Cytochrome P450 2E1: Its Role in Disease and Drug Metabolism

Lakshman MR, Garige M, Gong MA, Leckey L, Varatharajalu R, Redman RS, Seth D, Haber PS, Hirsch K, Amdur R, Shah R, M. Raj Lakshman, Mamatha Garige, Maokai A. Gong, Leslie Leckey, Ravi Varatharajalu, Robert S. Redman, Devanshi Seth, Paul S. Haber, Kenneth Hirsch, Richard Amdur, Ruchi Shah, Lakshman, M. Raj, Garige, Mamatha, Gong, Maokai A., Leckey, Leslie, Varatharajalu, Ravi, Redman, Robert S., Seth, Devanshi, Haber, Paul S., Hirsch, Kenneth, Amdur, Richard, Shah, Ruchi

Chronic alcohol-mediated down-regulation of hepatic ST6Gal1 gene leads to defective glycosylation of lipid-carrying apolipoproteins such as apo E and apo J, resulting in defective VLDL assembly and intracellular lipid and lipoprotein transport, which in turn is responsible for alcoholic hepatosteatosis and ALD. The mechanism of ethanol action involves thedepletion of a unique RNA binding protein that specifically interacts with its 3'-UTR region of ST6Gal1 mRNA resulting in its destabilization and consequent appearance of asialoconjugates as alcohol biomarkers. With respect to ETOH effects on Cardio-Vascular Diseases, we conclude that CYP2E1 and ETOH mediated oxidative stress significantly down regulates not only the hepatic PON1 gene expression, but also serum PON1 and HCTLase activities accompanied by depletion of hepatic GSH, the endogenous antioxidant. These results strongly implicate the susceptibility of PON1 to increased ROS production. In contrast, betaine seems to be both hepatoprotective and atheroprotective by reducing hepatosteatosis and restoring not only liver GSH that quenches free radicals, but also the antiatherogenic PON1 gene expression and activity.