Epidemiological studies show that cruciferous vegetables play a role in dietary protection against
cancers. The protective effects of crucifers are thought to be associated with secondary metabolites termed
glucosinolates, the hydrolysis products of which upregulate hepatic detoxification
enzymes.
Crambene, a
nitrile product of the
glucosinolate progoitrin, increases hepatic
quinone reductase (QR) when included in the diet of animals. Here we evaluate the mechanism of upregulation of detoxification
enzymes by
crambene. The regulatory region of the QR gene contains two response elements, the antioxidant response element (ARE) and the
xenobiotic response element (XRE), that respond to
glucosinolate hydrolysis products. We compared upregulation of QR
mRNA expression by
crambene in wild-type and
Ah receptor-deficient mouse
hepatoma cell lines. Both cell lines showed a similar increase in QR
mRNA, suggesting that the
Ah receptor-dependent XRE pathway is not required for
crambene to act. Transient transfection of HepG2 cells with reporter constructs containing portions of the 5' regulatory region of the rat QR gene confirmed this, revealing that
crambene significantly activated ARE, but not XRE, in a dose-dependent manner. Furthermore, both
indole-3-carbinol (I3C) and I3C
acid condensates (I3C-A) activated the ARE for QR gene expression whereas only I3C-A activated the XRE at the concentrations studied. In addition, co-treatment with
crambene and I3C-A caused synergistic increases in QR transcriptional activity and
mRNA levels in HepG2 cells. Based on these findings, we propose that synergistic upregulation of QR is due to co-activation of the ARE and the XRE by
crambene and I3C-A.