Inhibition by carboxamides and sulfoxides of liver alcohol dehydrogenase and ethanol metabolism

Abstract

Sulfoxides and amides were tested as inhibitors of liver alcohol dehydrogenase and ethanol metabolism in rats. With both series of compounds, increasing the hydrophobicity resulted in better inhibition, and introduction of polar groups reduced inhibition. Of the cyclic sulfoxides, tetramethylene sulfoxide was the best inhibitor as compared to the tri- and pentamethylene analogue and other compounds, and it may be a transition-state analogue. The most promising compounds, tetramethylene sulfoxide and isovaleramide, were essentially uncompetitive inhibitors of purified horse and rat liver alcohol dehydrogenases with respect to ethanol as substrate. These compounds also were uncompetitive inhibitors in vivo, which is advantageous since the inhibition is not overcome at higher concentrations of ethanol, as it is with competitive inhibitors, such as pyrazole. The uncompetitive inhibition constants for tetramethylene sulfoxide and isovaleramide for rat liver alcohol dehydrogenase were 200 and 20 microM, respectively, in vitro, whereas in vivo the values were 340 and 180 mumol/kg. The differences in the values may be due to metabolism or distribution of the compounds. Further studies will be required to determine if isovaleramide or tetramethylene sulfoxide is suitable for therapeutic purposes.

Formamides Mimic Aldehydes and Inhibit Liver Alcohol Dehydrogenases and Ethanol Metabolism

“…Blood samples (10 l) were drawn from the tail at intervals timed from the ethanol injection. The blood alcohol concentration was determined by gas chromatography as previously described (10).…”

“…The simplest kinetic explanation for the inhibition results is the Ordered Bi Bi mechanism where the inhibitor binds only to the enzyme-NADH complex. For this mechanism, the K i values represent true dissociation constants since the concentrations of coenzyme were saturating, and dissociation of NADH is rate-limiting for turnover (10).…”

“…It is significant, for instance, that the linear N-n-propyl-and N-n-butylformamides (1, 2) bind more tightly to EqADH and MmADH1 than to HsADH, whereas the secondary formamides that are branched at the one position (7, 8, 9, 10, 11, 12, 13, 14, and 20) bind more tightly to MmADH1 and HsADH than to EqADH. (R)-N-1-Methylhexylformamide (7), its heptyl analogue (10) and N-1,5-dimethylhexylformamide (11) are particularly potent inhibitors of the human and mouse enzymes, with K i values less than 1 M. The methylated cyclohexylformamides are also better inhibitors of MmADH1 and HsADH than of EqADH. It appears that MmADH1 and HsADH have more room in the active site than does EqADH.…”

“…Uncompetitive inhibitors could be especially useful for controlling alcohol metabolism since they are effective even when the concentrations of alcohol are saturating. Previous studies identified some potent uncompetitive inhibitors for human (14, 15), horse (10,11,14,15), monkey (11), and rat (10, 11) liver alcohol dehydrogenases. We now extend the studies with 14 new branched-chain and chiral formamides in order to explore active site topologies and to make more effective inhibitors for the mouse (MmADH1) and human (HsADH1C*2) enzymes.…”

“…Formamides and sulfoxides are analogues of the carbonyl substrates, are bound preferentially to the enzyme-NADH complex, and are potent uncompetitive inhibitors against varied concentrations of alcohol (7)(8)(9)(10)(11)(12)(13)(14)(15). Uncompetitive inhibitors could be especially useful for controlling alcohol metabolism since they are effective even when the concentrations of alcohol are saturating.…”