Selective Time- and NADPH-Dependent Inhibition of Human CYP2E1 by Clomethiazole

Stresser, David M.; Perloff, Elke S.; Mason, Andrew K.; Blanchard, Andrew P.; Dehal, Shangara S.; Creegan, Timothy P; Singh, Ritu; Gangl, Eric

doi:10.1124/dmd.116.070193

Cited by 18 publications

(10 citation statements)

References 27 publications

(41 reference statements)

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“…To further verify the hypothesis based on the human data, the effect of inhibition of CYP2E1 activity on DEN-induced hepatocarcinogenesis was evaluated. CMZ, previously described as an inhibitor of rat and human CYP2E1 both in vitro and in vivo (Chen et al, 2014;Stresser et al, 2016), was used in this intervention experiment. Although CYP2E1 activity was inhibited by about 80% by CMZ at 100 mg/kg, this inhibition could decrease, but not stop, hepatocarcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Higher CYP2E1 Activity Correlates with Hepatocarcinogenesis Induced by Diethylnitrosamine

Gao

Zhao

Wang

et al. 2018

J Pharmacol Exp Ther

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Hepatocellular carcinoma (HCC) is one of the most common types of primary liver cancer and the third most frequent cause of cancer death worldwide. Diethylnitrosamine (DEN) is one of the recognized risk factors for hepatocarcinogenesis likely due to CYP2E1-mediated metabolic activation. However, CYP2E1-mediated DEN metabolic activity in non-neoplastic liver tissue from HCC patients has not been determined; the role of CYP2E1 activity, in particular CYP2E1 constitutive activity and CYP2E1 inhibited activity, with respect to the hepatocarcinogenesis induced by DEN is not yet clear. Herein, we determined CYP2E1-mediated DEN metabolic activity in non-neoplastic liver tissue from HCC patients and found that CYP2E1-mediated DEN metabolic activity was significantly elevated with a 43.3% positive rate, and clinicopathologic parameters did not affect the activity. Then, using a Sprague-Dawley rat liver tumor model induced by DEN, the relationship between CYP2E1 constitutive/inhibited activity and hepatocarcinogenesis was explored. The results showed that the CYP2E1 constitutive activity was strongly correlated with tumor incidence and severity of liver tumorigenesis (nodule numbers and size), whereas inhibition of CYP2E1 activity decreased hepatocyte proliferation, liver injury, and liver carcinogenesis in the presence of DEN. In conclusion, the higher CYP2E1 activity would lead to an increased incidence of HCC as a result of CYP2E1-mediated DEN activation. Therefore, higher CYP2E1 activity might be a risk factor for HCC induced by DEN.

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Section: Discussionmentioning

confidence: 99%

Higher CYP2E1 Activity Correlates with Hepatocarcinogenesis Induced by Diethylnitrosamine

Gao

Zhao

Wang

et al. 2018

J Pharmacol Exp Ther

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“…CMZ was purchased from TCI Development Co., Ltd (Shanghai, China). CMZ is a widely used CYP2E1 inhibitor [ 24 ]. Mice of the model group and CMZ treatment group were injected with an H22 cells suspension and the sham group was injected with an equal amount of sterile saline.…”

Section: Methodsmentioning

confidence: 99%

Stat4 rs7574865 polymorphism promotes the occurrence and progression of hepatocellular carcinoma via the Stat4/CYP2E1/FGL2 pathway

et al. 2022

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Although there are many studies on the relationship between genetic polymorphisms and the incidence of diseases, mechanisms are rarely known. We report the mechanism by which signal transducer and activator of transcription 4 (stat4) rs7574865 promotes the occurrence and progression of hepatocellular carcinoma (HCC). We found that the GG genotype at stat4 rs7574865 was a risk genotype, and STAT4 levels in serum and peritumoral tissue from HCC patients with the GG genotype were significantly higher than those found in TT or TG carriers. Furthermore, HCC patients with the GG genotype or elevated STAT4 levels had poor prognoses. In vitro experiments demonstrated that STAT4 silencing promoted apoptosis and inhibited the invasion and migration of HepG2 and L02 cells. Proteomic analysis of HCC peritumors identified 273 proteins related to STAT4, of which CYP2E1 activity and FGL2 content exhibited the highest positive correlation. The relationship between CYP2E1 and FGL2 was also confirmed in cyp2e1−/− mice and in CYP2E1 inhibitor-treated mice. In conclusion, this study elucidates the mechanism by which the stat4 rs7574865 polymorphism promotes the occurrence and progression of HCC via the Stat4/CYP2E1/FGL2 pathway.

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“…Samples were analyzed by LC-MS/MS for 6α-OH-CBD and 7-OH-CBD (when CBD was used as a substrate), and 7-COOH-CBD (when 7-OH-CBD was used as a substrate). In addition to the experiment procedures described above, in which all reaction conditions were initiated with NADPH as a direct, reversible inhibition assay, experiments were also performed with a pre-incubation step for the time-dependent inhibitors furafylline, clomethiazole (a time-dependent CYP2E1 inhibitor) (Stresser et al, 2016), ticlopidine, and CYP3cide. Procedures for time-dependent inhibition assays are provided in the Supplementary Information.…”

Section: Effect Of Cyp-selective Inhibitors On Cbd and 7-oh-cbd Metabolismmentioning

confidence: 99%

Cytochrome P450–Catalyzed Metabolism of Cannabidiol to the Active Metabolite 7-Hydroxy-Cannabidiol

Beers

Jackson

2021

Drug Metab Dispos

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Cannabidiol (CBD) is a naturally occurring, non-psycho-toxic phytocannabinoid that has gained increasing attention as a popular consumer product and for its use in FDA-approved Epidiolex® (CBD oral solution) for the treatment of Lennox-Gastaut syndrome and Dravet syndrome. CBD was previously reported to be metabolized primarily by cytochrome P450 (CYP) 2C19 and CYP3A4, with minor contributions from UDP-glucuronosyltransferases. 7-Hydroxy-CBD (7-OH-CBD) is the primary active metabolite with equipotent activity compared to CBD. Given the polymorphic nature of CYP2C19, we hypothesized that variable CYP2C19 expression may lead to interindividual differences in CBD metabolism to 7-OH-CBD. The objectives of this study were to further characterize the roles of CYP enzymes in CBD metabolism, specifically to the active metabolite 7-OH-CBD, and to investigate the impact of CYP2C19 polymorphism on CBD metabolism in genotyped human liver microsomes. The results from reaction phenotyping experiments with recombinant CYP enzymes and CYP-selective chemical inhibitors indicated that both CYP2C19 and CYP2C9 are capable of CBD metabolism to 7-OH-CBD. CYP3A played a major role in CBD metabolic clearance via oxidation at sites other than the 7-position. In genotyped human liver microsomes, 7-OH-CBD formation was positively correlated with CYP2C19 activity but was not associated with CYP2C19 genotype. In a subset of single-donor human liver microsomes with moderate to low CYP2C19 activity, CYP2C9 inhibition significantly reduced 7-OH-CBD formation, suggesting that CYP2C9 may play a greater role in CBD 7hydroxylation than previously thought. Collectively, these data indicate that both CYP2C19 and CYP2C9 are important contributors in CBD metabolism to the active metabolite 7-OH-CBD.

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Selective Time- and NADPH-Dependent Inhibition of Human CYP2E1 by Clomethiazole

Cited by 18 publications

References 27 publications

Higher CYP2E1 Activity Correlates with Hepatocarcinogenesis Induced by Diethylnitrosamine

Higher CYP2E1 Activity Correlates with Hepatocarcinogenesis Induced by Diethylnitrosamine

Stat4 rs7574865 polymorphism promotes the occurrence and progression of hepatocellular carcinoma via the Stat4/CYP2E1/FGL2 pathway

Cytochrome P450–Catalyzed Metabolism of Cannabidiol to the Active Metabolite 7-Hydroxy-Cannabidiol

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