Ascorbic acid suppresses the 2,3,7,8-tetrachloridibenxo-p-dioxin (TCDD)-induced CYP1A1 expression in human HepG2 cells.

The mechanisms involving the inhibitory effects of ascorbic acid (AA) on carcinogenesis have not fully defined, except for its free-radical scavenging activity against oxidative DNA damage. In this study, we examined the effects of AA on the expression of the aryl hydrocarbon receptor (AhR)-regulated gene cytochrome P4501A1 (CYP1A1), which catalyzes the activation of genotoxic metabolites that can lead to mutagenesis. Cultured human HepG2 cells were incubated with AA with or without the potent AhR agonist/CYP1A1 inducer 2,3,7,8-tetrachloridibenxo-p-dioxin (TCDD). AA was highly effective at suppressing CYP1A1 induction following coincubation of the cells with 1nM TCDD. The preventive effects of AA were seen at the level of mRNA and protein expression as well as CYP1A1-specific 7-ethoxyresorufin O-deethylase (EROD) activity. A transient transfection assay using a dioxin response element (DRE)-linked luciferase reporter and an electrophoretic mobility shift assay revealed that AA reduced the amount of AhR that could form a complex with the DRE sequence in the promoter region of the CYP1A1 gene. In addition, AA inhibited the TCDD-induced Ecto-ATPase activity, which is known to be requiring for AhR translocation to the nucleus. These results suggest that AA may exert at least part of its anticarcinogenesis effect by controlling the expression of CYP1A1 at the transcription level.