Urinary excretion of biomarkers for radical-induced damage in rats treated with 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 oxidative damage was measured in rats treated with diquat or N-nitrosodimethylamine (NDMA), two compounds causing hepatic damage by different mechanisms. Furthermore, the effect of co-administration of the aldehyde dehydrogenase inhibitor, calcium carbimide (CC) on the urinary excretion of the aldehydes was determined. Slight hepatotoxicity was found at the end of the experiment after treatment with NDMA (0.5, 4 and 8 mg/kg at t = 0, 48 and 96 h, respectively) or diquat (6.8 and 13.6 mg/kg at t = 0 and 48 h, respectively). In diquat 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 excretion of several aldehydes was several-fold increased. An increase was also found in the urinary excretion of 8-OH-dG after the second dose of diquat. Treatment of rats with CC did not significantly influence the urinary excretion of aldehydes in control and NDMA rats. However, in rats treated with diquat, CC caused a potentiating effect on the excretion of acetaldehyde, hexanal and malondialdehyde (MDA), indicating that oxidation of aldehydes to carbonylic acids by aldehyde dehydrogenases (ALDHs) might be an important route 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 induced by this compound. No such increases were found after NDMA administration, which is consistent with a different toxicity mechanism for NDMA. Therefore, excretion of aldehydes, acetone, coproporphyrin III and 8-OH-dG might be used as easily accessible urinary biomarkers of free radical damage.
de Zwart
L L
LL
Leiden-Amsterdam Center for Drug Research, Department of Pharmacochemistry, Vrije Universiteit, Amsterdam, The Netherlands.
Vermeulen
N P
NP
Hermanns
R C
RC
Commandeur
J N
JN
Salemink
P J
PJ
Meerman
J H
JH
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000096:Acetone / Q000652:urine; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000447:Aldehydes / Q000652:urine; D000818:Animals; D015415:Biomarkers / Q000652:urine*; D001835:Body Weight / Q000187:drug effects; D003306:Coproporphyrins / Q000652:urine; D003484:Cyanamide / Q000378:metabolism / Q000633:toxicity*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D004178:Diquat / Q000378:metabolism / Q000633:toxicity*; D004338:Drug Combinations; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000633:toxicity*; D005609:Free Radicals / Q000378:metabolism; D006540:Herbicides / Q000378:metabolism / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D009603:Nitroso Compounds / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
D000447:Aldehydes; D015415:Biomarkers; D003306:Coproporphyrins; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D005609:Free Radicals; D006540:Herbicides; D009603:Nitroso Compounds; D000096:Acetone; C008651:4-nitrosodimethylaniline; C026971:coproporphyrin III; D003484:Cyanamide; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004178:Diquat; D000444:Aldehyde Dehydrogenase; D003849:Deoxyguanosine