The book deals with various clinical aspects of cytochrome P450 2E1 (CYP2E1) which is a potent source for oxidative stress. Oxidative stress is critical for pathogenesis of diseases and CYP2E1 is a major contributor for oxidative stress. Several clinical disorders are associated with changes in regulation of CYP2E1 and the consequent abnormalities which include alcoholic liver disease, alcoholic pancreatitis, carcinogenesis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, obesity, hepatitis C virus infection, reproductive organ toxicity, hepatocellular and cholestatic liver cirrhosis, inhibition of bone repair, cross-tolerance in smokers and people treated with nicotine, disorders of central nervous system, changes in metabolism of protoxicants in the circulatory system and susceptibility to human papillomavirus infection. Hence, CYP2E1 emerges as a new and potent player in aggravating injury and furthering disease complications.
Table of ContentsList of Contributors.- Preface.- Acknowledgements.- Chapter 1 Cytochrome P450 2E1 and its clinical aspects: an introduction and a brief perspective on the current research scenario, Aparajita Dey.- 1.1 Introduction.- 1.1.1 Purification and characterization of CYP2E1.- 1.1.2 The role of CYP2E1 as a potent source for oxidative stress.- 1.1.3 CYP2E1 and ethanol-mediated oxidative stress.- 1.1.4 Importance of CYP2E1 in health and disease.- 1.2 Research studies elucidating the role of CYP2E1 in disease and drug metabolism.- 1.3 Conclusions.- Chapter 2 Nrf2 and antioxidant defense against CYP2E1 toxicity, Arthur I Cederbaum.- 2.1 Introduction.- 2.2 Systems Producing ROS.- 2.2.1 Protection against ROS toxicity.- 2.2.2 Alcohol, oxidative stress, and cell injury.- 2.3 CYP2E1.- 2.3.1 CYP2E1 and alcohol-induced liver injury.- 2.3.2 Biochemical and toxicological properties of CYP2E1 in HepG2 cells.- 2.3.3 Upregulation of antioxidant defense in CYP2E1 expressing liver cells.- 2.4 Nrf2 Signaling.- 2.4.1 Nrf2 and CYP2E1-induced toxicity.- 2.4.2 Nrf2 protects HepG2 cells against CYP2E1 plus arachidonic acid toxicity.- 2.4.3 Nrf2 and ethanol-induced toxicity.- 2.5 Conclusions.- Chapter 3 The role of Cytochrome P-4502E1 in ethanol-mediated carcinogenesis, Helmut K Seitz and Xiang-Dong Wang.- 3.1 Introduction.- 3.2 Induction and inhibition of CYP2E1.- 3.3 Activation of procarcinogens via CYP2E1.- 3.4 Generation of ROS through ethanol metabolism via CYP2E1.- 3.5 The role of CYP2E1 in the metabolism of retinoids and their importance in carcinogenesis.- 3.6 The role of CYP2E1 in chemically induced hepatocarcinogenesis.- 3.7 Summary and Conclusion.- Chapter 4 The Importance of CYP2E1 in the pathogenesis of alcoholic liver disease and drug toxicity and the role of the proteasome, SW French.- 4.1 Introduction.- 4.2 The role of CYP2E1 in liver damage caused by ethanol.- 4.2.1 Hydroxyethyl radicals generated by CYP2E1/ethanol metabolism: significance in ethanol hepatotoxicity.- 4.3 The pathogenesis of liver pathology due to alcohol-induced CYP2E1.- 4.4 Drug hepatitis involving drugs that are metabolized by CYP2E1 when CYP2E1 has been induced by ethanol ingestion.- 4.5 CYP2E1 induction: effect on epigenetic expression.- 4.6 Role of the proteasome in CYP2E1 stabilization.- 4.7 Role of CYP2E1 in drug cholestatic hepatitis (DDC) plus ethanol.- 4.8 Role of CYP2E1 in non-alcoholic hepatitis (NASH).- 4.9 CYP2E1 polymorphism and genetic links to alcoholic liver disease.- 4.10 Conclusions.- Chapter 5 Relevance of CYP2E1 to non-alcoholic fatty liver disease, Ann K Daly.- 5.1 Introduction.- 5.2 CYP2E1 and NAFLD.- 5.3 Genetics of NAFLD including possible role of CYP2E1 polymorphisms.- 5.3.1 Background.- 5.3.2 Candidate gene studies on NAFLD.- 5.3.3 Candidate gene studies on CYP2E1 as a genetic risk factor in NAFLD.- 5.3.4 Genome-wide association studies on NAFLD.- 5.4 Concluding remarks.- Chapter 6 CYP2E1-catalyzed alcohol metabolism:role of oxidant generation in interferon signaling, antigen presentation and autophagy, Natalia A. Osna and Terrence M. Donohue Jr.- 6.1 CYP2E1 regulation by ethanol exposure.- 6.1.1 Hepatic ethanol oxidation in the liver.- 6.1.2 Induction of CYP2E1 by ethanol.- 6.2. Oxidant generation and interferon signaling.- 6.3 Proteasome activity and CYP2E1: reciprocal regulation by IFNγ and ethanol.- 6.4 Interferon-dependent antigen processing and presentation in liver cells.- 6.5 Involvement of CYP2E1 in the ethanol-induced regulation of autophagy.- 6.5.1 Physiological function of autophagy.- 6.5.2 Autophagy in liver during alcohol consumption.- 6.5.3 Alcohol-induced fatty liver.- 6.5.4 Interferon-induced autophagy.- 6.6. Summary and future directions.- Chapter 7 CYP2E1, oxidative stress, post-translational modifications and lipid metabolism, MR Lakshmanan.- 7.1 Introduction.- 7.2 Ethical guideline and alcoholic specimen criteria.- 7.3.1 Ethanol per se, not other liver pathological conditions, mediates the down-regulation of ST6Gal1 gene.- 7.3.2 Liver lipid deposition directly correlates with the amount of alcohol consumed.- 7.3.3Alcohol consumption correlates positively with hepatic steatosis.- 7.3.4 Strong multivariate relationships exist between alcohol-drinking history, ST6Gal1 gene expression, and liver lipid deposits.- 7.3.5 Expression of CYP2E1 and ADH in the respective HepG2 cell lines.- 7.3.6 Effect of ethanol on ST6Gal1 mRNA expression in CYP2E1 cells.- 7.3.7 Effect of ethanol on ST6Gal1 mRNA expression in HAD liver cells.- 7.3.8 Effect of ethanol and acetaldehyde on ST6Gal1 mRNA expression in wild-type HepG2 liver cells.- 7.3.9 Effect of HNE on ST6Gal1 mRNA expression in CYP2E1 cells.- 7.3.10 Partial identification of the liver cytosol protein that forms complex with the 3'-UTR of Rat ST6Gal1 mRNA.- 7.3.11 Importance of secondary structure of RNA in RNA-Protein Complex Formation.- 7.3.12 The RNA-Protein interaction protects 3'-UTR from RNase digestion.- 7.3.13 Partial characterization of protein interacting with 3'-UTR of ST6Gal1 mRNA by UV cross-linking.- 7.3.14 Thirteen-base pair motif of ST6Gal1 mRNA is sufficient for the specific protein to bind.- 7.3.15 The specificity of the cytosolic binding protein that interacts with ST6Gal1 mRNA.- 7.3.16 Effects of chronic ethanol exposure in vivo on the status of the binding protein.- 7.3.17 Influence of chronic ethanol and betaine on animal body and liver weights.- 7.3.18 Influence of chronic ethanol and betaine liver PON1 mRNA expression in rats fed low and high ω-3 PUFA diets.- 7.3.19 Influence of chronic ethanol and betaine on serum PON1 and HCTLase activities in rats fed low and high ω-3 PUFA diets.- 7.3.20 Influence of chronic ethanol, ω-3 PUFA and betaine on liver GSH levels in rats fed low and high ω-3 PUFA diets.- 7.3.21 Influence of chronic ethanol, ω-3 PUFA and betaine on serum ALT.- 7.3.22 Influence of chronic ethanol, ω-3 PUFA and betaine on liver lipid score.- 7.4 Significance of the results.- 7.5 Conclusions.- Chapter 8 The role of CYP2E1 in alcohol metabolism and sensitivity in the central nervous system, V.Vasiliou.- 8.1 Introduction.- 8.2 Ethanol metabolism in the CNS.- 8.3 Acetaldehyde in ethanol sensitivity of the brain.- 8.4 Acetaldehyde production in the brain.- 8.5 CYP2E1 expression in the brain.- 8.6 Regulation of CYP2E1 in the CNS.- 8.6 Regulation of CYP2E1 in the CNS.- 8.7 Genetic variation of CYP2E1 in ethanol sensitivity.- 8.8 Conclusion. Index.