Hepatic macromolecular binding and tissue distribution of ortho- and para-toluidine in rats

Abstract

The in vivo covalent binding of ortho- and para-toluidine (OT and PT) to rat hepatic macromolecules was investigated to determine if a relationship exists between the degree of binding for each isomer and its carcinogenic potency. The ortho-isomer has been shown to be a more potent hepatocarcinogen than the para-isomer. In addition to the macromolecular binding, the tissue distribution of each isomer was also measured. The degree of binding to hepatic macromolecules appeared to be at maximum for both at 24–28 h following dosing. At 24 h following dosing, the level of DNA binding of OT was approximately 1.2-fold lower than that of PT. The binding to RNA and protein was also lower for OT than PT, although the differences were not as great as that observed for DNA binding. There were subtle differences in tissue distribution for each isomer. However, in contrast to the macromolecular binding data, the area under the plasma concentration curve for OT was approximately 1.8-fold greater than that for PT. Based on the results of these studies, there was no direct correlation between the degree of macromolecular binding and carcinogenic potency.