolizing enzymes. These results indicated that metabolic interplay between microsomes and other subcellular organelles including mitochondria and peroxisome could be involved in heavy metals-induced liver injury.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Lipid Peroxidation and Microsomal Drug-metabolizing Enzyme Activity of Rat Hepatotoxicity under Heavy Metals from Slag Waste Exposure

Wan²,

Kuang

et al. 2023

Cell Biochem Biophys

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“…This study elucidated the compatibility in terms of CYP1A2, 2C11, 2C19, 2B1, 2E1, 2D4, and 3A1 through an in vivo cocktail assay in rats. CYP1A2, 2C subfamily, 2B1, 2E1, 2D4, and 3A1 make up about 13, 20, 4, 10, 1.3-4.3, and 40% of the total content of hepatic CYPs, respectively, and metabolize the majority of widely used drugs (Cheng et al, 2018;Zhao et al, 2016;Zhou et al, 2015 In recent years, notoginseng and safflower have gained importance in the treatment of CDs, especially the coronary heart disease (Han et al, 2010). Due to the general drug combination of TCM and synthetic drugs in clinical application, the research of DDI is important (Xu et al, 2017 (Berger et al, 2018;Hirota & Ieiri, 2015;Yang et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the effects of notoginseng total saponins (NS), safflower total flavonoids (SF), and the combination of NS and SF (CNS) on the activities of cytochrome P450 enzymes using a cocktail method in rats

Yuan

et al. 2021

Biomedical Chromatography

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Notoginseng total saponins (NS), safflower total flavonoids (SF), and the combination of NS and SF, namely CNS, are used for the treatment of cardiovascular diseases in clinic. This study developed a cocktail assay involving seven cytochrome P450 (CYP) enzymes to elucidate the effect of NS, SF, and CNS on CYP enzymes and to explore the synergistic effect of CNS in terms of CYP enzymes. Ultra-performance liquid chromatography-MS and reverse-transcription polymerase chain reaction were applied to detect the activities and mRNA expression levels of CYP enzymes. SF exhibited inhibitory effects on CYP1A2, 2B1, 2E1, and 2C11 and induction effects on CYP2C19 and 2D4. NS exhibited induction effects on CYP1A2, 2B1, 2E1, 2C11, 2C19, and 2D4. CNS exhibited induction effects on CYP1A2, 2B1, 2E1, 2C19, and 2D4 and inhibitory effects on CYP3A1 in vivo. Moreover, mRNA expression results were consistent with pharmacokinetic results. Potential herb-drug interactions should be studied closely when SF, NS, or CNS with clinical drugs are metabolized by CYP1A2, 2B1, 2E1, 2C11, 2C19, 2D4, and 3A1. CNS could change the inhibition or induction effects of CYP compared to the NS group, which might be one of the causes for the synergistic effects of the combination of NS and SF.

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“…Liver microsomes are the most widely used in drug metabolism research because of their low cost, simple operation, and rapid detection (Williams et al, 2004;Cheng et al, 2018;Lu et al, 2018). However, liver microsomes are difficult to use when simulating the complete metabolic environment in vivo and evaluating the induction ability of drugs on CYP enzymes, so it is hard to accurately and comprehensively reflect the effect of drugs on the activity of CYP enzymes (Diao and Huestis, 2019;Thiengsusuk et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

A Novel System for Evaluating the Inhibition Effect of Drugs on Cytochrome P450 Enzymes in vitro Based on Human-Induced Hepatocytes (hiHeps)

Jia

et al. 2021

Front. Pharmacol.

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Cytochrome P450 (CYP) is the most important phase I drug-metabolizing enzyme, and the effect of drugs on CYP enzymes can lead to decreased pharmacological efficacy or enhanced toxicity of drugs, but there are many deficiencies in the evaluation models of CYP enzymes in vitro. Human-induced hepatocytes (hiHeps) derived from human fibroblasts by transdifferentiation have mature hepatocyte characteristics. The aim was to establish a novel evaluation system for the effect of drugs on CYP3A4, 1A2, 2B6, 2C9, and 2C19 in vitro based on hiHeps. Curcumin can inhibit many CYP enzymes in vitro, and so the inhibition of curcumin on CYP enzymes was compared by human liver microsomes, human hepatocytes, and hiHeps using UPLC-MS and the cocktail method. The results showed that the IC50 values of CYP enzymes in the hiHeps group were similar to those in the hepatocytes group, which proved the effectiveness and stability of the novel evaluation system in vitro. Subsequently, the evaluation system was applied to study the inhibitory activity of notoginseng total saponins (NS), safflower total flavonoids (SF), and the herb pair of NS–SF on five CYP enzymes. The mechanism of improving efficacy after NS and SF combined based on CYP enzymes was elucidated in vitro. The established evaluation system will become a powerful tool for the research of the effect of drugs on the activity of CYP enzymes in vitro, which has broad application prospects in drug research.

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Interaction between 3,4‑dichlorophenyl‑propenoyl‑sec.‑butylamine (3,4‑DCPB), an antiepileptic drug, and cytochrome P450 in rat liver microsomes and recombinant human enzymes in vitro

Cited by 5 publications

References 35 publications

Mitochondrial Lipid Peroxidation and Microsomal Drug-metabolizing Enzyme Activity of Rat Hepatotoxicity under Heavy Metals from Slag Waste Exposure

Mitochondrial Lipid Peroxidation and Microsomal Drug-metabolizing Enzyme Activity of Rat Hepatotoxicity under Heavy Metals from Slag Waste Exposure

Evaluation of the effects of notoginseng total saponins (NS), safflower total flavonoids (SF), and the combination of NS and SF (CNS) on the activities of cytochrome P450 enzymes using a cocktail method in rats

A Novel System for Evaluating the Inhibition Effect of Drugs on Cytochrome P450 Enzymes in vitro Based on Human-Induced Hepatocytes (hiHeps)

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