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. 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.
Footnotes
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This work was supported by the National Cancer Institute Intramural Research Program.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.012492.
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ABBREVIATIONS: P450, cytochrome P450; MEOS, microsomal ethanol-oxidizing system; Hnf1α, hepatocyte nuclear factor 1α; ER, endoplasmic reticulum; PPARα, peroxisome proliferator-activated receptor α; AOM, azoxymethane; MAM, methylazoxymethanol; MAMAc, methylazoxymethanol acetate; ROS, reactive oxygen species; NASH, nonalcoholic steatohepatitis; APAP, acetaminophen; NAPQI, N-acetyl-p-benzoquinone-imine; PGHS, prostaglandin H synthase; GST, glutathione S-transferase; GSH, glutathione; CAR, constitutive androstane receptor; PCA, principal components analysis; UPLC-TOFMS, an ultra performance liquid chromatography-coupled time-of-flight mass spectrometry.
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Frank J. Gonzalez received a B.A. in Biology and M.A. in Microbiology from the University of South Florida, Tampa, and a Ph.D. in Oncology from the University of Wisconsin, Madison. He was a postdoctoral at the National Institute of Child Health and Human Development prior to joining the National Cancer Institute. His studies focus on xenobiotic-metabolizing enzymes, notably the cytochromes P450, and xenobiotics receptors, the molecular interfaces between the chemical environment and the body. Recently, his group has been developing and characterizing P450 and xenobiotic receptor humanized mice and has combined these and other gene knockout models with the use of LC-MS-based metabolomics to study xenobiotic metabolism and to develop biomarkers for P450 expression and receptor activation. - Received August 18, 2006.
- Accepted September 29, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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