The role of reactive oxygen species (ROS) and cytochrome P-450 2E1 in the generation of carcinogenic etheno-DNA adducts

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.

Diallyl Sulfide: Potential Use in Novel Therapeutic Interventions in Alcohol, Drugs, and Disease Mediated Cellular Toxicity by Targeting Cytochrome P450 2E1

“…In particular, genetic predisposition via inheritance of specific CYP2E1 polymorphism or overexpression of CYP2E1 mRNA have been observed in clinical samples [31–34]. CYP2E1-mediated metabolism has also been implicated in generating carcinogenic DNA adducts, further underscoring the importance of this metabolic enzyme in carcinogenicity [35]. Based on these observations, DAS-mediated inhibition of CYP2E1 (discussed in section 5) can be postulated as an additional mechanisms regulating its anticancer effects.…”

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

“…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).…”

The NOR1/OSCP1 proteins in cancer: from epigenetic silencing to functional characterization of a novel tumor suppressor

“…Oxidative stress plays a Janus-face like effect in cancer development and therapy 65. On one hand, reactive species can chemically interact with biological macromolecules such as DNA, protein or lipid and result in DNA damage, mutations, or loss of enzyme activities, consequently lead to increase of genome instability and cancer formation66, 67. On the other hand, sustained oxidative stress or too many free radicals can injure or kill cells 68, 69.…”