Identification of Aflatoxin M sub(1)-N super(7)-Guanine in Liver and Urine of Tree Shrews and Rats Following Administration of Aflatoxin B sub(1)

• Published in: Chemical research in toxicology 2003-09, Vol.16 (9), p.1174-1180
• Main Authors: Egner, P A, Yu, X, Johnson, J K, Nathasingh, C K, Groopman, J D, Kensler, T W, Roebuck, B D
• Format: Article
• Language: English
• Subjects: aflatoxin M1; Tupia belangeri chinensis
• ISSN: 0893-228X
• DOI: 10.1021/tx034106u

Epidemiological studies have shown that exposure to aflatoxin B sub(1) (AFB sub(1)) and concurrent infection with hepatitis B lead to a multiplicative risk of developing liver cancer. This chemical-viral interaction can be recapitulated in the tree shrew (Tupia belangeri chinensis). As an initial characterization of this model, the metabolism of AFB sub(1) in tree shrews has been examined and compared to a sensitive bioassay species, the rat. Utilizing LC/MS/MS, an unreported product, aflatoxin M sub(1)-N super(7)-guanine (AFM sub(1)-N super(7)-guanine), was detected in urine and hepatic DNA samples 24 h after administration of 400 mu g/kg AFB sub(1). In hepatic DNA isolated from tree shrews, AFM sub(1)-N super(7)-guanine was the predominant adduct, 0.74 plus or minus 0.14 pmol/mg DNA, as compared to 0.37 plus or minus 0.07 pmol/mg DNA of AFB sub(1)-N super(7)-guanine. Conversely, in rat liver, 6.56 plus or minus 2.41 pmol/mg DNA of AFB sub(1)-N super(7)-guanine and 0.42 plus or minus 0.13 pmol/mg DNA of AFM sub(1)-N super(7)-guanine were detected. Rats excreted 1.00 plus or minus 0.21 pmol AFB sub(1)-N super(7)-guanine/mg creatinine and 0.29 plus or minus 0.10 pmol AFM sub(1)-N super(7)-guanine/mg creatinine as compared to 0.60 plus or minus 0.12 pmol AFB sub(1)-N super(7)-guanine/mg creatinine and 0.69 plus or minus 0.16 pmol AFM sub(1)-N super(7)-guanine/mg creatinine excreted by the three shrew. Furthermore, tree shrew urine contained 40 times more of the hydroxylated metabolite, AFM sub(1), than was excreted by rats. In vitro experiments confirmed this difference in oxidative metabolism. Hepatic microsomes isolated from tree shrews failed to produce aflatoxin Q sub(1) or aflatoxin P sub(1) but formed a significantly greater amount of AFM sub(1) than rat microsomes. Bioassays indicated that the tree shrew was considerably more resistant than the rat to AFB sub(1) hepatocarcinogenesis, which may reflect the significant differences in metabolic profiles of the two species.