3-amino-1-4-dimethyl-5h-pyrido(4-3-b)indole and Cocarcinogenesis

Treatment of cultures of spontaneously immortalized human epidermal cells with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) sensitized them to carcinogen toxicity. While the tryptophan pyrolysis product 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and the mycotoxin sterigmatocystin were highly toxic to the cultures at moderate concentration (1 microgram/ml), the potency of each agent was increased > or = 10-fold in the presence of TCDD. A toxicity increase was also evident in the several-fold stimulation by TCDD of protein and DNA adducts formed by Trp-P-1. In contrast, the cells were insensitive to toxicity from 3-amino-1-methyl-5H-pyrido[4,3-b]indole. DNA damage mediated by Trp-P-1 was capable of producing inheritable effects, as judged by the induction of hprt mutants in a TCDD-stimulated fashion. Northern blotting showed that TCDD strongly stimulated expression of P4501A1 and 1B1 in the cells, enzymes important for xenobiotic metabolism. These findings demonstrate the potential usefulness of SIK cultures as a model for studying keratinocyte responses to carcinogens activated by TCDD-induced cytochromes P450.

Topics: 3T3 Cells; Animals; Base Sequence; Carbolines; Cell Division; Cell Line; Cocarcinogenesis; Cytochrome P-450 Enzyme System; DNA Damage; Drug Synergism; Enzyme Induction; Humans; Isoenzymes; Keratinocytes; Mice; Molecular Sequence Data; Mutagens; Polychlorinated Dibenzodioxins; Sensitivity and Specificity; Sterigmatocystin