DIQUAT-INDUCED AND ACETAMINOPHEN-INDUCED ALTERATIONS OF BILIARY EFFLUX OF IRON IN RATS

The effects of diquat on the biliary efflux of nonheme iron in rats we re studied as a means of examining the possible effects of diquat meta bolism on hepatocellular iron metabolism and the association of altere d iron metabolism with the initiation of acute hepatic necrosis. Admin istration of hepatotoxic doses (0.1 mmol/kg) of diquat to male Fischer -344 rats increased biliary iron concentrations from 6 mu M to more th an 15 mu M. However, increases in biliary efflux of iron were not obse rved during the first 60 min following exposure to diquat, despite the rapid increases in biliary glutathione disulfide concentrations, whic h increased maximally within 40 min. Biliary efflux of iron was not al tered by diquat in Sprague-Dawley rats, which are resistant to hepatic necrosis in response to diquat, despite the marked oxidant stress res ponses observed in these animals. Conversely, hepatotoxic doses of ace taminophen (1500 mg/kg) caused significant decreases in biliary iron e fflux. The rapid decreases in biliary iron caused by acetaminophen and the delay in diquat-induced iron efflux suggested the possibility tha t some fraction of the biliary iron was being excreted as reversibly f ormed GS-Fe2+ chelates, with inhibition of export by glutathione disul fide (GSSG) in the case of diquat, or by 3-(glutathion-S-yl) acetamino phen (GS-AAP) in the case of the acetaminophen-treated animals. Howeve r, 50-200 mg/kg doses of acetaminophen showed little effect on biliary iron excretion despite producing biliary GS-AAP conjugate concentrati ons almost 1000 times the 6 mu M concentrations of iron, which would n ot appear to support the hypothesis of excretion of GS-Fe2+ chelates. The data demonstrate a significant effect of diquat on hepatic iron me tabolism in Fischer-344 rats, and the possible importance of this iron redistribution to reactive oxygen-mediated cell damage in vivo is ind icated by the absence of similar responses in diquat-treated Sprague-D awley rats.