Conformational anti-cytochrome P4502E1 (CYP2E1) auto-antibodies contribute to necro-inflammatory injury in chronic hepatitis C
ABSTRACT Circulating auto-antibodies against cytochrome P4502E1 (CYP2E1) have been observed in a significant fraction of patients with chronic hepatitis C (CHC). This study investigated the clinical significance of these auto-antibodies in relation to their antigen specificity. The presence of anti-CYP2E1 IgG was investigated in 137 consecutive patients with biopsy-proven CHC. Anti-CYP2E1 IgG above control threshold levels was detected in 52 (38%) subjects. By combined immunoprecipitation and western blotting, we observed that among anti-CYP2E1 IgG-positive sera, 23 (44%) were unreactive towards denaturated CYP2E1, indicating a prevalent recognition of conformational CYP2E1 antigens. Conformational anti-CYP2E1 auto-antibodies were unrelated to circulating gamma-globulins, alcohol intake or infection by specific HCV genotypes. The presence of anti-CYP2E1 auto-antibodies was associated with an 11-fold (OR 10.9 95%CI 1.4-86.6 P = 0.008) increased prevalence of necro-inflammatory grading ≥ 4 (Ishack's criteria) and 4-fold (OR 4.0; 95%CI 1.3-11-7: P = 0.014) increased prevalence of fibrosis staging ≥ 2, respectively. Multivariate analysis confirmed conformational anti-CYP2E1 IgG (P = 0.005) and age (P = 0.033) as independent predictors of necro-inflammatory grading ≥ 4. The development of anti-CYP2E1 auto-antibodies targeting conformational CYP2E1 epitopes is associated with more severe liver damage in CHC.
- SourceAvailable from: Matteo Vidali
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- "From the clinical point of view, anti-CYP2E1 auto-antibodies in CHC are associated with a 11 fold increase in the prevalence of severe necro-inflammation (grading Z4 according to Ishack's criteria) and 4 fold increased risk of fibrosis. Moreover, multivariate analysis indicates anti-CYP2E1 IgG as an independent predictors of severe necro-inflammation in hepatitis C  . A further aspect of the involvement of anti-CYP2E1 auto-reactivity in CHC concerns the outcomes of the disease following liver transplantation. "
ABSTRACT: Autoimmune reactions involving cytochrome P4502E1 (CYP2E1) are a feature of idiosyncratic liver injury induced by halogenated hydrocarbons and isoniazid, but are also detectable in about one third of the patients with advanced alcoholic liver disease (ALD) and chronic hepatitis C (CHC). In these latter the presence of anti-CYP2E1 auto-antibodies is an independent predictor of extensive necro-inflammation and fibrosis and worsens the recurrence of hepatitis following liver transplantation, indicating that CYP2E1-directed autoimmunity can contribute to hepatic injury. The molecular characterization of the antigens recognized by anti-CYP2E1 auto-antibodies in ALD and CHC has shown that the targeted conformational epitopes are located in close proximity on the molecular surface. Furthermore, these epitopes can be recognized on CYP2E1 expressed on hepatocyte plasma membranes where they can trigger antibody-mediated cytotoxicity. This does not exclude that T cell-mediated responses against CYP2E1 might also be involved in causing hepatocyte damage. CYP2E1 structural modifications by reactive metabolites and molecular mimicry represent important factors in the breaking of self-tolerance against CYP2E1 in, respectively, ALD and CHC. However, genetic or acquired interferences with the mechanisms controlling the homeostasis of the immune system are also likely to contribute. More studies are needed to better characterize the impact of anti-CYP2E1 autoimmunity in liver diseases particularly in relation to the fact that common metabolic alterations such as obesity and diabetes stimulates hepatic CYP2E1 expression. Copyright © 2014. Published by Elsevier B.V.11/2014; 3C:72-78. DOI:10.1016/j.redox.2014.11.004
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ABSTRACT: Research on Cytochrome P450 2E1 (CYP2E1), a key enzyme in alcohol metabolism has been very well documented in literature. Besides the involvement of CYP2E1 in alcohol metabolism as illustrated through the studies discussed in the chapter, recent studies have thrown light on several other aspects of CYP2E1 i.e. its extrahepatic expression, its involvement in several diseases and pathophysiological conditions; and CYP2E1 mediated carcinogenesis and modulation of drug efficacy. Studies involving these interesting facets of CYP2E1 have been discussed in the chapter focusing on the recent observations or ongoing studies illustrating the crucial role of CYP2E1 in disease development and drug metabolism.Sub-cellular biochemistry 01/2013; 67:1-104. DOI:10.1007/978-94-007-5881-0_1
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ABSTRACT: Cytochrome P450 2E1 (CYP2E1) is one of two major enzymes that catalyze ethanol oxidation in the liver. CYP2E1 is also unique because it is inducible, as its hepatic content rises after continuous (chronic) ethanol administration, thereby accelerating the rate of ethanol metabolism and affording greater tolerance to heavy alcohol consumption. However, the broad substrate specificity of CYP2E1 and its capacity to generate free radicals from alcohol and other hepatotoxins, places CYP2E1 as a central focus of not only liver toxicity, but also as an enzyme that regulates cytokine signaling, antigen presentation, and macromolecular degradation, all of which are crucial to liver cell function and viability. Here, we describe our own and other published work relevant to the importance of CYP2E1-catalyzed ethanol oxidation and how this catalysis affects the aforementioned cellular processes to produce liver injury.Sub-cellular biochemistry 01/2013; 67:177-97. DOI:10.1007/978-94-007-5881-0_6