ToxSci Advance Access published online on January 23, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp003
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Transgenic expression of aflatoxin aldehyde reductase (AKR7A1) modulates aflatoxin B1 metabolism but not hepatic carcinogenesis in the rat
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* Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755
Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205
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; Telephone, 603-650-1676; Fax, 603-650-1129; e-mail Bill.D.Roebuck{at}dartmouth.edu; TRS; Telephone, 901-678-8391; FAX, 901-678-2458; e-mail tsutter{at}memphis.edu
Received August 29, 2008; revision received December 20, 2008; accepted January 5, 2009
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Abstract |
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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 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 over express 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.