TY - GEN
T1 - Translational Implications of the Alcohol-Metabolizing Enzymes, Including Cytochrome P450-2E1, in Alcoholic and Nonalcoholic Liver Disease
AU - Song, Byoung Joon
AU - Akbar, Mohammed
AU - Jo, Inho
AU - Hardwick, James P.
AU - Abdelmegeed, Mohamed A.
N1 - Funding Information:
This research was supported by the Intramural Program Fund at the National Institute on Alcohol Abuse and Alcoholism. The authors thank Dr. Klaus Gawrisch for his support.
PY - 2015
Y1 - 2015
N2 - Fat accumulation (hepatic steatosis) in alcoholic and nonalcoholic fatty liver disease is a potentially pathologic condition which can progress to steatohepatitis (inflammation), fibrosis, cirrhosis, and carcinogenesis. Many clinically used drugs or some alternative medicine compounds are also known to cause drug-induced liver injury, which can further lead to fulminant liver failure and acute deaths in extreme cases. During liver disease process, certain cytochromes P450 such as the ethanol-inducible cytochrome P450-2E1 (CYP2E1) and CYP4A isozymes can be induced and/or activated by alcohol and/or high-fat diets and pathophysiological conditions such as fasting, obesity, and diabetes. Activation of these P450 isozymes, involved in the metabolism of ethanol, fatty acids, and various drugs, can produce reactive oxygen/nitrogen species directly and/or indirectly, contributing to oxidative modifications of DNA/RNA, proteins and lipids. In addition, aldehyde dehydrogenases including the mitochondrial low Km aldehyde dehydrogenase-2 (ALDH2), responsible for the metabolism of acetaldehyde and lipid aldehydes, can be inactivated by various hepatotoxic agents. These highly reactive acetaldehyde and lipid peroxides, accumulated due to ALDH2 suppression, can interact with cellular macromolecules DNA/RNA, lipids, and proteins, leading to suppression of their normal function, contributing to DNA mutations, endoplasmic reticulum stress, mitochondrial dysfunction, steatosis, and cell death. In this chapter, we specifically review the roles of the alcohol-metabolizing enzymes including the alcohol dehydrogenase, ALDH2, CYP2E1, and other enzymes in promoting liver disease. We also discuss translational research opportunities with natural and/or synthetic antioxidants, which can prevent or delay the onset of inflammation and liver disease.
AB - Fat accumulation (hepatic steatosis) in alcoholic and nonalcoholic fatty liver disease is a potentially pathologic condition which can progress to steatohepatitis (inflammation), fibrosis, cirrhosis, and carcinogenesis. Many clinically used drugs or some alternative medicine compounds are also known to cause drug-induced liver injury, which can further lead to fulminant liver failure and acute deaths in extreme cases. During liver disease process, certain cytochromes P450 such as the ethanol-inducible cytochrome P450-2E1 (CYP2E1) and CYP4A isozymes can be induced and/or activated by alcohol and/or high-fat diets and pathophysiological conditions such as fasting, obesity, and diabetes. Activation of these P450 isozymes, involved in the metabolism of ethanol, fatty acids, and various drugs, can produce reactive oxygen/nitrogen species directly and/or indirectly, contributing to oxidative modifications of DNA/RNA, proteins and lipids. In addition, aldehyde dehydrogenases including the mitochondrial low Km aldehyde dehydrogenase-2 (ALDH2), responsible for the metabolism of acetaldehyde and lipid aldehydes, can be inactivated by various hepatotoxic agents. These highly reactive acetaldehyde and lipid peroxides, accumulated due to ALDH2 suppression, can interact with cellular macromolecules DNA/RNA, lipids, and proteins, leading to suppression of their normal function, contributing to DNA mutations, endoplasmic reticulum stress, mitochondrial dysfunction, steatosis, and cell death. In this chapter, we specifically review the roles of the alcohol-metabolizing enzymes including the alcohol dehydrogenase, ALDH2, CYP2E1, and other enzymes in promoting liver disease. We also discuss translational research opportunities with natural and/or synthetic antioxidants, which can prevent or delay the onset of inflammation and liver disease.
KW - ALDH2
KW - Alcohol-metabolizing enzymes
KW - CYP2E1
KW - Liver disease
KW - Mitochondrial dysfunction
KW - Nitroxidative stress
KW - Posttranslational modifications
UR - http://www.scopus.com/inward/record.url?scp=84933057119&partnerID=8YFLogxK
U2 - 10.1016/bs.apha.2015.04.002
DO - 10.1016/bs.apha.2015.04.002
M3 - Conference contribution
C2 - 26233911
AN - SCOPUS:84933057119
SN - 9780128031193
T3 - Advances in Pharmacology
SP - 303
EP - 372
BT - Cytochrome P450 Function and Pharmacological Roles in Inflammation and Cancer, 2015
A2 - Hardwick, James P.
PB - Academic Press Inc.
ER -