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Research ArticleArticle

Cytochrome P4502E1 Induction Increases Thioacetamide Liver Injury in Diet-Restricted Rats

Shashi K. Ramaiah, Udayan Apte and Harihara M. Mehendale
Drug Metabolism and Disposition August 2001, 29 (8) 1088-1095;
Shashi K. Ramaiah
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Udayan Apte
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Harihara M. Mehendale
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Abstract

Earlier studies have shown highly exaggerated mechanism-based liver injury of thioacetamide (TA) in rats following moderate diet restriction (DR) and in diabetes. The objective of the present study was to investigate the mechanism of higher liver injury of TA in DR rats. Since both DR and diabetes induce CYP2E1, we hypothesized that hepatic CYP2E1 plays a major role in the bioactivation-based liver injury of TA. When male Sprague-Dawley rats (250–275 g) were maintained on diet restriction (DR, 35% of ad libitum fed rats, 21 days) the total hepatic microsomal cytochrome P450 (CYP450) was increased 2-fold along with a 4.6-fold increase in CYP2E1 protein, which corresponded with a 3-fold increase in CYP2E1 activity as measured by chlorzoxazone hydroxylation. To further test the involvement of CYP2E1, 24 and 18 h after pretreatment with pyridine (PYR) and isoniazid (INZ), specific inducers of CYP2E1, male Sprague-Dawley rats received a single administration of 50 mg of TA/kg (i.p.). TA liver injury was >2.5- and >3-fold higher at 24 h in PYR + TA and INZ + TA groups, respectively, compared with the rats receiving TA alone. Pyridine pretreatment resulted in significantly increased total CYP450 content accompanied by a 2.2-fold increase in CYP2E1 protein and 2-fold increase in enzyme activity concordant with increased liver injury of TA, suggesting mechanism-based bioactivation of TA by CYP2E1. Hepatic injury of TA in DR rats pretreated with diallyl sulfide (DAS), a well known irreversible in vivo inhibitor of CYP2E1, was significantly decreased (60%) at 24 h. CCl4 (4 ml/kg i.p.), a known substrate of CYP2E1, caused lower liver injury and higher animal survival confirming inhibition of CYP2E1 by DAS pretreatment. The role of flavin-containing monooxygenase (FMO) in TA bioactivation implicated by previous in vitro studies, and consequent increased TA-induced liver injury in DR rats was tested in vivo with a relatively selective inhibitor of FMO, indole-3-carbinol, and then treated with 50 mg of TA/kg. FMO activity and alanine aminotransferase levels measured at different time points revealed that TA liver injury was not decreased although FMO activity was significantly decreased, suggesting that hepatic FMO is unlikely to bioactivate TA. These findings suggest induction of CYP2E1 as the primary mechanism of increased bioactivation-based liver injury of TA in DR rats.

Footnotes

  • This study was supported by Grant ES-09870 from the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health, and by the Louisiana Board of Regents through the Kitty DeGree Endowed Chair in Toxicology made possible through the Eminent Scholars Endowment Program established at The University of Louisiana at Monroe. Preliminary results of this study were presented at the EB99 Annual Meeting of Federation of American Societies for Experimental Biology, Washington, DC. FASEB J (1999)13:A811.

  • 1 Present Address: Clinical Pathology, Department of Physiological Sciences, College of Veterinary Medicine, Veterinary Medical Teaching Hospital, University of Florida, Gainesville, FL 32610-0103.

  • Abbreviations used are::
    TA
    thioacetamide
    CYP450
    cytochrome P450
    FMO
    flavin-containing monooxygenase
    DR
    diet restriction/diet restricted
    HPLC
    high-performance liquid chromatography
    AL
    ad libitum
    PYR
    pyridine
    INZ
    isoniazid
    Veh
    vehicle
    DAS
    diallyl sulfide
    ALT
    alanine aminotransferase
    I3C
    indole-3-carbinol
    • Received December 4, 2000.
    • Accepted April 18, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (8)
Drug Metabolism and Disposition
Vol. 29, Issue 8
1 Aug 2001
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Research ArticleArticle

Cytochrome P4502E1 Induction Increases Thioacetamide Liver Injury in Diet-Restricted Rats

Shashi K. Ramaiah, Udayan Apte and Harihara M. Mehendale
Drug Metabolism and Disposition August 1, 2001, 29 (8) 1088-1095;

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Research ArticleArticle

Cytochrome P4502E1 Induction Increases Thioacetamide Liver Injury in Diet-Restricted Rats

Shashi K. Ramaiah, Udayan Apte and Harihara M. Mehendale
Drug Metabolism and Disposition August 1, 2001, 29 (8) 1088-1095;
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