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Drug Metabolism and Disposition Fast Forward
First published on October 4, 2006; DOI: 10.1124/dmd.106.012492

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Received for publication August 21, 2006.
Revised September 29, 2006.
Accepted for publication September 29, 2006.

THE 2006 BERNARD B. BRODIE AWARD LECTURE: CYP2E1

Frank J. Gonzalez 1*

1 National Cancer Institute

* Address correspondence to: E-mail: fjgonz{at}helix.nih.gov

Abstract

Bernard B. Brodie's laboratory was the first to examine the mechanisms of drug-induced toxicity at the molecular level. They found that acetaminophen hepatotoxicity was due to the metabolic activation of the drug to a highly reactive toxic metabolite that depleted cellular glutathione and covalently bound to protein. Subsequent studies revealed that activation of acetaminophen to an active metabolite is primarily carried out by CYP2E1, an ethanol-inducible cytochrome P450 that was first suggested by characterization of the microsomal ethanol oxidation system (MEOS). CYP2E1 is developmentally regulated, under liver-specific control and undergoes substrate-induced protein stabilization. It is also regulated by starvation and diabetes through insulin-dependent mRNA stabilization. In addition to acetaminophen, CYP2E1 metabolically activates a large number of low Mr toxicants and carcinogens and thus is of great toxicological importance. The mechanism of regulation CYP2E1 and its role in acetaminophen toxicity will be discussed.


Key words: CYP2E, cytochrome P450 catalyzed oxidations, glutathione transferases, toxicity


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