Respiration and glycolysis in relation to cell population kinetics in mouse epidermis treated with carcinogenic or irritant substances: With special reference to the Crabtree and Pasteur effects

Abstract

The changes in epidermal respiration and glycolysis have been investigated in hairless mice after a single application of the strong carcinogen 20-methylcholanthrene. The results have been compared to similar changes after a single application of cantharidin, a strong irritant, which gives a comparable degree of cellular damage with subsequent proliferation and hyperplasia. Measurements have also been performed with the solvent, benzene, which acts as a weak irritant to the skin. The alterations could be classified into 4 different phases: 1. (1) A toxic phase during the first 4 hr after application where both compounds caused profound cellular damage with depression of both respiration of glycolysis. 2. (2) An intermediary phase from 4 to 24 hr after the treatment where most of the resulting cell loss occurs. A temporary increase of respiration and glycolysis at this stage was found to be solely due to the solvent. Later the solvent did not interfere with the results. 3. (3) A growth phase from 34 to 48 hr, characterized by an explosive proliferation in the epidermal basal cell layer. Isolated basal cells from MCA treated skin exerted a low respiration, while a normal respiration was seen after cantharidin treatment. In both cases the glycolysis of the skin was very high. 4. (4) A hyperplastic phase from 2 to 21 days after painting, where the epidermal cells had very low respiration and glycolysis. The main conclusions of these studies are: 1. (1) The quantitative metabolic alterations after treatment with carcinogenic as well as non-carcinogenic irritants are due to changes both within each single cell and changes in the composition of the tissue due to altered cell population kinetics. The interpretation of metabolic studies is therefore impossible without correlating the data to simultaneous cell population studies. 2. (2) The Crabtree effect, which normally is of a magnitude of 10% in hairless mouse epidermis, is rapidly changing in the different phases after treatment. It is temporarily increased by the solvent. During high proliferative activity the Crabtree effect is very low, indicating that it is not related to the proliferative process. During hyperplasia, the newly formed, young cells, despite their low respiration, exert a very high Crabtree effect, which after MCA treatment is nearly 60%. 3. (3) The Pasteur effect is only slightly altered in the different phases after treatment. It is moderately reduced after MCA treatment. 4. (4) It is suggested that the low respiration and high glycolysis during high proliferative activity after MCA treatment may have some relation to carcinogenesis.