Inhibition of human aldehyde reductase by drugs for testing the function of liver and kidney.
Drugs for testing the function of liver and kidney (sulfobromophthalein, phenolsulfonphthalein, indigo carmine and indocyanine green) and other organic anions (rose bengal and haematin) were found to potently inhibit human liver aldehyde reductase that is involved in the detoxification of 3-deoxyglucosone and methylglyoxal, reactive intermediates, during the formation of advanced glycation end products. The inhibition patterns by the compounds were non-competitive with respect to both coenzyme (NADPH) and substrate (D-glucuronate). The kinetics of the inhibition by a mixture of the 2 inhibitors suggests that all the inhibitory compounds bind to overlapping sites on the enzyme. The binding of rose bengal, sulfobromophthalein and phenylsulfonphthalein to the free enzyme was detected by ultrafiltration assay. However, in the reverse reaction, the enzyme was inhibited competitively with respect to the alcohol substrate by rose bengal, haematin, phenolsulfonphthalein, sulfobromophthalein, indigo carmine and indocyanine green, which showed Ki values of 0.1, 1, 3, 4, 4 and 10 microM, respectively. The results suggest that these potent inhibitors bind weakly to the free enzyme and tightly to the enzyme-NADP binary complex.
Shinoda
M
M
Chunou Hospital, Seki, Japan.
Mori
S
S
Shintani
S
S
Ishikura
S
S
Hara
A
A
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000838:Anions / Q000494:pharmacology; D001667:Binding, Competitive; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007203:Indigo Carmine / Q000494:pharmacology; D007208:Indocyanine Green / Q000494:pharmacology; D007677:Kidney Function Tests; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008111:Liver Function Tests; D010637:Phenolsulfonphthalein / Q000494:pharmacology; D012395:Rose Bengal / Q000494:pharmacology; D013448:Sulfobromophthalein / Q000494:pharmacology; D013451:Sulfonic Acids / Q000737:chemistry / Q000494:pharmacology*
D000838:Anions; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D013451:Sulfonic Acids; D013448:Sulfobromophthalein; D012395:Rose Bengal; D007203:Indigo Carmine; D000449:Aldehyde Reductase; D010637:Phenolsulfonphthalein; D007208:Indocyanine Green