Cytochrome P450 2E1: Its Clinical Aspects and a Brief Perspective on the Current Research Scenario

Dey, Aparajita

doi:10.1007/978-94-007-5881-0_1

Cited by 17 publications

(7 citation statements)

References 272 publications

(717 reference statements)

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“…Although drug interaction studies are not specified in the FDA guidance for CYP2A6 and CYP2E1, these enzymes may also cause drug-botanical interactions. CYP2A6 is involved in the metabolism of some tobacco compounds including nicotine, cotinine and N 1 -nitrosonornicotine (Pelkonen et al, 2000), and CYP2E1 has been reported to metabolize ethanol, caffeine, acetaminophen, and chlorzoxazone (Hrycay and Bandiera, 2008; Dey 2013). In this study, we used a cocktail assay approach (Li et al ., 2015) with ultrahigh-pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to measure possible inhibition of all seven CYP isoforms recommended by the FDA as well as CYP2A6 and CYP2E1 by extracts of G. glabra, G. uralensis and G. inflata and 14 compounds (Fig.…”

Section: Introductionmentioning

confidence: 99%

Cytochrome P450 inhibition by three licorice species and fourteen licorice constituents

Simmler

Chen

et al. 2017

European Journal of Pharmaceutical Sciences

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The potential of licorice dietary supplements to interact with drug metabolism was evaluated by testing extracts of three botanically identified licorice species (Glycyrrhiza glabra L., Glycyrrhiza uralensis Fish. ex DC. and Glycyrrhiza inflata Batalin) and 14 isolated licorice compounds for inhibition of 9 cytochrome P450 enzymes using a UHPLC-MS/MS cocktail assay. G. glabra showed moderate inhibitory effects against CYP2B6, CYP2C8, CYP2C9, and CYP2C19, and weak inhibition against CYP3A4 (testosterone). In contrast, G. uralensis strongly inhibited CYP2B6 and moderately inhibited CYP2C8, CYP2C9 and CYP2C19, and G. inflata strongly inhibited CYP2C enzymes and moderately inhibited CYP1A2, CYP2B6, CYP2D6, and CYP3A4 (midazolam). The licorice compounds isoliquiritigenin, licoricidin, licochalcone A, 18β-glycyrrhetinic acid, and glycycoumarin inhibited one or more members of the CYP2C family of enzymes. Glycycoumarin and licochalcone A inhibited CYP1A2, but only glycycoumarin inhibited CYP2B6. Isoliquiritigenin, glabridin and licoricidin competitively inhibited CYP3A4, while licochalcone A (specific to G. inflata roots) was a mechanism-based inhibitor. The three licorice species commonly used in botanical dietary supplements have varying potential for drug-botanical interactions as inhibitors of cytochrome P450 isoforms. Each species of licorice displays a unique profile of constituents with potential for drug interactions.

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Section: Introductionmentioning

confidence: 99%

Cytochrome P450 inhibition by three licorice species and fourteen licorice constituents

Simmler

Chen

et al. 2017

European Journal of Pharmaceutical Sciences

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“…Under normal conditions, CYP2E1 accounts for 10% of ethanol oxidation, but it is inducible by chronic ethanol ingestion [ 8 ]. Enhanced CYP2E1 activity not only causes increased ROS formation but also results in an increased activation of various environmental pro-carcinogens that require CYP2E1 to be activated [ 3 , 9 ]. MEOS plays a major role in the oxidation of ethanol, as well as the formation of ROS, appearing to be mechanism for hepatotoxic-induced ethanol [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Antioxidant and Hepatoprotective Effects of Procyanidins from Wild Grape (Vitis amurensis) Seeds in Ethanol-Induced Cells and Rats

Bak

Truong

et al. 2016

IJMS

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In the present study, we characterized the antioxidant and hepatoprotective mechanisms underlying of wild grape seed procyanidins (WGP) against oxidative stress damage in ethanol-treated HepG2 cell and Sprague-Dawley (SD)-rat models. In HepG2 cells, WGP not only diminished the ethanol (EtOH, 100 mM)-induced reactive oxygen species (ROS) formation and cytochrome P450 2E1 (CYP2E1) expression, but also renovated both the activity and expression of antioxidant enzymes including catalase, superoxide dismutase, and glutathione peroxidase. Additionally, to investigate the hepatoprotective effect of WGP, rats were orally administered 10 or 50 mg/kg WGP once daily for seven days prior to the single oral administration of EtOH (6 g/kg). The results show that WGP administration decreased the EtOH-induced augment of the levels of serum aspartate transaminase and alanine transaminase as well as serum alcohol and acetaldehyde. WGP treatment upregulated the activities and protein levels of hepatic alcohol dehydrogenase, aldehyde dehydrogenase, and antioxidant enzymes but downregulated the protein expression level of liver CYP2E1 in EtOH-treated rats. Moreover, the decreased phosphorylation levels of mitogen activated protein kinases (MAPKs) by ethanol were induced in both HepG2 cell and rat models. Overall, pretreatment of WGP displayed the protective activity against EtOH-mediated toxicity through the regulation of antioxidant enzymes and alcohol metabolism systems via MAPKs pathways.

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“…CYP2E1 plays an important role in the metabolic clearance of pollutants (aniline and styrene) and beverages (ethanol), and its activity is also involved in the hepatotoxic effects of many drugs, such as acetaminophen, an analgesic-antipyretic agent widely used, and cisplatin, an anticancer agent. Interactions between acetaminophen or cisplatin and CYP2E1 generate reactive metabolites and reactive oxygen species [25][26][27]. So, an increase CYP2E1 activity may also potentiate the risk of hepatotoxic effects caused by the accumulation of toxic compounds in the body that lead to oxidative stress, liver injury, and other detrimental effects.…”

Section: Resultsmentioning

confidence: 99%

In Vitro Inhibition of Human CYP450s 1A2, 2C9, 3A4/5, 2D6 and 2E1 by Grandisin

et al. 2017

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Grandisin, a lignan isolated from many species of plants, such as , is a potential drug candidate due to its biological properties, highlighted by its antitumor and trypanocidal activities. In this study, the inhibitory effects of grandisin on the activities of human cytochrome P450 enzymes were investigated by using human liver microsomes. Results showed that grandisin is a competitive inhibitor of CYP2C9 and a competitive and mechanism-based inhibitor of CYP3A4/5. The apparent K value for CYP2C9 was 50.60 µM and those for CYP3A4/5 were 48.71 µM and 31.25 µM using two different probe substrates, nifedipine and midazolam, respectively. The apparent K, k, and k/K ratio for the mechanism-based inhibition of CYP3A4/5 were 6.40 µM, 0.037 min, and 5.78 mL · min µmol, respectively, by examining nifedipine oxidation, and 31.53 µM, 0.049 min, and 1.55 mL · min µmol, respectively, by examining midazolam 1'-hydroxylation. These apparent k/K values were comparable to or even higher than those for several therapeutic drugs that act as mechanism-based inhibitors of CYP3A4/5. CYP1A2 and CYP2D6 activities, in turn, were not substantially inhibited by grandisin (IC > 200 µM and 100 µM, respectively). In contrast, from a concentration of 4 µM, grandisin significantly stimulated CYP2E1 activity. These results improve the prediction of grandisin-drug interactions, suggesting that the risk of interactions with drugs metabolized by CYP3A4/5 and CYP2E1 cannot be overlooked.

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Cytochrome P450 2E1: Its Clinical Aspects and a Brief Perspective on the Current Research Scenario

Cited by 17 publications

References 272 publications

Cytochrome P450 inhibition by three licorice species and fourteen licorice constituents

Cytochrome P450 inhibition by three licorice species and fourteen licorice constituents

Antioxidant and Hepatoprotective Effects of Procyanidins from Wild Grape (Vitis amurensis) Seeds in Ethanol-Induced Cells and Rats

In Vitro Inhibition of Human CYP450s 1A2, 2C9, 3A4/5, 2D6 and 2E1 by Grandisin

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