Isolated airway exposure to toluene diisocyanate results in skin sensitization.

Toluene diisocyanate (TDI), a highly reactive industrial chemical is a leading cause of occupational asthma in westernized countries. It has also been reported to be a skin sensitizer in mice and guinea pigs although instances of skin sensitivity in humans are rare. It is uncertain if skin-contact is necessary to initiate the dermal sensitization. This study sought to determine if exclusive airway exposure to TDI could result in skin sensitivity. A group of guinea pigs was administered 50 microl of 0.6% TDI intratracheally (it.), another group received intranasal (in.) application of 0.6, 1.2, or 1.8% TDI. Eighty percent (4/5) of the it.-dosed animals, and 92% (11/12) of in.-dosed animals exhibited skin sensitivity. None of 14 control animals gave a positive reaction to patch challenge with TDI. These findings indicate that exclusive exposure of the airways to TDI can result in skin sensitivity and suggest that such events may be possible in TDI workers and should be considered in all workers exposed via the airways to chemical sensitizers.

High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes.

Nrf2, which belongs to the basic leucine zipper (bZip) transcription factor family, has been implicated as a key molecule involved in antioxidant-responsive element (ARE)-mediated gene expression. In order to examine the role of Nrf2 in protection against xenobiotic toxicity, the sensitivity of nrf2 knockout mice to acetaminophen (N-acetyl-4-aminophenol (APAP)) was analyzed. The saturation of detoxification pathways after high levels of exposure to APAP is known to induce hepatotoxicity. Two factors important in its detoxification are UDP-glucuronosyltransferase (UDP-GT), an ARE-regulated phase-II drug-metabolizing enzyme, and glutathione (GSH), an antioxidant molecule whose synthesis depends on ARE-regulated gamma-glutamylcysteine synthetase (gammaGCS). Two- to 4-month-old male mice were orally administered a single dose of APAP at 0, 150, 300, or 600 mg/kg. Doses of 300 mg/kg APAP or greater caused death in the homozygous knockout mice only, and those that survived showed a greater severity in hepatic damage than the wild-type mice, as demonstrated by increased plasma alanine aminotransferase activity, decreased hepatic non-protein sulfhydryl (NPSH) content, and centrilobular hepatocellular necrosis. The high sensitivity of Nrf2-deficient mice was confirmed from observations made at 0, 2, 8, and 24 h after dosing with 300 mg/kg APAP; increased anti-APAP immunoreactivity was also noted in their livers at 2 h. Untreated homozygous knockout mice showed both a lower UDP-GT activity and NPSH content, which corresponded to decreased mRNA levels of UDP-GT (Ugt1a6) and the heavy chain of gammaGCS, respectively. These results show that Nrf2 plays a protective role against APAP hepatotoxicity by regulating both drug metabolizing enzymes and antioxidant genes through the ARE.