TY - JOUR
T1 - Transgenic expression of aflatoxin aldehyde reductase (AKR7A1) modulates aflatoxin B1 metabolism but not hepatic carcinogenesis in the rat
AU - Roebuck, Bill D.
AU - Johnson, Denise N.
AU - Sutter, Carrie Hayes
AU - Egner, Patricia A.
AU - Scholl, Peter F.
AU - Friesen, Marlin D.
AU - Baumgartner, Karen J.
AU - Ware, Nicholas M.
AU - Bodreddigari, Sridevi
AU - Groopman, John D.
AU - Kensler, Thomas W.
AU - Sutter, Thomas R.
PY - 2009
Y1 - 2009
N2 - 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, AFB1dialdehyde, 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.
AB - 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, AFB1dialdehyde, 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.
KW - Aflatoxin
KW - Aldo-keto reductase
KW - Chemoprevention, hepatic carcinogenesis
KW - Hepatotoxicity
KW - Transgenic rat
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U2 - 10.1093/toxsci/kfp003
DO - 10.1093/toxsci/kfp003
M3 - Article
C2 - 19168568
AN - SCOPUS:65549160528
SN - 1096-6080
VL - 109
SP - 41
EP - 49
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 1
ER -