This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Blackburn, G. R. Articles by Sorof, S. Search for Related Content PubMed PubMed Citation Articles by Blackburn, G. R. Articles by Sorof, S.

Early Events during Liver Carcinogenesis Involving Two Carcinogen:Protein Complexes¹

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

This report describes the relationships between the levels of two principal carcinogen:protein complexes and histological alterations that occur during carcinogenesis in rat liver by three carcinogens. An intragastric tracer dose of N-[9-¹⁴C]2-fluorenylacetamide interacts in normal rat liver to form the principal cytosolic ¹⁴C-carcinogen:protein complex (2S; M.W. 14,700). Continued ingestion of any of three hepatocarcinogens causes the marked loss of the 2S complex and the concurrent gain of a large-molecular-weight carcinogen:protein complex (7.5S; M.W. 150,000) 48 hr following a dose of N-[9-¹⁴C]-2-fluorenylacetamide. The reciprocal changes in amounts of the two complexes have the following properties. The alterations occur early during hepatocarcinogenesis. In contrast to other reported early events, chemical carcinogen is directly involved. The two labeled fluorenyl proteins are the principal ¹⁴C-carcinogen:protein complexes in rat liver cytosol. Formation of the two complexes apparently involves activation of the carcinogen N-2-fluorenylacetamide. The reciprocal effects are brought on by the ingestion of any of three hepatocarcinogens, the aromatic amide N-2-fluorenylacetamide, the aminoazo dye 3'-methyl-4-dimethylaminoazobenzene, and the amino acid analog ethionine. In contrast, neither their noncarcinogenic chemical analogs, fluorene and aminoazobenzene, nor the inducers of the microsomal monooxygenases, 3-methylcholanthrene and phenobarbital, nor control diets (without carcinogens) cause these effects. The loss of the 2S complex was previously demonstrated by this laboratory to be associated with the loss of the 2S protein itself (14,700-daltons polypeptide) to which the carcinogen is bound. The rate of inversion in concentrations of the two complexes is apparently related to the susceptibility of the strain and sex of rat to the carcinogen; the greater the susceptibility the more rapid is the rate. The time of the maximal inversion coincides approximately with the appearance of putative premalignant lesions. Cessation of N-2-fluorenylacetamide ingestion results in the symmetrical reversal of the reciprocal changes in the levels of the two complexes. Liver regeneration following partial hepatectomy brings about a moderate inversion of the levels of the two complexes, suggestive of the possibility that the cell proliferation associated with hepatocarcinogenesis may be causally related to the effects. Consistent with this possibility, the 2S protein has a molecular weight like those of known polypeptide growth regulators. The effects on the 2S and 7.5S carcinogen:protein complexes are carcinogen group specific, inasmuch as the ingestion of any of three other types of liver carcinogens, namely, diethylnitrosamine, aflatoxin B₁, and thioacetamide, does not induce the reciprocal changes in the levels of the two complexes. The existence of such carcinogen group specificity suggests that chemical classes of carcinogens may be grouped on the basis of their common actions and effects on their target macromolecules. The generalizations to be derived from a classification of carcinogen group specificities seem likely to advance understanding of underlying events in chemical oncogenesis.

¹ Supported in part by USPHS Grants CA-05945, CA-21522, CA-06927, and RR-05539 from the National Cancer Institute and by an appropriation from the Commonwealth of Pennsylvania. Presented in part at the 72nd Meeting of the American Association for Cancer Research, Washington, D. C., April 1981 (1).

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

Received 5/ 8/81. Accepted 7/ 9/81.