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Mechanism of Alteration of Poly(Adenosine Diphosphate-Ribose) Metabolism by Hyperthermia¹

Departments of Biochemistry and Medicine, Texas College of Osteopathic Medicine, University of North Texas, Fort Worth, Texas 76107

The effects of hyperthermia on adenine nucleotide metabolism including NAD and poly(ADP-ribose) have been studied in confluent cultures of C3H10T1/2 cells. Cells replated immediately following hyperthermic treatment showed only 9% survival relative to controls while after a 24-h recovery period at 37°C survival was 87% of control. Hyperthermic treatment caused no detectable effect on total cellular levels of either NAD or ATP but produced a prolonged increase in cellular content of poly(ADP-ribose). Studies of the mechanism of this effect show that a major alteration of poly(ADP-ribose) metabolism caused by hyperthermia involves a decrease in the rate of turnover of polymers of ADP-ribose. Normal polymer turnover rates were restored during recovery at 37°C even in the presence of cyclohexamide. The results argue that poly(ADP-ribose) glycohydrolase activity is reversibly altered by hyperthermia. Inhibition of poly(ADP-ribose) synthesis following hyperthermia delays recovery of normal rates of protein synthesis and recovery of the ability of the cells to plate and form colonies.

¹ This work was supported in part by grants from the National Institutes of Health (CA43894), The Medical Research Council, Stockholm, Sweden, The Medical Faculty, University of Lund, Lund, Sweden, The Anna Cederbergs Foundation for Medical Research, Karolinska Institute, Stockholm, Sweden, and The John and Augusta Persson's Foundation for Medical Research, Lund, Sweden.

² Permanent address: Department of Molecular Ecogenetics, The Wallenberg Laboratory, University of Lund, Box 7031, S-22007 Lund, Sweden.

³ To whom requests for reprints should be addressed, at Department of Biochemistry, Texas College of Osteopathic Medicine, Fort Worth, TX 76107.

Received 11/ 9/87. Revised 2/22/88. Accepted 4/27/88.

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