Role of CYP2E1 in the pathogenesis of alcoholic liver disease: modifications by cAMP and ubiquitin-proteasome pathway.

Z. Q. Gouillon, K. Miyamoto, T. M. Donohue, Yu-Jui Yvonne Wan, B. A. French, Y. Nagao, P. Fu, R. C. Reitz, A. Hagbjork, C. Yap, Q. X. Yuan, M. Ingelman-Sundberg, S. W. French

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

The ethanol inducible isoform of cytochrome P450, CYP2E1, may play a role in ethanol-induced liver injury. Therefore, the factors which govern CYP2E1 degradation and turnover were investigated. These factors include cAMP, ubiquitin, proteasomal enzymes and CYP2E1 mRNA. Rats fed ethanol or pair-fed isocaloric dextrose were pair-fed with rats fed ethanol or dextrose treated with cAMP for 2 months. The liver pathology, regenerative activity, fatty acid composition, NFkappaB activation, ubiquitin conjugates and proteasomal enzymes were measured as were the apoprotein levels of CYP2E1, CYP3A, CYP4A and mRNA levels for CYP2E1 and ubiquitin expression. The results showed, that the cAMP treatment ameliorated the increase liver fat storage and changes in the fatty acid composition in the livers of ethanol fed rats. Other histologic features of alcoholic liver disease were not changed. Western blot quantitation showed that the amount of ubiquitin and ubiquitin conjugates were markedly reduced by ethanol treatment. Similarly, ethanol decreased the level of ubiquitin mRNA. cAMP ameliorated the inhibition of the proteasomal enzyme proteolysis caused by ethanol feeding. The ethanol-induced increase in the CYP2E1 protein was partially inhibited by cAMP treatment. cAMP treatment decreased CYP2E1 mRNA levels in both ethanol-fed and pair fed control rats. Likewise NFkappaB activation was not increased by ethanol but cAMP reduced the level of NFkappaB activation. CAMP treatment also reduced CYP4A but not CYP3A. The results support the concept that cAMP treatment partially protects the liver from ethanol-induced fatty liver by reducing CYP2E1 induction through cAMP's effects on CYP2E1 synthesis.

Original languageEnglish (US)
JournalFrontiers in bioscience : a journal and virtual library
Volume4
StatePublished - 1999

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Cytochrome P-450 CYP2E1
Alcoholic Liver Diseases
Proteasome Endopeptidase Complex
Ubiquitin
Liver
Ethanol
Cytochrome P-450 CYP4A
Rats
Cytochrome P-450 CYP3A
Messenger RNA
Chemical activation
Enzymes
Fatty Acids
Rat control
Proteolysis
Enzyme inhibition
Glucose
Apoproteins
Pathology
Fatty Liver

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Role of CYP2E1 in the pathogenesis of alcoholic liver disease : modifications by cAMP and ubiquitin-proteasome pathway. / Gouillon, Z. Q.; Miyamoto, K.; Donohue, T. M.; Wan, Yu-Jui Yvonne; French, B. A.; Nagao, Y.; Fu, P.; Reitz, R. C.; Hagbjork, A.; Yap, C.; Yuan, Q. X.; Ingelman-Sundberg, M.; French, S. W.

In: Frontiers in bioscience : a journal and virtual library, Vol. 4, 1999.

Research output: Contribution to journalArticle

Gouillon, ZQ, Miyamoto, K, Donohue, TM, Wan, Y-JY, French, BA, Nagao, Y, Fu, P, Reitz, RC, Hagbjork, A, Yap, C, Yuan, QX, Ingelman-Sundberg, M & French, SW 1999, 'Role of CYP2E1 in the pathogenesis of alcoholic liver disease: modifications by cAMP and ubiquitin-proteasome pathway.', Frontiers in bioscience : a journal and virtual library, vol. 4.
Gouillon, Z. Q. ; Miyamoto, K. ; Donohue, T. M. ; Wan, Yu-Jui Yvonne ; French, B. A. ; Nagao, Y. ; Fu, P. ; Reitz, R. C. ; Hagbjork, A. ; Yap, C. ; Yuan, Q. X. ; Ingelman-Sundberg, M. ; French, S. W. / Role of CYP2E1 in the pathogenesis of alcoholic liver disease : modifications by cAMP and ubiquitin-proteasome pathway. In: Frontiers in bioscience : a journal and virtual library. 1999 ; Vol. 4.
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abstract = "The ethanol inducible isoform of cytochrome P450, CYP2E1, may play a role in ethanol-induced liver injury. Therefore, the factors which govern CYP2E1 degradation and turnover were investigated. These factors include cAMP, ubiquitin, proteasomal enzymes and CYP2E1 mRNA. Rats fed ethanol or pair-fed isocaloric dextrose were pair-fed with rats fed ethanol or dextrose treated with cAMP for 2 months. The liver pathology, regenerative activity, fatty acid composition, NFkappaB activation, ubiquitin conjugates and proteasomal enzymes were measured as were the apoprotein levels of CYP2E1, CYP3A, CYP4A and mRNA levels for CYP2E1 and ubiquitin expression. The results showed, that the cAMP treatment ameliorated the increase liver fat storage and changes in the fatty acid composition in the livers of ethanol fed rats. Other histologic features of alcoholic liver disease were not changed. Western blot quantitation showed that the amount of ubiquitin and ubiquitin conjugates were markedly reduced by ethanol treatment. Similarly, ethanol decreased the level of ubiquitin mRNA. cAMP ameliorated the inhibition of the proteasomal enzyme proteolysis caused by ethanol feeding. The ethanol-induced increase in the CYP2E1 protein was partially inhibited by cAMP treatment. cAMP treatment decreased CYP2E1 mRNA levels in both ethanol-fed and pair fed control rats. Likewise NFkappaB activation was not increased by ethanol but cAMP reduced the level of NFkappaB activation. CAMP treatment also reduced CYP4A but not CYP3A. The results support the concept that cAMP treatment partially protects the liver from ethanol-induced fatty liver by reducing CYP2E1 induction through cAMP's effects on CYP2E1 synthesis.",
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T2 - modifications by cAMP and ubiquitin-proteasome pathway.

AU - Gouillon, Z. Q.

AU - Miyamoto, K.

AU - Donohue, T. M.

AU - Wan, Yu-Jui Yvonne

AU - French, B. A.

AU - Nagao, Y.

AU - Fu, P.

AU - Reitz, R. C.

AU - Hagbjork, A.

AU - Yap, C.

AU - Yuan, Q. X.

AU - Ingelman-Sundberg, M.

AU - French, S. W.

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