![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
JL Raucy, JM Lasker, JC Kraner, DE Salazar, CS Lieber and GB Corcoran
University of New Mexico, Toxicology Program, College of Pharmacy, Albuquerque 87131.
Cytochrome P450IIE1 (IIE1) is a microsomal xenobiotic-activating enzyme that is inducible not only by various chemical agents but also by fasting and diabetes. Using a rat model that mimics human obesity, we have found that hepatic IIE1 levels are also increased by this common clinical disorder. Liver microsomes from rats made obese by feeding with an energy-dense diet displayed elevated aggregate P450 content (+28%) and enhanced catalytic activities associated with IIE1, including low-Km N-nitrosodimethylamine demethylation (+66%), aniline hydroxylation (+52%), p-nitrophenol hydroxylation (+170%), and acetaminophen-cysteine conjugate formation (+28%). In contrast, obesity had no significant effect on cytochrome b5 content, P450 reductase activity, benzphetamine demethylation, or erythromycin demethylation, with the latter two reactions being linked with rat IIC11 and IIIA1, respectively. The enhancement of IIE1-dependent drug-metabolizing activities noted in liver microsomes from obese rats was paralleled by a similar increase (111%) in hepatic IIE1 protein content in these animals, as assessed on immunoblots developed with anti-hamster IIE1 IgG. Anti-IIE1-inhibitable rates of microsomal p-nitrophenol metabolism, a reaction highly correlated with IIE1 content (r = 0.88, p less than 0.01), were over 3-fold higher in obese rats than in nonobese controls, providing additional evidence for the obesity-related increase of hepatic IIE1. The induction of IIE1 by the pathophysiological condition of obesity may provide a biochemical basis for the increased incidence of occult liver disease and certain cancers noted in obese individuals.
This article has been cited by other articles:
|
|
 |
|
  T. Ito, K. Asakura, K. Tougou, T. Fukuda, R. Kubota, S. Nonen, Y. Fujio, and J. Azuma Regulation of Cytochrome P450 2E1 under Hypertonic Environment through TonEBP in Human Hepatocytes Mol. Pharmacol., July 1, 2007; 72(1): 173 - 181. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Bai and A. I. Cederbaum Adenovirus-Mediated Expression of CYP2E1 Produces Liver Toxicity in Mice Toxicol. Sci., June 1, 2006; 91(2): 365 - 371. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Cheung, A.-M. Yu, J. M. Ward, K. W. Krausz, T. E. Akiyama, L. Feigenbaum, and F. J. Gonzalez THE CYP2E1-HUMANIZED TRANSGENIC MOUSE: ROLE OF CYP2E1 IN ACETAMINOPHEN HEPATOTOXICITY Drug Metab. Dispos., March 1, 2005; 33(3): 449 - 457. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E Dennison, P. L Bigelow, and M. E Andersen Occupational exposure limits in the context of solvent mixtures, consumption of ethanol, and target tissue dose Toxicology and Industrial Health, July 1, 2004; 20(6-10): 165 - 175. [Abstract] [PDF]
|
|
|
|
|
|
J. L. Raucy, J. Lasker, K. Ozaki, and V. Zoleta Regulation of CYP2E1 by Ethanol and Palmitic Acid and CYP4A11 by Clofibrate in Primary Cultures of Human Hepatocytes Toxicol. Sci., June 1, 2004; 79(2): 233 - 241. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. S Lieber, M. A Leo, K. M Mak, Y. Xu, Q. Cao, C. Ren, A. Ponomarenko, and L. M DeCarli Model of nonalcoholic steatohepatitis Am. J. Clinical Nutrition, March 1, 2004; 79(3): 502 - 509. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Watson, S. M. Poloyac, G. Howard, and R. A. Blouin Effect of Leptin on Cytochrome P-450, Conjugation, and Antioxidant Enzymes in the ob/ob Mouse Drug Metab. Dispos., June 1, 1999; 27(6): 695 - 700. [Abstract] [Full Text]
|
|
|
|
|
|
J. Y. Chien, K. E. Thummel, and J. T. Slattery Pharmacokinetic Consequences of Induction of CYP2E1 by Ligand Stabilization Drug Metab. Dispos., October 1, 1997; 25(10): 1165 - 1175. [Abstract] [Full Text]
|
|
|
|
 |
|
 S. P. Carpenter, D. D. Savage, E. D. Schultz, and J. L. Raucy Ethanol-Mediated Transplacental Induction of CYP2E1 in Fetal Rat Liver J. Pharmacol. Exp. Ther., August 1, 1997; 282(2): 1028 - 1036. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
