Regulation of Human Cytochrome P4501A1 (hCYP1A1): A Plausible Target for Chemoprevention?
The phytochemical dibenzoylmethane (DBM) has been shown to prevent polycyclic aromatic hydrocarbon (PAH)-induced tumorigenesis in rodents. However, the biochemical basis of this activity is unclear. We have therefore investigated the effects of DBM on the activity and expression of carcinogen-activating enzymes, the cytochromes P450 (CYP) 1A1, 1A2, and 1B1. Oral administration of DBM to female Sprague Dawley rats inhibited the increase in hepatic enzyme activity and mRNA levels of CYP1A1, 1A2, and 1B1 caused by the PAH 7,12-dimethylbenz[a]anthracene (DMBA). However, DBM administration alone caused an increase in both activity and expression in the liver, albeit to levels much lower than that induced by DMBA. To characterize the molecular mechanisms involved in this dual action of DBM, we examined the effects of DBM in vitro. In HepG2 human hepatoma cells, DBM inhibited DMBA- and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced enzyme activity and CYP1A1, 1A2, and 1B1 mRNA levels, whereas DBM itself induced activity and mRNA expression. Modulation of CYP1A1 expression by DBM occurred at the transcriptional level, as transient transfection assays demonstrated. Because the transcription of CYP1A1 is regulated by the aryl hydrocarbon receptor (AhR), we investigated the effect of DBM on AhR activation. DBM inhibited TCCD-induced DNA-binding of the AhR to the xenobiotic-responsive element (XRE) of CYP1A1 as measured by electrophoretic mobility shift assay. These data suggest that the chemopreventive activity of DBM results from its ability to affect Phase 1 enzyme expression by modulation of AhR function.