Cytochrome P450 2E1: Its Role in Disease and Drug Metabolism
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
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Cytochrome P450 2E1: Its Clinical Aspects and a Brief Perspective on the Current Research Scenario Aparajita Dey
Abstract Research on Cytochrome P450 2E1 (CYP2E1), a key enzyme in alcohol metabolism has been very well documented in literature. Besides the involvement of CYP2E1 in alcohol metabolism as illustrated through the studies discussed in the chapter, recent studies have thrown light on several other aspects of CYP2E1 i.e. its extrahepatic expression, its involvement in several diseases and pathophysiological conditions; and CYP2E1 mediated carcinogenesis and modulation of drug efficacy. Studies involving these interesting facets of CYP2E1 have been discussed in the chapter focusing on the recent observations or ongoing studies illustrating the crucial role of CYP2E1 in disease development and drug metabolism. Keywords Cytochrome P450 2E1 • Drugs • Reactive oxygen species • Diseases • Injury
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Introduction
Cytochrome P450 2E1 (CYP2E1) is implicated in several diseases and is a key player in alcohol metabolism and oxidative stress (Gonzalez 2005; Brzezinski et al. 1999; Wu and Cederbaum 2005). CYP2E1 which is induced due to alcohol consumption plays a major role in human health due to its ability to bioactivate numerous hepatotoxins and metabolize alcohol (Koop 1992; Cederbaum 2010). The abundance of expression of CYP2E1 in liver and extrahepatic tissues holds importance
A. Dey, Ph.D. (*) AU-KBC Research Centre, Anna University, MIT Campus, Chromepet, Chennai, Tamil Nadu 600044, India e-mail: [email protected]; [email protected]; [email protected] A. Dey (ed.), Cytochrome P450 2E1: Its Role in Disease and Drug Metabolism, Subcellular Biochemistry 67, DOI 10.1007/978-94-007-5881-0_1, © Springer Science+Business Media Dordrecht 2013
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keeping in view its role in generating oxidative stress (Joshi and Tyndale 2006a). Further, due to its ability to modulate the effects of drugs, CYP2E1 plays a crucial role in drug metabolism (Lieber 2004; Joshi and Tyndale 2006a).
1.1.1
Purification and Characterization of CYP2E1
The initial purification of CYP2E1 from rabbits led to its discovery in several other animal species and humans (Koop et al. 1982). CYP2E1 is primarily an endoplasmic reticulum resident protein (Lieber 2004; Konishi and Ishii 2007), but recent studies have also shown that CYP2E1 is also present in mitochondria (Bhagwat et al. 1995; Neve and Ingelman-Sundberg 1999; Robin et al. 2001). The localization of hepatic CYP2E1 is predominantly restricted to petrivenous region in liver (Bühler et al. 1991; Lieber 1993). Regulation of CYP2E1 occurs through transcriptional activation, mRNA stabilization, increased mRNA translatability and decreased protein degradation and the principal mechanism which controls the induction process depends on several factors such as the chemical nature of the inducer, the age, and the nutritional and hormonal status of the animal (Koop and Tierney 1990).
1.1.2
The Role of CYP2E1 as a Potent Source for Oxidative Stress
CYP2E1 catalyzes s
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