Metabolism of polycyclic aromatic hydrocarbons and phorbol esters by mouse skin: relevance to mechanism of action and trans-species/strain carcinogenesis.
Mouse epidermal cells are a useful model system for studying chemical carcinogenesis in epithelial tissues. The available data suggest that some aspects of the metabolic activation and covalent binding of PAH carcinogens are similar in mouse and in human epidermis, whereas notable differences include conjugation pathways and wide interindividual differences, especially in adduct formation. Further work is necessary to determine the role of these differences in susceptibility to PAH carcinogenesis. Clearly, future in vitro assay systems for species extrapolation of epidermal carcinogenesis data must take into account the differentiation state of the cells, among other factors. We showed that the differentiation state of keratinocytes may profoundly influence the metabolic activation of PAHs. Also needed are in vivo assay systems in which quantitative data such as specific DNA adduct levels can be related to the biologic end point of cellular transformation. Several systems were discussed that may fulfill this need. With regard to skin tumor promoters, much less is known about the role of metabolism in mediating species and strain differences in responsiveness. The data available for phorbol esters indicate that differences in the metabolic inactivation of TPA cannot explain the marked species differences in sensitivity to this class of promoters. Much less is known about other chemical classes of promoters, which also require further investigation.
DiGiovanni
J
J
Department of Carcinogenesis, University of Texas, M. D. Anderson Cancer Center, Smithville 78957.
D000818:Animals; D002273:Carcinogens; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010703:Phorbol Esters / Q000378:metabolism*; D011083:Polycyclic Compounds / Q000378:metabolism*; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D013045:Species Specificity
D002273:Carcinogens; D010703:Phorbol Esters; D011083:Polycyclic Compounds