BIOCHEMICAL CHRONOLOGY OF 2-ACETYLAMINOFLUORENE - INDUCED HEPATOCARCINOGENESIS: UDP KINASE AND CTP SYNTHETASE

WILLIAM LEON ELLIOTT, Purdue University

Abstract

Previous studies indicated a cascade of biochemical events leading to glycolipid simplification in experimental liver cancer (J. Natl. Cancer Inst. 60:1313, 1978). The products of the enzymatic reactions UDP kinase and CTP synthetase, UTP and CTP, serve not only as substrates for RNA and DNA biosynthesis but also, through intermediary metabolites as substrates in the biogenesis of membrane glycolipids. These enzymes were analyzed during an 11 week continuum of hepatocarcinogenesis in the rat to investigate alterations in these enzymes with respect to the glycolipid cascade. The carcinogen, 2-acetylaminofluorene, was administered in a basal diet (0.25 g/kg) according to a modified Farber schedule. Three test animals were sacrificed at each time point and the experiment repeated three times. Animals fed basal diet lacking carcinogen were compared to animals fed normal rat chow as controls. Two cycles, each composed of a rise in UDP kinase followed by a rise in CTP synthetase specific activity, were observed prior to the initiation of the glycolipid cascade after which a third cycle began. Peaks in UDP kinase specific activity were observed at 11 (2-fold), 28 (3-fold), and 49 days (3.6-fold). These were followed by peaks in CTP synthetase activity at 14 (2-fold), 49 (2.5-fold), and 70 days (3-fold). Enzyme activity, once elevated in the test series, never returned to normal levels. AAF liver toxicity was not responsible for the alterations observed during carcinogenesis since feeding 1.87% 4-acetamidophenol (AAP), a non-carcinogenic hepatotoxin structurally related to AAF, did not induce the same enzymatic alterations. Further comparison of the carcinogenesis alterations with regenerating liver values and values from diet stressed animals verified that the elevations observed were specific for carcinogenesis. Results indicate that alterations in UDP kinase and CTP synthetase during hepatocarcinogenesis are part of a larger biochemical cascade including enzymes of glycolipid biosynthesis. Results also verified that alterations observed in transplantable tumors also extend to the carcinogenic process. The findings provide a basis for an ongoing series of investigations with a view toward identifying the minimal deviation events of carcinogenesis to enable the design of novel chemotherapeutic/chemopreventive agents.

Degree

Ph.D.

Subject Area

Biochemistry

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