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Systematic Oscillations in Metabolic Activity in Rat Liver and in Hepatomas

I. Morris Hepatoma No. 7793¹

McArdle Laboratory, Medical Center, University of Wisconsin, Madison, Wisconsin

Environmentally induced changes in rat liver were used to determine the capability of a minimal deviation hepatoma (Morris hepatoma 7793) to respond to regulatory influences. Hepatomabearing rats were divided among 20 experimental groups testing all possible combinations of 5 levels of dietary protein and 4 different times in the 24-hr day. Casein was fed at levels of 0, 12, 30, 60, and 90%, with glucose as the other variable. Lighting was 6 A.M. to 6 P.M., and animals were killed at 06:00, 12:00, 18:00, and 24:00. Only 2 rats were used in each group, but each group was reenforced by either 4 or 3 other adjacent groups in the experimental pattern. The hepatoma was 1 of the most slowly growing hepatomas available, and the animals were killed 149 days after transplantation, when the hepatomas weighed between 3 and 6 gm in most cases. The animals were adapted to the diet for 44 days before they were killed. Incorporation of thymidine into DNA showed marked cycling in rate with a maximum at 6 A.M. and minimum at 6 P.M. Thymidine kinase also showed daily cycling in activity. A striking generalization could be made in the case of all of the enzymes studied, which included serine dehydrase, ornithine transaminase, tyrosine transaminase, and glucose-6-phosphate dehydrogenase. It was noted that at dietary protein levels that depressed enzyme activity in host liver, enzyme activities in the hepatomas attained values 10–100 times higher than those of livers in the same animals. Since the enhanced enzyme activities in the hepatomas were in the range of the highest values that could be produced in liver under conditions optimal for liver, the phenomenon appears to be some kind of a "feedback deletion" the mechanism of which is as yet unspecified.

¹ This study was supported in part by Departmental Grant CA-07125 and Training Grant CRTY-5002 from the National Cancer Institute, USPHS. This publication is in honor of the 70th birthday of Dr. Jacob Furth. Cf. Cancer Res., 26: No. 3, 1966.

² Present address: Biological Division, Argonne National Laboratory.

³ The autoradiographic measurements were performed at the Argonne National Laboratory in the laboratory of S. L.

⁴ The hepatoma-bearing rats wee produced at the National Cancer Institute in the laboratory of H. M. and shipped to Madison.

Received 9/13/65. Revised 2/11/66.