Cyp2e1 is not involved in early alcohol-induced liver injury

Hiroshi Kono, Blair U. Bradford, Ming Yin, Kathleen K. Sulik, Dennis Koop, Jeffrey M. Peters, Frank J. Gonzalez, Tasha McDonald, Anna Dikalova, Maria B. Kadiiska, Ronald P. Mason, Ronald G. Thurman

Research output: Contribution to journalArticle

152 Citations (Scopus)

Abstract

The continuous intragastric enteral feeding protocol in the rat was a major development in alcohol-induced liver injury (ALI) research. Much of what has been learned to date involves inhibitors or nutritional manipulations that may not be specific. Knockout technology avoids these potential problems. Therefore, we used long-term intragastric cannulation in mice to study early ALI. Reactive oxygen species are involved in mechanisms of early ALI; however, their key source remains unclear. Cytochrome P-450 (CYP)2E1 is induced predominantly in hepatocytes by ethanol and could be one source of reactive oxygen species leading to liver injury. We aimed to determine if CYP2E1 was involved in ALI by adapting the enteral alcohol (EA) feeding model to CYP2E1 knockout (-/-) mice. Female CYP2E1 wild-type (+/+) or -/- mice were given a high-fat liquid diet with either ethanol or isocaloric maltose-dextrin as control continuously for 4 wk. All mice gained weight steadily over 4 wk, and there were no significant differences between groups. There were also no differences in ethanol elimination rates between CYP2E1 +/+ and -/- mice after acute ethanol administration to naive mice or mice receiving EA for 4 wk. However, EA stimulated rates 1.4-fold in both groups. EA elevated serum aspartate aminotransferase levels threefold to similar levels over control in both CYP2E1 +/+ and -/- mice. Liver histology was normal in control groups. In contrast, mice given ethanol developed mild steatosis, slight inflammation, and necrosis; however, there were no differences between the CYP2E1 +/+ and -/- groups. Chronic EA induced other CYP families (CYP3A, CYP2A12, CYP1A, and CYP2B) to the same extent in CYP2E1 +/+ and -/- mice. Furthermore, POBN radical adducts were also similar in both groups. Data presented here are consistent with the hypothesis that oxidants from CYP2E1 play only a small role in mechanisms of early ALI in mice. Moreover, this new mouse model illustrates the utility of knockout technology in ALI research.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume277
Issue number6 40-6
StatePublished - Dec 1999

Fingerprint

Cytochrome P-450 CYP2E1
Alcohols
Liver
Wounds and Injuries
Ethanol
Small Intestine
Enteral Nutrition
Cytochrome P-450 Enzyme System
Reactive Oxygen Species
Technology
Cytochrome P-450 CYP3A
Maltose
High Fat Diet
Aspartate Aminotransferases
Research
Oxidants
Knockout Mice
Catheterization
Hepatocytes
Histology

Keywords

  • CYP2E1 knockout mouse
  • Intragastric feeding

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology
  • Physiology (medical)

Cite this

Kono, H., Bradford, B. U., Yin, M., Sulik, K. K., Koop, D., Peters, J. M., ... Thurman, R. G. (1999). Cyp2e1 is not involved in early alcohol-induced liver injury. American Journal of Physiology - Gastrointestinal and Liver Physiology, 277(6 40-6).

Cyp2e1 is not involved in early alcohol-induced liver injury. / Kono, Hiroshi; Bradford, Blair U.; Yin, Ming; Sulik, Kathleen K.; Koop, Dennis; Peters, Jeffrey M.; Gonzalez, Frank J.; McDonald, Tasha; Dikalova, Anna; Kadiiska, Maria B.; Mason, Ronald P.; Thurman, Ronald G.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 277, No. 6 40-6, 12.1999.

Research output: Contribution to journalArticle

Kono, H, Bradford, BU, Yin, M, Sulik, KK, Koop, D, Peters, JM, Gonzalez, FJ, McDonald, T, Dikalova, A, Kadiiska, MB, Mason, RP & Thurman, RG 1999, 'Cyp2e1 is not involved in early alcohol-induced liver injury', American Journal of Physiology - Gastrointestinal and Liver Physiology, vol. 277, no. 6 40-6.
Kono, Hiroshi ; Bradford, Blair U. ; Yin, Ming ; Sulik, Kathleen K. ; Koop, Dennis ; Peters, Jeffrey M. ; Gonzalez, Frank J. ; McDonald, Tasha ; Dikalova, Anna ; Kadiiska, Maria B. ; Mason, Ronald P. ; Thurman, Ronald G. / Cyp2e1 is not involved in early alcohol-induced liver injury. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 1999 ; Vol. 277, No. 6 40-6.
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AU - Gonzalez, Frank J.

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