Apoptosis/Cell Death, Cytokines, Enzymology, Glutathione, Heme Proteins, Liver, Macrophage, Mitochondria, Oxidative Stress, Protein Degradation
Biophysics and Systems Pharmacology [BSP]
Fellowship, Princeton University
PhD, Rutgers University
Fellowship, Mount Sinai School of Medicine
Lifetime Achievement Award
Research Society on Alcoholism
Mount Sinai Faculty Council Award for Academic Excellence
Ronald G. Thurman Lectureship Award
University of North Carolina
Outstanding Faculty Achievement Award Basic Sciences
Excellence in Teaching Medical School
Summary of Research Studies:
The main research efforts are to evaluate the production of an increased state of oxidative stress by ethanol, and the role of reactive oxygen species in the hepatotoxicity produced by ethanol. We are focusing on the ability of ethanol to increase the levels of a cytochrome P450 isoform called CYP2E1, which has been shown to be powerful producer of superoxide radical and H2O2. We have developed stable HepG2 cell lines which over-express CYP2E1 and have shown that ethanol produces cytotoxicity in cells expressing CYP2E1, but not cells lacking CYP2E1. The cytotoxicity is apoptotic in nature and can be prevented by a variety of antioxidants, inhibitors of CYP2E1, caspase 3 inhibitors and transfection with a plasmid which expresses bcl-2. Ethanol toxicity is enhanced by administration of polyunsaturated fatty acids or by iron, which promote lipid peroxidation. Impairment of mitochondrial function is an early step in the CYP2E1 plus ethanol toxicity. The role of calcium in! the overall mechanism of toxicity and up-regulation of protective factors such as glutathione and antioxidants is under evaluation. Protection by adenoviral vectors expressing antioxidant enzymes such as catalase has been demonstrated. We are currently co-incubating our CYP2E1 cell lines with stellate or Kupffer cells to evaluate possible activation of collagen or cytokine production. Reactive oxygen species are detected by ESR spectroscopy but new HPLC spin-trapping methods have been developed which are more sensitive and we are characterizing the utility of these new approaches. A major mechanism by which ethanol enhances the level of CYP2E1 is by stabilizing the enzyme against degradation. We are characterizing this degradation process and the role of the proteasome-ubiquitin system, and molecular chaperones.
Hong F, Liu X, Ward SS, Xiong H, Cederbaum AI, Lu Y. Absence of cytochrome P450 2A5 enhances alcohol-induced liver injury in mice. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 2015 Mar;.
Cederbaum AI. Molecular mechanisms of the microsomal mixed function oxidases and biological and pathological implications. Redox biology 2015; 4.
Cederbaum AI, Lu Y, Wang X, Wu D. Synergistic toxic interactions between CYP2E1, LPS/TNFα, and JNK/p38 MAP kinase and their implications in alcohol-induced liver injury. Advances in experimental medicine and biology 2015; 815.
Cederbaum AI. Methodology to assay CYP2E1 mixed function oxidase catalytic activity and its induction. Redox biology 2014 Oct; 2C.
Liu H, Lou G, Li C, Wang X, Cederbaum AI, Gan L, Xie B. HBx inhibits CYP2E1 gene expression via downregulating HNF4α in human hepatoma cells. PloS one 2014; 9(9).
Wang Y, Kou Y, Wang X, Cederbaum A, Wang R. Multifactorial comparative proteomic study of cytochrome P450 2E1 function in chronic alcohol administration. PloS one 2014; 9(3).
Yang L, Rozenfeld R, Wu D, Devi LA, Zhang Z, Cederbaum A. Cannabidiol protects liver from binge alcohol-induced steatosis by mechanisms including inhibition of oxidative stress and increase in autophagy. Free radical biology & medicine 2014 Mar; 68.
Wu D, Cederbaum AI. Inhibition of autophagy promotes CYP2E1-dependent toxicity in HepG2 cells via elevated oxidative stress, mitochondria dysfunction and activation of p38 and JNK MAPK. Redox Biology 2013 Nov; 1(1): 552-65.
Lu Y, Ward SC, Cederbaum AI. Nicotine enhances ethanol-induced fat accumulation and collagen deposition but not inflammation in mouse liver. Alcohol 2013 Aug; 47(5): 353-7.
Wang X, Wu D, Yang L, Gan L, Cederbaum AI. Cytochrome P450 2E1 potentiates ethanol induction of hypoxia and HIF-1α in vivo. Free Radical Biology and Medicine 2013 Oct; 63: 175-86.
Cederbaum AI. Nrf2 and Antioxidant Defense Against CYP2E1 Toxicity. Sub-cellular Biochemistry 2013; 67: 105-30.
Wu D, Wang X, Zhou R, Yang L, Cederbaum AI. Alcohol steatosis and cytotoxicity: the role of cytochrome P4502E1 and autophagy. Free Radical Biology and Medicine 2012 Sep; 53(6): 1346-57.
Yang L, Wu D, Wang X, Cederbaum AI. Cytochrome P4502E1, oxidative stress, JNK, and autophagy in acute alcohol-induced fatty liver. Free Radical Biology and Medicine 2012 Sep; 53(5): 1170-80.
Lu Y, Zhang XH, Cederbaum AI. Ethanol induction of CYP2A5: role of CYP2E1-ROS-Nrf2 pathway. Toxicological Sciences 2012 Aug; 128(2): 427-38.
Cederbaum AI, Yang L, Wang X, Wu D. CYP2E1 Sensitizes the Liver to LPS- and TNF α-Induced Toxicity via Elevated Oxidative and Nitrosative Stress and Activation of ASK-1 and JNK Mitogen-Activated Kinases. International Journal of Hepatology 2012; 2012.
Yang L, Wu D, Wang X, Cederbaum AI. Depletion of cytosolic or mitochondrial thioredoxin increases CYP2E1-induced oxidative stress via an ASK-1-JNK1 pathway in HepG2 cells. Free Radical Biology and Medicine 2011 Jul; 51(1): 185-96.
Lu Y, Wu D, Wang X, Ward SC, Cederbaum AI. Ethanol induction of CYP2A5: permissive role for CYP2E1. Drug Metabolism and Disposition 2011 Feb; 39(2): 330-6.
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Dr.Cederbaum did not report having any of the following types of financial relationships with industry during 2015 and/or 2016: consulting, scientific advisory board, industry-sponsored lectures, service on Board of Directors, participation on industry-sponsored committees, equity ownership valued at greater than 5% of a publicly traded company or any value in a privately held company. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.
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