Effects of aldose reductase inhibitors on antioxidant defense in rat and rabbit liver.
Aldose reductase has been implicated in the etiology of diabetic complications, atherosclerosis, and ischemia-reperfusion injury. Aldose reductase inhibitors are known to have species-dependent differences in biotransformation enzyme induction. Whether aldose reductase inhibitors, which have antioxidant potential, alter the oxidative stress pathway is unknown. This study has determined whether four daily ip treatments of either low (10 mg/kg) or high (50 mg/kg) doses of AL-1576 or AL-4114 alter the activities of the antioxidant defense enzymes catalase, glutathione reductase, glutathione peroxidase, superoxide dismutase, and the concentrations of reduced and oxidized glutathione in livers of normal rats and rabbits. There was no change in the concentration of thiobarbituric acid reactive substances in either rat or rabbit livers, indicating that lipid peroxidation was not increased by any treatment. Hepatic catalase, superoxide dismutase, and glutathione peroxidase activities and concentrations of reduced and oxidized glutathione were not significantly altered in rat, though glutathione reductase activity was increased after high doses of both drugs. However, in rabbit liver, glutathione reductase activity decreased in a dose-dependent manner after AL-4114 treatment, while superoxide dismutase and glutathione peroxidase activities decreased only after the low dose of AL-4114. Although AL-4114 and AL-1576 did not directly generate increased lipid peroxidation within normal rat and rabbit livers, some of the enzymes responsible for oxidative defense were altered, particularly in rabbit livers.
Thomas
T
T
Medical Sciences Program, Indiana University School of Medicine, Bloomington 47405-7005, USA.
Rauscher
F
F
Sanders
R
R
Veltman
J
J
Watkins
J B
JB
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005449:Fluorenes / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006827:Hydantoins / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013141:Spiro Compounds / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D000975:Antioxidants; D004791:Enzyme Inhibitors; D005449:Fluorenes; D006827:Hydantoins; D013141:Spiro Compounds; D017392:Thiobarbituric Acid Reactive Substances; C052241:imirestat; C079554:AL 4114; D010088:Oxidoreductases; D000449:Aldehyde Reductase; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005980:Glutathione Reductase; D005978:Glutathione; D019803:Glutathione Disulfide