Inverse correlation between species life span and capacity of cultured fibroblasts to metabolize polycyclic hydrocarbon carcinogens

Abstract

Many investigators have hypothesized that the aging process may result from an accumulation of DNA damage, and, if valid, this necessitates a means by which this accumulation can be related to the potential life span of an organism. Using an assay for cell-mediated mutagenesis, we have tested multiple diploid fibroblast strains from six mammalian species of widely differing life spans, and found a very good inverse correlation between species life span and ability to activate 7,12-dimethylbenz(a)anthracene (DMBA) to mutagenic forms. We have also found a very good inverse correlation between species life span and ability to activate DMBA to forms capable of covalent binding to DNA. Since the polycyclic hydrocarbon carcinogens such as DMBA and benzo(a)pyrene (BP) are chemically non-reactive in their native forms and must be metabolically activated by mixed-function oxidases to their biologically active forms, these data indicate that the capacity of fibroblasts to activate polycyclic hydrocarbon carcinogens to DNA-damaging forms is a species property related to potential life span. To determine the role of carcinogen metabolism in this phenomenon the capacity of diploid fibroblasts from eight mammalian species to convert BP and DMBA to water-soluble metabolites was then determined. This rate of conversion varies widely among different species and shows a very good inverse correlation with species life span. As a whole, these findings suggest that the ability of cultured cells to metabolize the polycyclic hydrocarbon carcinogens is related to species life span, and may be important in the occurrence of spontaneous cancer.