Skip Navigation


ToxSci Advance Access originally published online on January 23, 2009
Toxicological Sciences 2009 109(1):41-49; doi:10.1093/toxsci/kfp003
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
109/1/41    most recent
kfp003v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
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 Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Roebuck, B. D.
Right arrow Articles by Sutter, T. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Roebuck, B. D.
Right arrow Articles by Sutter, T. R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

HIGLIGHTED ARTICLE

Transgenic Expression of Aflatoxin Aldehyde Reductase (AKR7A1) Modulates Aflatoxin B1 Metabolism but not Hepatic Carcinogenesis in the Rat

Bill D. Roebuck*,1, Denise N. Johnson{dagger}, Carrie Hayes Sutter§, Patricia A. Egner{dagger}, Peter F. Scholl{dagger},{ddagger}, Marlin D. Friesen{dagger}, Karen J. Baumgartner*, Nicholas M. Ware*, Sridevi Bodreddigari§, John D. Groopman{dagger}, Thomas W. Kensler{dagger} and Thomas R. Sutter§,1

* Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755 {dagger} Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205 {ddagger} Center for Food Safety and Nutrition, United States Food and Drug Administration, College Park, Maryland 20740 § W. Harry Feinstone Center for Genomic Research, University of Memphis, Memphis, Tennessee 38152

1 Correspondence to either author: BDR, Tel: (603) 650-1676. Fax: (603) 650-1129. E-mail: Bill.D.Roebuck{at}dartmouth.edu; TRS, Tel: (901) 678-8391. Fax: (901) 678-2458. E-mail: tsutter{at}memphis.edu.

Received August 29, 2008; accepted January 5, 2009


  Abstract

In both experimental animals and humans, aflatoxin B1 (AFB1) is a potent hepatic toxin and carcinogen against which a variety of antioxidants and experimental or therapeutic drugs (e.g., oltipraz, related dithiolethiones, and various triterpenoids) protect from both acute toxicity and carcinogenesis. These agents induce several hepatic glutathione S-transferases (GST) as well as aldo-keto reductases (AKR) which are thought to contribute to protection. Studies were undertaken in transgenic rats to examine the role of one inducible enzyme, AKR7A1, for protection against acute and chronic actions of AFB1 by enhancing detoxication of a reactive metabolite, AFB1 dialdehyde, by reduction to alcohols. The AFB1 dialdehyde forms adducts with protein amino groups by a Schiff base mechanism and these adducts have been theorized to be at least one cause of the acute toxicity of AFB1 and to enhance carcinogenesis. A liver-specific AKR7A1 transgenic rat was constructed in the Sprague-Dawley strain and two lines, AKR7A1Tg2 and AKR7A1Tg5, were found to overexpress AKR7A1 by 18- and 8-fold, respectively. Rates of formation of AFB1 alcohols, both in hepatic cytosols and as urinary excretion products, increased in the transgenic lines with AKR7A1Tg2 being the highest. Neither line offered protection against acute AFB1-induced bile duct proliferation, a functional assessment of acute hepatotoxicity by AFB1, nor did they protect against the formation of GST-P positive putative preneoplastic foci as a result of chronic exposure to AFB1. These results imply that the prevention of protein adducts mediated by AKR are not critical to protection against AFB1 tumorigenicity.

Key Words: aflatoxin; aldo-keto reductase; chemoprevention, hepatic carcinogenesis; hepatotoxicity; transgenic rat.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.