JPET Celsis microsomes equal better data

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wang, T.
Right arrow Articles by Mehendale, H. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wang, T.
Right arrow Articles by Mehendale, H. M.

Vol. 294, Issue 2, 473-479, August 2000

Potentiation of Thioacetamide Liver Injury in Diabetic Rats Is Due to Induced CYP2E11

Tao Wang, Kartik Shankar, Martin J. J. Ronis and Harihara M. Mehendale

Division of Toxicology, College of Pharmacy, The University of Louisiana at Monroe, Monroe, Louisiana (T.W., K.S., H.M.M.); and Arkansas Children's Hospital Research Institute, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas (M.J.J.R.)

Thioacetamide (TA)-induced hepatotoxicity is potentiated in streptozotocin (STZ)-induced diabetic rats. The relative roles of CYP2E1 and FMO1 in the mechanism of TA-associated liver injury were investigated. In the STZ-induced diabetic rat, hepatic CYP2E1 protein concentration and p-nitrophenol hydroxylation were induced 8- and 5.6-fold, respectively. Pretreatment with the CYP2E1 inducer, isoniazid (INH, 250 mg/kg, i.p.) before TA (300 mg/kg, i.p.) administration significantly increased TA-associated liver injury as assessed by plasma alanine aminotransferase (ALT). Hepatic CYP2E1 expression and p-nitrophenol hydroxylation were induced 2.2- and 2.5-fold in the INH-pretreated rat, respectively. Inhibition of CYP2E1 by diallyl sulfide (DAS, 200 mg/kg, p.o., two doses) before TA administration, decreased plasma ALT activity by 60% in the nondiabetic rat and by 75% in the diabetic rat. Abolition of microsomal p-nitrophenol hydroxylation and CCl4-induced liver injury confirmed that hepatic CYP2E1 was highly inhibited by DAS. Hepatic flavin-containing monooxygenase (FMO) form 1 expression and methimazole-dependent oxidation of thiocholine were induced 2.5- and 1.8-fold in the diabetic rat, respectively. Dietary administration of 0.25% indole-3-carbinol (I3C) for 10 days inhibited FMO1 expression and enzyme activity in both nondiabetic and diabetic rats. Paradoxically, TA-induced liver injury was increased in these I3C-pretreated rats. These findings indicate that hepatic CYP2E1 appears to be primarily involved in bioactivation of TA. In the STZ-induced diabetic rat, diabetes-induced CYP2E1 appears to be responsible for the potentiated liver injury; Even though hepatic FMO1 is induced in the diabetic rat, it is unlikely to mediate the potentiated TA hepatotoxicity.

1 This study was supported by the Louisiana Board of Regents Fund through the University of Louisiana at Monroe, Kitty DeGree Chair in Pharmacy (Toxicology). Preliminary (1999) results of this study were presented at the EB99 Annual Meeting of FASEB, Washington DC (Wang et al., 1999).

0022-3565/00/2942-0473$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
J. N. Baumgardner, K. Shankar, S. Korourian, T. M. Badger, and M. J. J. Ronis
Undernutrition enhances alcohol-induced hepatocyte proliferation in the liver of rats fed via total enteral nutrition
Am J Physiol Gastrointest Liver Physiol, July 1, 2007; 293(1): G355 - G364.
[Abstract] [Full Text] [PDF]

Home page
 Appl. Environ. Microbiol.Home page
A. G. Dodge, J. E. Richman, G. Johnson, and L. P. Wackett
Metabolism of Thioamides by Ralstonia pickettii TA
Appl. Envir. Microbiol., December 1, 2006; 72(12): 7468 - 7476.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
S. P. Sawant, A. V. Dnyanmote, M. S. Mitra, J. Chilakapati, A. Warbritton, J. R. Latendresse, and H. M. Mehendale
Protective Effect of Type 2 Diabetes on Acetaminophen-Induced Hepatotoxicity in Male Swiss-Webster Mice
J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 507 - 519.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
J. Chilakapati, K. Shankar, M. C. Korrapati, R. A. Hill, and H. M. Mehendale
SATURATION TOXICOKINETICS OF THIOACETAMIDE: ROLE IN INITIATION OF LIVER INJURY
Drug Metab. Dispos., December 1, 2005; 33(12): 1877 - 1885.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
K. Minami, T. Saito, M. Narahara, H. Tomita, H. Kato, H. Sugiyama, M. Katoh, M. Nakajima, and T. Yokoi
Relationship between Hepatic Gene Expression Profiles and Hepatotoxicity in Five Typical Hepatotoxicant-Administered Rats
Toxicol. Sci., September 1, 2005; 87(1): 296 - 305.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol PatholHome page
H. M. Mehendale
Tissue Repair: An Important Determinant of Final Outcome of Toxicant-Induced Injury
Toxicol Pathol, January 1, 2005; 33(1): 41 - 51.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol PatholHome page
U. M. Apte, R. Mcree, and S. K. Ramaiah
Hepatocyte Proliferation is the Possible Mechanism for the Transient Decrease in Liver Injury During Steatosis Stage of Alcoholic Liver Disease
Toxicol Pathol, August 1, 2004; 32(5): 567 - 576.
[Abstract] [PDF]

Home page
 Toxicol SciHome page
K. Shankar, V. S. Vaidya, U. M. Apte, J. E. Manautou, M. J. J. Ronis, T. J. Bucci, and H. M. Mehendale
Type 1 Diabetic Mice Are Protected from Acetaminophen Hepatotoxicity
Toxicol. Sci., June 1, 2003; 73(2): 220 - 234.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
U. M. Apte, P. B. Limaye, D. Desaiah, T. J. Bucci, A. Warbritton, and H. M. Mehendale
Mechanisms of Increased Liver Tissue Repair and Survival in Diet-Restricted Rats Treated with Equitoxic Doses of Thioacetamide
Toxicol. Sci., April 1, 2003; 72(2): 272 - 282.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
S. K. Ramaiah, U. Apte, and H. M. Mehendale
Cytochrome P4502E1 Induction Increases Thioacetamide Liver Injury in Diet-Restricted Rats
Drug Metab. Dispos., August 1, 2001; 29(8): 1088 - 1095.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2000 by the American Society for Pharmacology and Experimental Therapeutics.