Structural influence of isothiocyanates on expression of cytochrome P450, phase II enzymes, and activation of Nrf2 in primary rat hepatocytes.

Primary cultures of rat hepatocytes were used to investigate whether and how eight isothiocynates (ITCs) with aromatic and aliphatic structures, derived from hydrolyzed glucosinolates , were able to modulate cytochrome P450 (CYP), antioxidant/detoxifying enzymes and to activate the Nrf2 transcription factor. The aromatic ITCs, unlike the aliphatic ones, at 40 ?M increased the transcription of CYP1A1 and 1A2 mRNA and the associated ethoxyresorufin O-deethylase activity after 24 hours of treatment. On the other hand, all the ITCs at 40 ?M caused a striking and similar transcriptional repression of CYP3A2, and the corresponding benzyloxyquinoline debenzylase activity. In the same culture conditions, most of the antioxidant/detoxifying enzymes were significantly up-regulated by 40 ?M ITCs and in particular, NAD(P)H:quinone oxidoreductase and heme oxygenase-1. As for the Nrf2, a partial translocation of its protein from the cytosol to the nucleus was revealed by immunoblotting after 1h of treatment for all the ITCs tested. The ability of ITCs to induce the antioxidant and phase II enzymes did not appear to be affected by their hydrophilicity. Taken together, these results show that these ITCs are effective inducers of ARE/Nrf2-regulated antioxidant/detoxifying genes and have the potential to inhibit the bioactivation of carcinogens dependent on CYP3A2 catalysis.