Development of monitoring system of toxic chemicals base on the Nrf2-dependent detoxification pathway

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Analysis using Nrf2-LacZ miceAfter feeding NrfZ-LacZ mice with dietary BHA for 3 days, accumulation of LacZ activity was observed in intestine, liver and peritoneal macrophages. The result suggested that Nrf2-LacZ mice are useful for detecting toxic chemicals in foods or medicines. In addition, we found a posttranseriptional accumulation of Nrf2 protein in response to electrophiles.Analysis of Nrf2 knockout miceNrf2 knockout mice was susceptible to benzo[o]pyrene-induced neoplasia in the forestomach, diesel exhaust-induced hyperplasia and oxidative DNA adduct formation in the lung, and acetaminophen-induced hepatotoxicity. These results demonstrated that Nrf2 knockout mice are highly sensitive to carcinogen and/or oxidative stress, and that they will be useful for detecting toxic chemicals in foods or medicines.Zebrafish system for xenobiotic studiesWe showed that Nrf2-based induction of phase II detoxifying enzymes was conserved in fish and that a possibility of monitoring carcinogens using zebra fish system. Thus the GFP reporter construct fused to the transcriptional regulatory region of zebrafish GSTpi gene was prepared. In a transient reporter analysis, we could observed a GFP induction by electrophiles in zebra fish larvae. We are now trying to establish a stable transgenic zebrafish line which contains the construct.