Fig. 7.

Lack of hepatotoxicity of compounds 3b and 3r. (A) Hematoxylin and Eosin-stained liver sections (100x). Centrilobular hepatic hemorrhagic necrosis is evident after exposure of male CD1 mice to toxic doses (600 mg/kg) ApAP via po injection, but not compounds 3b or 3r. Note that a healthy liver architecture if maintained with compounds 3b and 3r. (B) Nitrotyrosine-labeled hepatic sections (100x). (C) (Zonula Occludens-1 (ZO-1) staining demonstrating the loss of “chicken wire” hepatic tight junctions, which exist between hepatocytes. Flat, 2-dimensional hepatocyte cultures show clear “chicken wire” tight junction labeling with ZO-1, a constituent protein. ZO-1 labeled sections of vehicle (0.9% NaCl) control, ApAP, 3b, and 3r (all 200x) show good ZO-1 label (brown bands, white arrows); however, the ZO-1 bands tend to run out of the section plane (these are liver sections). Note the very dark ZO-1 labeling around the small associate blood vessels. (D) 3-dimensional stacking of Zo-1 staining (1000x) for sections from vehicle (0.9% NaCl) control, ApAP, 3b, and 3r. (E) Cell death was observed in ApAP-treated mice, unlike in the vehicle (0.9% NaCl) treated controls or in the 3b- or 3r-treated mice, as assessed by TUNEL-positive nuclear staining for apoptosis (all 200x). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)