CYP2E1 autoantibodies in liver diseases

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.

Role of CYP2E1 in Mitochondrial Dysfunction and Hepatic Injury by Alcohol and Non-Alcoholic Substances

“…Consequently suppression of ALDH2, a protective enzyme, would lead to accumulation of reactive aldehydes including lipid peroxidation products such as 4-HNE and malondialdehyde (MDA) [207], leading to protein adduct formation and hepatic cell death. In addition, these lipid peroxides can be also involved in the development and progression of hepatic fibrogeneis due to the activation of immune system and hepatic stellate cells [43, 45, 208–210]. ALDH2 and other ALDH isoforms are generally expressed in the liver in large amounts.…”

PharmGKB summary

“…Moreover, anti-INH and anti-CYP2E1 antibodies have been found in the serum of patients with INH-induced liver failure; INH-CYP2E1 covalent adducts were also detected, as well as antibodies against them [45]. Such auto-antibodies are considered markers of CYP2E1-directed autoimmunity, which may lead to liver injury [98]. INH has been shown to induce CYP2E1 enzyme activity [99] and experiments with animal models support CYP2E1-mediated hepatotoxicity when INH is administered [100].…”

Translational Implications of the Alcohol-Metabolizing Enzymes, Including Cytochrome P450-2E1, in Alcoholic and Nonalcoholic Liver Disease

“…In addition, ALDH2 is known to metabolize many other aldehydes including lipid peroxides which are produced from the degradation of numerous fatty acids. Inactivation of ALDH2 and its isozymes is likely to cause accumulation of toxic carbonyl compounds such as acetaldehyde, 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), and acrolein (ACR), all of which can promote protein adduct formation and necroapoptotic cell death while activating the immune cells and hepatic stellate cells, further contributing to the development of fibrosis in the liver and other tissues (Fritz & Petersen, 2013;Lieber, 1997;Mottaran et al, 2002;Sutti, Rigamonti, Vidali, & Albano, 2014). One report suggested that acetaldehyde can be responsible for the onset and maintenance of fibrogenesis (Mello, Ceni, Surrenti, & Galli, 2008).…”

“…In this case, decreased levels of PPARα may lead to disrupted cell protection with a reduced supply of alternative energy ketone bodies, thereby contributing to acute death of hepatocytes in rodents and people. Acetaldehyde has been also shown to be conjugated with numerous proteins including tubulin (Israel, 1997;Jennett, Sorrell, Saffari-Fard, Ockner, & Tuma, 1989;Niemelä et al, 1998Niemelä et al, , 1994Sutti et al, 2014) to activate immune reactions. Critical roles of ALDH2 and CYP2E1 in producing MAA or advanced glycation end product (AGE) adducts and other protein adducts have been suggested (Anderson et al, 2014;Duryee et al, 2005;Jeong et al, 2000;Kwon et al, 2014;Swaminathan, Kumar, Clemens, & Dey, 2013;Thiele et al, 2001).…”

“…These PTMs include acetaldehyde-protein adduct formation Niemelä et al, 1994), hydroxyethyl radical protein adducts Clot et al, 1996;Moncada, Torres, Varghese, Albano, & Israel, 1994), oxidation (Suh et al, 2004), nitration Abdelmegeed et al, 2010), proteasomal degradation (Bardag-Gorce, , gammaketoaldehyde-protein adducts (Roychowdhury et al, 2009), AGE-adducts in high glucose exposed VL-17A cells (Swaminathan, Kumar, et al, 2013), MAA adduct in VL-17A cells , etheno-DNA adduct formation (Linhart, Bartsch, & Seitz, 2014), and formation of CYP2E1 auto-antibodies detected in experimental models and alcoholic subjects (French et al, 1993;Sutti et al, 2014). In contrast, CYP2E1 was shown to suppress diethyl-1, 4-dihydro-2, 4, 6-trimethyl-3, 5-pyridinedicarboxylate (DDC)-induced Mallory Body formation in the liver (Bardag-Gorce, Wilson, et al, 2005).…”