The reactivities of isomers of dichlorodiammine-platinum (II) with dehydrogenase enzymes: Evidence for inhibition via cross-linkage

Abstract

The reversible inhibition of malate dehydrogenase ( l-malate:NAD + oxidoreductase, EC 1.1.1.37), lactate dehydrogenase ( l-lactate:NAD + oxidoreductase, EC 1.1.1.27) and horse liver alcohol dehydrogenase (alcohol:NAD + oxidoreductase, EC 1.1.1.1) by both cis- and trans-dichlorodiammine-platinum (II) (Pt(NH 3) 2Cl 2) were carried out at pH 7.1 and 25°C. Inhibition of both liver and yeast alcohol dehydrogenase were measured at 4°C due to the latter's instability at higher temperature for long periods of time under the experimental conditions used in this study. The equilibrium constant ( K e) was calculated for each enzyme-platinum complex system. It was shown that inhibition of both malate dehydrogenase and liver alcohol dehydrogenase was independent of the particular platinum isomer, while the trans isomer was a significantly better inhibitor than the cis form when either yeast alcohol dehydrogenase or lactate dehydrogenase was used. Thus, it has been proposed that the two former enzymes are being inhibited by a monodentate chelation with the platinum derivatives while the latter enzymes are being inhibited by a bidendate chelation. It has also been proposed that absolute differences in inhibition of various enzymes by a specific platinum inhibitor is due to different goemetries about the inhibitor site while similar inhibition values are caused by similar geometries.