Urinary excretion of biomarkers for radical-induced damage in rats treatedwith NDMA or diquat and the effects of calcium carbimide co-administration

The urinary excretion of seven aldehydes, acetone, coproporphyrin III and 8 -hydroxy-2'-deoxyguanosine (8-OH-dG) as non-invasive biomarkers of oxidativ e damage was measured in rats treated with diquat or N-nitrosodimethylamine (NDMA), two compounds causing hepatic damage by different mechanisms. Furt hermore, the effect of co-administration of the aldehyde dehydrogenase inhi bitor, calcium carbimide (CC) on the urinary excretion of the aldehydes was determined. Slight hepatotoxicity was found at the end of the experiment a fter treatment with NDMA (0.5, 4 and 8 mg/kg at t = 0, 48 and 96 h, respect ively) or diquat (6.8 and 13.6 mg/kg at t = 0 and 38 h, respectively). In d iquat treated rats slight nephrotoxicity was also found. Urinary excretion of aldehydes, acetone and coproporphyrin III remained largely unchanged in rats treated with NDMA. In the rats treated with diquat, the urinary excret ion of several aldehydes was several-fold increased. An increase was also f ound in the urinary excretion of 8-OH-dG after the second dose of diquat. T reatment of rats with CC did not significantly influence the urinary excret ion of aldehydes in control and NDMA rats. However, in rats treated with di quat, CC caused a potentiating effect on the excretion of acetaldehyde, hex anal and malondialdehyde (MDA), indicating that oxidation of aldehydes to c arbonylic acids by aldehyde dehydrogenases (ALDHs) might be an important ro ute of metabolism of aldehydes. In conclusion, increased urinary excretion of various aldehydes, acetone, coproporphyrin III and 8-OH-dG was observed after administration of diquat, probably reflecting oxidative damage induce d by this compound. No such increases were found after NDMA administration, which is consistent with a different toxicity mechanism for NDMA. Therefor e, excretion of aldehydes, acetone, coproporphyrin III and 8-OH-dG might be used as easily accessible urinary biomarkers of free radical damage. (C) 1 999 Elsevier Science Ireland Ltd. All rights reserved.