Induction of cytochrome P450 2E1 increases hepatotoxicity caused by Fas agonistic Jo2 antibody in mice

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
Hepatology (Impact Factor: 11.19). 08/2005; 42(2):400-10. DOI: 10.1002/hep.20792
Source: PubMed

ABSTRACT Cytochrome P450 2E1 (CYP2E1) may be a central pathway in generating oxidative stress, reactive oxygen species, and causing hepatotoxic injury by alcohol and various hepatotoxins. This study evaluated the ability of CYP2E1 to potentiate or synergize the hepatotoxicity of Fas in vivo. C57BL/6 mice were injected intraperitoneally with pyrazole (Pyr) to induce CYP2E1. Then, 16-hour fasted mice were administered agonistic Jo2 anti-Fas antibody ip. Other mice were treated with Pyr or Jo2 alone. Levels of serum aminotransferase were 8.3- and 6.3-fold higher in the Pyr/Jo2 group compared with Jo2 alone, respectively. Histological evaluation of liver showed more extensive acidophilic necrosis and severe pathological changes in the Pyr/Jo2-treated mice. DNA fragmentation and caspase-8 and -3 activities were more elevated in the Pyr/Jo2 group compared with Jo2 alone. CYP2E1 activity and protein levels were higher in the Pyr/Jo2 group than in Jo2 alone. Levels of inducible nitric oxide synthase, 3-nitrotyrosine protein adducts, malondialdehyde, and protein carbonyls were also higher in the Pyr/Jo2 group compared with Jo2 alone. Glutathione and activities of catalase and Cu-Zn superoxide dismutase were decreased in the Pyr/Jo2 group. Administration of chlormethiazole, an inhibitor of CYP2E1, to the Pyr/Jo2-treated mice caused a significant decrease of alanine aminotransferase and liver pathological changes in association with a decrease in CYP2E1 protein and activity. In conclusion, enhanced hepatotoxicity of Fas was found in mice with elevated levels of CYP2E1. We speculate that overexpression of CYP2E1 might synergize and increase the susceptibility to Fas induced-liver injury.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: ARTICLE INFO ABSTRACT Article history Received 16/05/2013 Available online 30/06/2013 Keywords Amla, anti-diabetic, anti-oxidant, anti-cancer, anti-hyperlipidemic anti-inflammatory. Phytogenic agents have traditionally been used by herbalists and indigenous healers for the prevention and treatment of various diseases. Emblica officinalis (Amla) is a deciduous tree belonging to family Euphorbiacea. Growing body of evidences have shown that amla possess anti diabetic activity and have been used to treat diabetes-induced complications. Amla is a potent antioxidant. Wide array of studies such as hepatoprotective, anticancer, anti inflammatory, analgesic, anti hyperlipidemic etc are associated with this plant. The present review demonstrates the pleiotropic actions of amla in various disorders. Moreover, the underlying mechanisms of amla-induced protection in various diseases have been delineated. Please cite this article in press as Jagdeep Kaur Emblica officinalis: A Meritocratic Drug for Treating Various Disorders. Indo American Journal of Pharm Research.2013:3(6).
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Isoniazid is reported to be the most reliable and cost-effective remedy for tuberculosis treatment and prophylaxis among first line anti-tuberculosis drugs. Conventionally, the most common and best studied adverse effect of isoniazid is hepatotoxicity, but as for testicular toxicity the problem has not yet explored extensively. The aim of the study was to identify in vivo influence of isoniazid on induction of testicular cytochrome Р-450 2Е1 (CYP2E1) mRNA expression and enzymatic activity, testes DNA fragmentation, serum total testosterone level, and spermatogenesis indices. The significant induction of CYP2E1 was demonstrated in rat's testes following isoniazid administration, specifically CYP2E1 mRNA expression and p-nitrophenolhydroxylase activity was increased in 28 and 7 times as compared with control, respectively. These changes were accompanied by activating of testicular GST in 32%, changing in levels and character of DNA fragmentation, as well as damaging of the spermatogenic epithelium, decreasing in serum testosterone content (1.62 fold), sperm count (19%), and losing of fertility in comparison with untreated males. We assume that in testes of isoniazid-treated rats CYP2E1 may act as a trigger in generating of reactive oxygen species and other toxic metabolites which subsequently mediates DNA damage, spermatogenesis disturbances, and altered male fertilizing capacity. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Toxicology Letters 02/2015; 234(2). DOI:10.1016/j.toxlet.2015.02.008 · 3.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Exocyclic etheno-DNA adducts are mutagenic and carcinogenic and are formed by the reaction of lipidperoxidation (LPO) products such as 4-hydoxynonenal or malondialdehyde with DNA bases. LPO products are generated either via inflammation driven oxidative stress or via the induction of cytochrome P-450 2E1 (CYP2E1). In the liver CYP2E1 is induced by various compounds including free fatty acids, acetone and ethanol. Increased levels of CYP2E1 and thus, oxidative stress are observed in the liver of patients with non-alcoholic steatohepatitis (NASH) as well as in the chronic alcoholic. In addition, chronic ethanol ingestion also increases CYP2E1 in the mucosa of the oesophagus and colon. In all these tissues CYP2E1 correlates significantly with the levels of carcinogenic etheno-DNA adducts. In contrast, in patients with non-alcoholic steatohepatitis (NASH) hepatic etheno-DNA adducts do not correlate with CYP2E1 indicating that in NASH etheno-DNA adducts formation is predominately driven by inflammation rather than by CYP2E1 induction. Since etheno-DNA adducts are strong mutagens producing various types of base pair substitution mutations as well as other types of genetic damage, it is strongly believed that they are involved in ethanol mediated carcinogenesis primarily driven by the induction of CYP2E1. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.
    09/2014; 3. DOI:10.1016/j.redox.2014.08.009