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Evidence for DNA Repair Synthesis and Turnover in Rat Liver following Ingestion of 3'-Methyl-4-dimethylaminoazobenzene¹

McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin 53706

Immature (50 g, 25-day-old) rats were given injections of thymidine-methyl-¹⁴C for labeling of their hepatic DNA. When the animals reached 200 g (53 days old), they were placed on a diet containing 0.05% (w/w) of the hepatic carcinogen 3'-methyl-4-dimethylaminoazobenzene. Groups of animals were sacrificed at weekly intervals over a period of 5 weeks. Two hr prior to sacrifice, each animal was given an injection of thymidine-methyl-³H. The radioactivity in total hepatic DNA, in the DNA of suspensions of hepatic cells, and in different classes of hepatic nuclei was determined. Over the course of the experiment, there was a marked and progressive loss of DNA (t_1/2 = 13 days) from the livers of the animals on the carcinogen diet, accompanied by an increase in the rate of thymidine-methyl-³H incorporation. Total liver weight, as well as mg of DNA per liver, remained constant over the course of the experiment. These studies were confirmed in a series of experiments in which hepatic DNA was labeled with thymidine-methyl-³H during liver regeneration following partial hepatectomy, and the animals were allowed 4 weeks to recover from the operation before being placed on the 3'-methyl-4-dimethylaminoazobenzene diet. The degree of necrosis seen in histological sections appeared insufficient to account for the loss of DNA observed. Studies involving the sedimentation of DNA in alkaline sucrose gradients indicated that repair synthesis of hepatic DNA is an early consequence of 3'-methyl-4-dimethylaminoazobenzene ingestion and accounts for some of the increased DNA turnover. The possible relationship between DNA repair synthesis and alterations in gene expression is discussed.

¹ Financial support was provided by Grants CA-07175 and TO1-CA5002 from the National Cancer Institute. Preliminary reports have appeared (14, 15).

² Recipient of a USPHS postdoctoral fellowship (1-FO2-CA-43985) awarded by the National Cancer Institute. Present address: Department of Pharmacology, Michigan State University, East Lansing, Mich. 48823.

Received 9/13/71. Accepted 12/15/71.