Temporal effects of the detoxification enzyme inducer, benzyl isothiocyanate: Activation of c-Jun N-terminal kinase prior to the transcription factors AP-1 and NF kappa B

Benzyl isothiocyanate (BIT), a microconstituent found in cruciferous vegeta bles, is known to be a potent inducer of the detoxification enzyme, NAD(P)H : quinone reductase (QR). QR catalyzes a two-electron transfer to a wide va riety of redox-cycling species, including quinones, transforming them into dihydrodiols, thereby preventing the mutation of DNA and reducing cancer ri sk. The upstream signaling mechanisms that lead to the induction of QR rema in unclear. The 5' promoter region of the human QR gene contains the cis-ac ting AP-1 and NF kappa B transcription factor binding sites. When HT29 huma n colon cells were exposed to 25 mu M benzyl isothiocyanate, AP-1 binding i ncreased, beginning at 3 hours and increasing until 16 hours. NF kappa B bi nding also increased, reaching a maximum at around 6 hours. We also found t hat c-Jun N-terminal kinase (JNK), which phosphorylates c-Jun, a component of AP-1, was activated 9-fold over controls, beginning at 60 minutes. The t emporal sequence of these events supports the idea that JNK is involved in the induction of QR and that this is an initial event preceding an increase in transcription factor binding and subsequent QR activity. (C) 1999 Acade mic Press.