Activation of aldose reductase in rat lens and metal-ion chelation by aldose reductase inhibitors and lipoic acid.
Sorbitol formation in rat lenses incubated with high levels of glucose was related to activation of aldose reductase (AR). The hyperglycaemia-activated aldose reductase was inhibited by alpha-lipoic (thioctic) acid, O-phenanthroline and aldose reductase inhibitors (ARIs) including Zeopolastat (ZPLS), Sorbinil (SBN) and AL-1576. This study also examined ARIs for the ability to chelate metal ions. We found that ARIs suppress copper-dependent ascorbate oxidation, lipid peroxidation and hydrogen peroxide production in erythrocytes. ARIs also increased partition of copper ions into noctanol, which indicates formation of lipophilic complexes. Our data support the hypothesis that transition metals may be involved in activation of the polyol (aldose reductase) pathway. Also, ARIs function as metal-chelating antioxidants that may contribute to their therapeutic role for diabetic complications.
Department of Medicine, University College London, England.
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P
Ou
J
J
Nourooz-Zadeh
H J
HJ
Tritschler
S
S
Wolff
D020003:1-Octanol; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005449:Fluorenes / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006827:Hydantoins / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D066298:In Vitro Techniques; D007477:Ions; D007908:Lens, Crystalline / Q000187:drug effects / Q000201:enzymology*; D015227:Lipid Peroxidation / Q000187:drug effects; D009249:NADP / Q000096:biosynthesis / Q000378:metabolism; D000442:Octanols / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D010618:Phenanthrolines / Q000494:pharmacology; D051381:Rats; D008063:Thioctic Acid / Q000494:pharmacology*
D002614:Chelating Agents; D004791:Enzyme Inhibitors; D005449:Fluorenes; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; D007477:Ions; D000442:Octanols; D010618:Phenanthrolines; C052241:imirestat; D009249:NADP; D008063:Thioctic Acid; D003300:Copper; D006861:Hydrogen Peroxide; D000449:Aldehyde Reductase; C026411:sorbinil; D005947:Glucose; D020003:1-Octanol; D001205:Ascorbic Acid; C025205:1,10-phenanthroline