Abstract
Xenobiotic and oxidative stresses provoke a common integrated response composed of two consecutive reactions. Phase I reaction and subsequent phase II reaction are transcriptionally regulated by arylhydrocarbon receptor (AhR) and Nrf2, respectively. To clarify the functional contributions of each reaction in vivo as well as the molecular mechanisms underlying the phase II reaction in particular, we generated several lines of mice with altered activities of phase I or phase II reaction and performed in vivo analysis of structure-function relationship of Keap1, an inhibitor of Nrf2. Increased AhR activity in skin caused severe dermatitis. Hepatocyte-specific Keap1 deficiency conferred increased resistance against drug toxicity. Several cysteine residues in Keap1 were found critical for sensing electrophiles derived from xenobiotic metabolites and oxidative stress. These results suggested that finely tuned regulation of phase I and phase II activities are the basis of our health and many diseases seem to be caused by their imbalance.
