Cytotoxicity and keratinocyte microsome-mediated mutagenic activation of carcinogens in cultured epidermal cells

Four model carcinogens (aflatoxin B-1, 6-nitrochrysene, 3-amino-1-dimethyl- 5H-pyrido[4.3-b]indole (Trp-P-1), 3-amino-1-methyl-5H-pyrido[4,3-b]indole ( Trp-P-2)) were examined for their ability to inhibit the growth of cultured human and rat epidermal cells. To find a basis for observed differences in growth inhibition, aflatoxin B-1, Trp-P-1 and Trp-P-2 were tested for acti vation by microsomes isolated from these cells in a bacterial mutagenesis a ssay. Treated rat cultures exhibited sensitivity to Trp-P-l and Trp-P-2 and especially aflatoxin toxicity (growth inhibition) despite their microsomes being unable to induce bacterial mutagenicity. In treated human cultures, the toxicities of Trp-P-1, Trp-P-2 and AFB(1) were stimulated by 2,3,7,8-te trachlorodibenzo-p-dioxin (TCDD), consistent with their dependence on the b iotransformation reactions this agent induces; however, the toxicity correl ated poorly with observed bacterial mutagenicity mediated by their isolated microsomes. 6-Nitrochrysene, a known direct-acting mutagen in bacteria, wa s highly toxic to the rat but not to the human cells. Since toxic effects c an modify carcinogenic outcomes, these findings are compatible with a compl ex relationship between toxicity, mutagenicity and carcinogenicity and indi cate the utility of keratinocytes for clarifying this relationship. (C) 200 0 Elsevier Science Ireland Ltd. All rights reserved.