Transgenic expression of aflatoxin aldehyde reductase (AKR7A1) modulates aflatoxin B1 metabolism but not hepatic carcinogenesis in the rat.
In both experimental animals and humans, aflatoxin B(1) (AFB(1)) 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 AFB(1) by enhancing detoxication of a reactive metabolite, AFB(1) dialdehyde, by reduction to alcohols. The AFB(1) 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 AFB(1) and to enhance carcinogenesis. A liver-specific AKR7A1 transgenic rat was constructed in the Sprague-Dawley strain and two lines, AKR7A1(Tg2) and AKR7A1(Tg5), were found to overexpress AKR7A1 by 18- and 8-fold, respectively. Rates of formation of AFB(1) alcohols, both in hepatic cytosols and as urinary excretion products, increased in the transgenic lines with AKR7A1(Tg2) being the highest. Neither line offered protection against acute AFB(1)-induced bile duct proliferation, a functional assessment of acute hepatotoxicity by AFB(1), nor did they protect against the formation of GST-P positive putative preneoplastic foci as a result of chronic exposure to AFB(1). These results imply that the prevention of protein adducts mediated by AKR are not critical to protection against AFB(1) tumorigenicity.
Roebuck
Bill D
BD
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Johnson
Denise N
DN
Sutter
Carrie Hayes
CH
Egner
Patricia A
PA
Scholl
Peter F
PF
Friesen
Marlin D
MD
Baumgartner
Karen J
KJ
Ware
Nicholas M
NM
Bodreddigari
Sridevi
S
Groopman
John D
JD
Kensler
Thomas W
TW
Sutter
Thomas R
TR
D016604:Aflatoxin B1 / Q000378:metabolism* / Q000633:toxicity*; D000438:Alcohols / Q000378:metabolism; D000449:Aldehyde Reductase / Q000235:genetics / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D018736:DNA Adducts / Q000378:metabolism; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic
D000438:Alcohols; D000447:Aldehydes; D002273:Carcinogens; D018736:DNA Adducts; D011506:Proteins; C000717609:Tgm2 protein, rat; D016604:Aflatoxin B1; C442302:AKR7A1; D000449:Aldehyde Reductase; D000091345:Protein Glutamine gamma Glutamyltransferase 2