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Metabolic Adaptations during Hepatocarcinogenesis: Dietary Induction of Some Enzymes of Carbohydrate Metabolism during 3'-Methyl- and 2-Methyl-N,N-dimethyl-4-amino-azobenzene Feeding¹

Department of Oncology and Pathology, McArdle Laboratory, The Medical School, University of Wisconsin, Madison, Wisconsin 53706

The dietary induction of the hepatic liver enzymes, glucokinase (ATP:D-glucose-6-phosphotransferase, EC 2.7.1.2), glucose-6-phosphate dehydrogenase (D-glucose-6-phosphate:NADP oxidoreductase, EC 1.1.1.49), 6-phosphogluconate dehydrogenase [6-phospho-D-gluconate:NAD(P) oxidoreductase, EC 1.1.1.43], malic enzyme [L-malate:NADP oxidoreductase (decarboxylating), EC 1.1.1.40), and citrate cleavage [ATP:citrate oxaloacetate lyase (CoA-acetylating and ATP-dephosphorylating), EC 4.1.3.8] in rats fasted for 3 days before and after a 27-hr refeeding period with a 30% protein diet was investigated in rats fed a low-protein, low-riboflavin diet or the same diet containing 0.054% 3'-methyl-4-dimethyl-aminoazobenzene (3'-methyl-DAB) or 0.054% 2-methyl-4-dimethylaminoazobenzene (2-methyl-DAB). The metabolic responses of all of the enzymes studied were found to be absent or diminished in the animals fed the 3'-methyl-DAB diet for 3 to 5 weeks. Except for 6-phosphogluconate dehydrogenase, the adaptation of which was found to be slightly diminished at the end of 5 weeks of administration of the basal diet, the metabolic responses of each of the enzymes in the control animals remained essentially normal throughout the experimental period. The chronic administration of the noncarcinogenic dye, 2-methyl-DAB, appeared to produce a loss in the inducibility of 6-phosphogluconate dehydrogenase, a diminished response of glucose-6-phosphate dehydrogenase, and no effect on the metabolic adaptations of the other 3 enzymes investigated. Feeding 3'-methyl-DAB appeared to produce an increase in the base level of glucose-6-phosphate dehydrogenase and a marked decrease in the base levels of glucokinase and malic enzyme; the base levels of this latter enzyme were also diminished in the livers of rats fed either 2-methyl-DAB or the basal diet. The base levels of all of the other adaptive enzymes tested appeared to be unaffected by any of the diets used in these experiments. The data indicate that, as with rats fed 2-acetylaminofluorene, the normal metabolic responses of the enzymes of carbohydrate metabolism were lost or diminished in the livers of rats fed 3'-methyl-DAB. Although the effects of 3'-methyl-DAB on the adaptive responses of these enzymes were less striking than those produced by AAF, they were still considerably more marked than those observed in rats fed the basal diet with or without 2-methyl-DAB.

¹ This work was supported in part by grant CA-07175 from the National Cancer Institute, USPHS, and Grant P-134 from the American Cancer Society.

² Postdoctoral Fellow of the National Cancer Institute (CA-30715). Present address: Institut du Cancer de Montreal, Hôpital Notre-Dame, et Departement de Biochimie, Universite de Montreal, Montreal, Quebec, Canada.

Received 10/17/69. Accepted 3/ 6/70.