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Carcinogen-Protein Complexes in Liver during Hepatocarcinogenesis by Aflatoxin B₁¹

The Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111

To furnish a basis for evaluation of the roles of individual carcinogen-protein complexes in carcinogenesis, this study provides the initial description of the different kinds of aflatoxin-protein complexes that are present in liver throughout hepatocarcinogenesis by aflatoxin B₁ (AFB₁) in rats. The various classes of carcinogen-protein complexes have been separated according to molecular size and charge, quantitated, and characterized in part. Male rats were fed a diet containing AFB₁ (1 mg/kg) for 0, 4, 8, 16, or 24 weeks or the same diet without carcinogen (control) for 24 weeks. The rats were then given a single intragastric dose of [³H]AFB₁ and sacrificed 18 or 48 hr later. The kinds and relative amounts of labeled aflatoxin-protein complexes present in liver cytosol were essentially unchanged throughout the period of carcinogen feeding. At least eight macromolecular size classes of labeled complexes were separated by gel filtration, and their amounts and modal molecular weights were determined. In addition, three major and one minor weakly acidic classes and two weakly basic species of radioactive macromolecular complexes were resolved by chromatography involving ion exchange and molecular sieving. In contrast, direct incubation (2 hr; 1–4°) of [³H]AFB₁ at 1 x 10^-7 M with nonradioactive liver cytosols of rats fed similarly the AFB₁ diet produced mainly one size class of labeled aflatoxin-protein complexes with a modal molecular weight of 45,000 to 50,000 daltons, the molecular size like that of the class of complexes present in greatest amount in vivo. These in vitro-generated complexes, assumed to result from hydrophobic associations, were distributed over the entire charge-size profile. In addition to macromolecular aflatoxin complexes, both liver cytosols labeled in vivo or in vitro also had a radioactive nonmacromolecular aflatoxin adduct with an estimated molecular weight of 500 to 5000 daltons.

The ability of metabolites of AFB₁ to interact in vivo with a wide variety of liver proteins (this report) as well as extensively with DNA and RNA (the studies of others) suggests that metabolites of AFB₁ react nonspecifically with liver macromolecules generally. It appears reasonable to speculate that the extraordinary carcinogenic potency of AFB₁ may be due to its related capacity to inflict multiple molecular insults on target cells. Finally, the presence of multiple aflatoxin macromolecular adducts in liver undergoing carcinogenesis by AFB₁ raises the level of complexity of the problem of determining which interactions between activated aflatoxins and target macromolecules are of importance in the oncogenic process.

¹ Supported in part by NIH Grants CA-05945, CA-06927, and RR-05539 and by an appropriation from the Commonwealth of Pennsylvania.

² To whom requests for reprints should be addressed, at The Institute for Cancer Research, 7701 Burholme Avenue, Philadelphia, Fox Chase, Pa. 19111.

Received 6/ 2/77. Accepted 8/30/77.