Effects of Phorbol Myristate Acetate, Phorbol Dibutyrate, Ethanol, Dimethylsulfoxide, Phenol, and Seven Metabolites of Phenol on Metabolic Cooperation Between Chinese Hamster V79 Lung Fibroblasts

The effect of phorbol myristate acetate, phorbol dibutyrate, ethanol, dimethylsulfoxide, phenol, and seven metabolites of phenol on metabolic cooperation were assessed as a function of mutant cell recovery from populations of cocultivated hypoxanthine-guanine phosphoribosyl transferase-deficient mutant (HGPRT-) and wild-type (HGPRT+) Chinese hamster V79 lung fibroblasts. Phorbol myristate acetate and phorbol dibutyrate, two established tumor promoters, were potent inhibitors of metabolic cooperation. Ethanol and dimethylsulfoxide, solvents commonly used to prepare chemicals for testing, weakly inhibited metabolic cooperation. Phenol and phenylglucuronide had no effect on metabolic cooperation. Four oxidative metabolites (1,4-benzoquinone, catechol, hydroxyquinol and quinol) inhibited metabolic cooperation. Phenylsulfate weakly inhibited metabolic cooperation. Conversely, 2-methoxyphenol, a methylated derivative of catechol, appeared to enhance metabolic cooperation. These results generally support the hypothesis that tumor promoters inhibit metabolic cooperation and illustrate the importance of considering metabolites when testing this hypothesis. The weak capacity of five metabolites of phenol to inhibit metabolic cooperation correlates with the weakness of phenol as a tumor promoter. Interpretation of these results is complicated because two metabolic cooperation-inhibiting metabolites (catechol and quinol) are nonpromoting when tested individually in the same assay where phenol shows promoting activity. Such metabolites may be incomplete (stage) promoters, and exposure to two or more may be required for a promoting effect. The significance of enhanced metabolic cooperation requires further investigation, particularly in relation to antipromoting effects.