Aflatoxin-albumin adducts: a basis for comparative carcinogenesis between animals and humans.
The study objectives were (a) to correlate AFB1 serum albumin adduct levels with AFB1-DNA adduct levels in liver in different rodent species to determine whether the former could serve as a marker of hepatic DNA adduct levels irrespective of species, and (b) to relate the levels of both adducts to differences in susceptibility to tumor induction by AFB1 in the different species. Finally, an attempt was made to compare the dose response for AFB1-albumin adduct formation in the rodent species with that in human populations exposed environmentally to AFB1. Three strains of rat (Fischer 344, Wistar, and Sprague-Dawley), and one strain each of guinea pig (Hartley), hamster (Syrian golden), and mouse (C57BL) were treated by gavage with up to 14 daily doses of between 1 and 80 mug AFB1/kg body weight. Animals were killed 24 h after 1, 3, 7, or 14 days treatment. A dose response in both AFB1-albumin and AFB1-DNA adducts was seen for all species and strains with steady-state adduct levels at 14 days. In rat strains at 14 days after treatment with 20 mu g/kg, the mean AFB1-albumin levels were between 24 and 26 pg AFB1-lysine equivalent/mg albumin, and the mean AFB1-DNA adduct levels were between 1.5 and 2.5 pmol (8, 9-dihydro-8- (2, 6-diamino-4-oxo-3, 4-dihydro-pyrimid-5-ylforamido-)- 9-hydroxy) AFB1/mg DNA. The level of both adducts was in the following order: rat > guinea pig > hamster > mouse. In the case of AFB1-albumin, the mean adduct level at 14 days in the three rat strains was approximately 1.5, 3.0, and 8-fold higher than in the guinea pig, hamster, and mouse, respectively. When the levels of the albumin and DNA adducts at 14 days were plotted against each other for all species and strains, a correlation was observed (r = 0.83; P = < 0.0001; n = 57; two-tailed test) suggesting a constant relationship between the level of binding of AFB1 to serum albumin and liver DNA. The levels of AFB1-albumin adduct also reflect at least qualitatively the relative susceptibility of the different species to AFB1 carcinogenesis; the rat is sensitive and the hamster and mouse are resistant. The level of AFB1-albumin adduct formed as a function of a single dose of AFB1 in rodents was compared to data from humans exposed environmentally to AFB1. This comparison yielded a value for the three rat strains of between 0.3 and 0.51 pg AFB1-lysine equivalent/mg albumin/1 mu g AFB1/kg body weight and a value for the mouse of <0.025. The best estimate for people from The Gambia and southern China was 1.56 pg/mg albumin for the same exposure. These data suggest that humans exposed to AFB1 form amounts of albumin addducts, and by extrapolation amounts of DNA adducts, closer to those observed in AFB1-sensitive species and 1-2 orders of magnitude higher levels than the AFB1-resistant species.
Wild
C P
CP
International Agency for Research on Cancer, Lyon, France.
Hasegawa
R
R
Barraud
L
L
Chutimataewin
S
S
Chapot
B
B
Ito
N
N
Montesano
R
R
D000348:Aflatoxins / Q000009:adverse effects / Q000032:analysis*; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D001835:Body Weight; D002273:Carcinogens / Q000009:adverse effects / Q000032:analysis*; D002681:China; D006224:Cricetinae; D018736:DNA Adducts / Q000032:analysis*; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure; D005714:Gambia; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000209:etiology*; D008239:Lysine / Q000032:analysis; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012709:Serum Albumin / Q000032:analysis*; D013045:Species Specificity; D013997:Time Factors
D000348:Aflatoxins; D014408:Biomarkers, Tumor; D002273:Carcinogens; D018736:DNA Adducts; D012709:Serum Albumin; D008239:Lysine