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 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.
Chun
H S
HS
Department of Environmental Toxicology, 1 Shields Avenue, University of California, Davis, CA 95616-8588, USA.
Kuzmicky
P A
PA
Rucoba
L
L
Kado
N Y
NY
Rice
R H
RH
D016604:Aflatoxin B1 / Q000633:toxicity; D000818:Animals; D001711:Biotransformation; D002243:Carbolines / Q000633:toxicity; D015197:Carcinogenicity Tests / Q000379:methods; D002273:Carcinogens / Q000633:toxicity*; D018929:Cell Culture Techniques; D016923:Cell Death; D002911:Chrysenes / Q000633:toxicity; D000078404:Epidermal Cells; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000502:physiology; D008861:Microsomes / Q000187:drug effects* / Q000502:physiology; D009153:Mutagens / Q000633:toxicity; D051381:Rats
D002243:Carbolines; D002273:Carcinogens; D002911:Chrysenes; D009153:Mutagens; C019133:3-amino-1-methyl-5H-pyrido(4,3-b)indole; C035986:6-nitrochrysene; D016604:Aflatoxin B1; C019132:3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole