On the thermodynamics of cell injury. Some insights into the molecular mechanisms.

A method is presented for determining the thermodynamic parameters of the rate-limiting chemical reaction in cell injury. From these parameters one can deduce certain molecular details of this reaction, such as the number of molecular events required for a specific observable injury, the approximate number of the chemical bonds broken and the degree of molecular configurational change involved. Inactivation of cell division in vitro by heat and by an alkylating agent have been studied by this method. In each case cell injury involved only one to three catastrophic molecular events, which were irreparable within a 3-day period. This suggests that in each case there had been an alteration of a genome essential for cell division. In the case of thermal injury this critical molecular event had the thermodynamic characteristics of a massive configurational change, compatible with the uncoiling of a DNA segment. In the case of alkylation injury the thermodynamic parameters were those of a small localized event with little configurational change and energetically compatible with an alkylation-depurination of DNA.