2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related polychlorinated aromatic hydrocarbons exert a pattern of toxicity related to their binding to a common receptor, the Ah (aryl hydrocarbon) or dioxin receptor. No information is available, however, on the toxicological properties of 2,3,7,8-tetrafluorodibenzo-p-dioxin (TFDD). In our experiments, TFDD was found to act as a highly potent dioxin receptor agonist leading to a transient induction of cytochrome P450(CYP)1A1 mRNA and protein in receptor-proficient mouse Hepa-1 hepatoma cells treated with 10 - 1 0 M TFDD. However, no significant induction of 7-ethoxyresorufin O-deethylase (EROD) activity was observable in TFDD-treated Hepa-1 cells or mouse hepatocytes in primary culture, suggesting an interference with the catalytic activity of CYP1A1. Parallel experiments with 10 - 1 0 M TCDD showed a sustained induction of CYP1A1 mRNA and protein, and of EROD activity. When a reporter gene construct comprising a xenobiotic-responsive element (XRE) in 5 -position was transfected in Hepa-1c-1c-7 cells, 5 10 - 8 M TFDD and 5 10 - 9 M TCDD induced transcription to a comparable extent. Both inducers were inactive when a mutant XRE with a guanine replaced by thymine was transfected. In metabolism studies in mouse liver homogenate, TFDD was rapidly degraded in the presence of an NADPH-regenerating system, and metabolism was enhanced in liver homogenate from β-naphthoflavone-pretreated mice indicating that TFDD is metabolized in a CYP-catalyzed pathway. The open ring products dihydroxytetrafluororbiphenyl ether, and 1,2-difluoro-o-benzoquinone, probably derived from 1,2-difluorocatechol, were identified by GC-MS analysis of the incubation mixtures, whereas no phenolic metabolites/and or metabolites with an intact dioxin ring could be found. It is concluded that TFDD, in contrast to its chlorinated analogue, is metabolically unstable, and thus currently does not fulfill the criteria for the recommendation of a TCDD or toxicity equivalency factor (TEF).