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

• Published in: Toxicology letters Vol. 115; no. 2; pp. 165 - 172
• Main Authors: Chun, Hyang-Sook, Kuzmicky, Paul A, Rucoba, Laura, Kado, Norman Y, Rice, Robert H
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ireland Ltd 19.05.2000
• Subjects: 6-nitrochrysene; Aflatoxin; Aflatoxin B1 - toxicity; Animals; Biotransformation; Carbolines - toxicity; Carcinogenicity Tests - methods; Carcinogens - toxicity; Cell Culture Techniques; Cell Death; Chrysenes - toxicity; Cytochrome P450; Epidermal Cells; Humans; Keratinocytes - drug effects; Keratinocytes - physiology; Microsomes - drug effects; Microsomes - physiology; Mutagens - toxicity; Nitroaromatics; Rats; TCDD; Trp-P-1; Trp-P-2; TCDD; Trp-P-2; Trp-P-1; Nitroaromatics; Cytochrome P450; Aflatoxin
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/S0378-4274(00)00190-9

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 activation by microsomes isolated from these cells in a bacterial mutagenesis assay. Treated rat cultures exhibited sensitivity to Trp-P-1 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-tetrachlorodibenzo- p-dioxin (TCDD), consistent with their dependence on the biotransformation reactions this agent induces; however, the toxicity correlated poorly with observed bacterial mutagenicity mediated by their isolated microsomes. 6-Nitrochrysene, a known direct-acting mutagen in bacteria, was highly toxic to the rat but not to the human cells. Since toxic effects can modify carcinogenic outcomes, these findings are compatible with a complex relationship between toxicity, mutagenicity and carcinogenicity and indicate the utility of keratinocytes for clarifying this relationship.