Effect of azo-dye carcinogenesis on enzymes concerned with urea synthesis in rat liver

Abstract

The activities of the urea-cycle enzymes (carbamoyl phosphate synthetase and ornithine trans-carbamoylase, located in the mitochondira, and arginine synthetase, argininosuccinase and arginase, located in the soluble fraction of the cell) have been measured in rat liver in both the precancerous stage and in the tumours resulting from giving carcinogenic azo-dyes in the diet. The activities of all the urea-cycle enzymes are very low in primary liver tumours induced with 4-dimethylamino-azobenzene and its derivatives. The relative activities of the urea-cycle enzymes have been studied after different periods of giving azo-dyes. The earliest change found was a transient increase in the activity of carbamoyl phosphate synthetase after giving the diet containing azo-dye for 5 days; after 2 weeks'' treatment arginase activity was also increased but ornithine transcarbamoylase activity was decreased significantly. With longer periods of treatment with azo-dyes a gradual decline in the activities of the urea-cycle enzymes was noted, although those of the enzymes located in the soluble fraction of the cell decreased less rapidly. Removal of the azo-dye after 4 weeks'' treatment results in almost complete reversal of these changes within 12 days. The activity of liver glucose 6-phos-phate dehydrogenase was almost doubled when rats were given 4-dimethylamino-3[image]-methylazobenzene for 2.5 weeks; in contrast, the activity of 6-phosphogluconate dehydrogenase was unchanged. These results are discussed in relation to control at branch points of metabolism; in particular the very low activities of carbamoyl phosphate synthetase and ornithine transcarbamoylase in primary hepatomas are considered in relation to the requirements for carbamoyl phosphate for both urea production and pyrimidine synthesis.