The aim of our study was to identify the form(s) of cytochrome P450 responsible for the metabolism of deramciclane, a new anxiolytic drug candidate. The main routes of biotransformation in hepatic microsomes were side chain modification (N-demethylation or total side chain cleavage) and hydroxylation at several points of the molecule. Although several cytochrome P450 forms were involved in the ...

Bernard B. Brodie's laboratory was the first to examine the mechanisms of drug-induced toxicity at the molecular level. They found that acetaminophen hepatotoxicity was due to the metabolic activation of the drug to a highly reactive toxic metabolite that depleted cellular glutathione and covalently bound to protein. Subsequent studies revealed that activation of acetaminophen to an active meta...

Human microsomal cytochrome P450 2E1 (CYP2E1) can oxidize not only low molecular weight xenobiotic compounds such as ethanol, but also many endogenous fatty acids. The crystal structure of CYP2E1 in complex with indazole reveals that the active site is deeply buried into the protein center. Thus, the unbinding pathways and associated unbinding mechanisms remain elusive. In this study, random ac...

Incubation systems were established to investigate the effects of quercetin, kaempferol, isoquercitrin and astragalin in Lysimachia clethroides Duby on the activities of CYP2E1 and CYP3A4 in rat liver microsomes in vitro. Probe substrates of 4-nitrophenol and testosterone as well as flavonoids at different concentrations were added to the incubation systems. After incubation, a validated high p...

Disulfiram and its primary metabolite diethyldithiocarbamate are effective mechanism-based inhibitors of cytochrome P-450 2E1 (CYP2E1)1 in vitro. Single-dose disulfiram diminishes CYP2E1 activity in vivo and has been used to identify CYP2E1 participation in human drug metabolism and prevent CYP2E1-mediated toxification. Specificity of single-dose disulfiram toward CYP2E1 in vivo, however, remai...

Vinyl carbamate (VC) is derived from ethyl carbamate, a carcinogen formed in fermentation of food and alcoholic products. We have undertaken studies to test the hypothesis that an epoxide generated from VC oxidation leads to formation of 1,N6-ethenodeoxyadenosine (epsilon dAS). We have developed approaches using liquid chromatography-mass spectrometry and liquid chromatography-tandem mass spect...

Elevated LPS and elevated cytochrome P-450 2E1 (CYP2E1) in liver are two major independent risk factors in alcoholic liver disease. We investigated possible synergistic effects of the two risk factors in causing oxidative stress and liver injury. Sprague-Dawley rats were injected intraperitoneally with pyrazole (inducer of CYP2E1) for 2 days, and then LPS was injected via tail vein. Other rats ...

Chronic alcohol use can result in many pathological effects including alcoholic liver disease (ALD). While alcohol is necessary for the development of ALD, only 20-30% of alcoholics develop alcoholic steatohepatitis (ASH) with progressive liver disease leading to cirrhosis and liver failure (ALD). This suggests that while chronic alcohol consumption is necessary it is not sufficient to induce c...

Background/Aims: Several pathways contribute to mechanisms by which ethanol induces oxidant stress. While some studies support a role for cytochrome P450 2E1 (CYP2E1), others do not. There is a need to develop oral models of significant ethanol-induced liver injury and to evaluate the possible role of CYP2E1 in ethanol actions in such models. Methods: We evaluated chronic ethanol-induced liver ...

Background/Aims: Several pathways contribute to mechanisms by which ethanol induces oxidant stress. While some studies support a role for cytochrome P450 2E1 (CYP2E1), others do not. There is a need to develop oral models of significant ethanol-induced liver injury and to evaluate the possible role of CYP2E1 in ethanol actions in such models. Methods: We evaluated chronic ethanol-induced liver ...