title: Identification of aflatoxin M1-N7-guanine in liver and urine of tree shrews and rats following administration of aflatoxin B1.
abstract: Epidemiological studies have shown that exposure to aflatoxin B(1) (AFB(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(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(1)-N(7)-guanine (AFM(1)-N(7)-guanine), was detected in urine and hepatic DNA samples 24 h after administration of 400 microg/kg AFB(1). In hepatic DNA isolated from tree shrews, AFM(1)-N(7)-guanine was the predominant adduct, 0.74 +/- 0.14 pmol/mg DNA, as compared to 0.37 +/- 0.07 pmol/mg DNA of AFB(1)-N(7)-guanine. Conversely, in rat liver, 6.56 +/- 2.41 pmol/mg DNA of AFB(1)-N(7)-guanine and 0.42 +/- 0.13 pmol/mg DNA of AFM(1)-N(7)-guanine were detected. Rats excreted 1.00 +/- 0.21 pmol AFB(1)-N(7)-guanine/mg creatinine and 0.29 +/- 0.10 pmol AFM(1)-N(7)-guanine/mg creatinine as compared to 0.60 +/- 0.12 pmol AFB(1)-N(7)-guanine/mg creatinine and 0.69 +/- 0.16 pmol AFM(1)-N(7)-guanine/mg creatinine excreted by the tree shrew. Furthermore, tree shrew urine contained 40 times more of the hydroxylated metabolite, AFM(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(1) or aflatoxin P(1) but formed a significantly greater amount of AFM(1) than rat microsomes. Bioassays indicated that the tree shrew was considerably more resistant than the rat to AFB(1) hepatocarcinogenesis, which may reflect the significant differences in metabolic profiles of the two species.
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA. pegner@jhsph.edu
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Egner
authors.forename: Xiang
authors.initials: X
authors.lastname: Yu
authors.forename: Jesse K
authors.initials: JK
authors.lastname: Johnson
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Nathasingh
authors.forename: John D
authors.initials: JD
authors.lastname: Groopman
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kensler
authors.forename: Bill D
authors.initials: BD
authors.lastname: Roebuck
mesh_terms: D000284:Administration, Oral; D016604:Aflatoxin B1 / Q000008:administration & dosage* / Q000009:adverse effects / Q000652:urine; D016607:Aflatoxin M1 / Q000737:chemistry / Q000378:metabolism / Q000652:urine*; D000818:Animals; D002853:Chromatography, Liquid; D018736:DNA Adducts / Q000096:biosynthesis / Q000302:isolation & purification / Q000652:urine; D004249:DNA Damage / Q000187:drug effects; D006147:Guanine / Q000737:chemistry / Q000378:metabolism / Q000652:urine; D006900:Hydroxylation; D008099:Liver / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000201:enzymology; D023421:Models, Animal; D051381:Rats; D011916:Rats, Inbred F344 / Q000652:urine*; D014418:Tupaiidae / Q000652:urine*
chemical_list: D018736:DNA Adducts; D006147:Guanine; D016607:Aflatoxin M1; D016604:Aflatoxin B1