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The Content of the Principal Protein Target of a Hepatic Carcinogen in Liver Tumors¹

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

It has been variously suggested that chemical carcinogens interact with a protein regulator of cell growth, ultimately causing neoplastic cells to arise in which the protein target of the carcinogen is reduced or absent. As a test of the target reduction aspect of these hypotheses, the amount of the principal protein target of a hepatic carcinogen was determined immunologically in liver tumors caused by that carcinogen.

Specific antiserum against the principal liver protein target of a hepatic azocarcinogen was obtained by immunization with the highly purified liver azoprotein isolated from rats fed 3'-methyl-4-dimethylaminoazobenzene for 15 to 18 days. The amount of the target protein in serially diluted liver and liver tumor cytosols was measured by gel double immunodiffusion with a precision of 10% (S.D.) or less.

Little difference in the relative content of the principal target protein was found in the liver cytosols of normal rats and of those fed a diet containing or lacking the azocarcinogen for 15 to 18 days. In contrast, in 15 cytosols of primary liver tumors of 15 rats fed the azocarcinogen until sacrifice, the content of protein target of azocarcinogen was 6 to 31% (average, 18 ± 8% S.D.) of that present in normal rat liver cytosol. In 7 cytosols of livers around tumors, the quantity of target protein was 66 to 116% (average, 83 ± 19% S.D.).

An additional series of assays examined 4 types of transplanted hepatomas that were originally caused by fluorenyl amide and biphenyl amide carcinogens. These carcinogens probably have principal target proteins that are different from those of azocarcinogens. Three kinds of well-differentiated hepatomas had mean levels (85 to 98%) of the protein target of azocarcinogens like that of normal liver. One type of poorly differentiated hepatoma had < 3%.

The finding of a reduction in amount of principal protein target of a carcinogen in primary tumors caused by that carcinogen, and not in transplanted differentiated tumors caused by other carcinogens, suggests two alternatives, namely, either the reduction need be specifically that of the target protein of the carcinogen which caused the neoplasm or it is due to other causes, e.g., tumor progression, and therefore is not essential for neoplasia per se. These alternatives are separate from the more basic question of the role (if any) of the carcinogen-protein interaction in chemical carcinogenesis, possibly as part of a mechanism not involving target protein depletion in tumors.

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

Received 6/14/73. Accepted 8/ 9/73.

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