Abstract
In order to decrease the rate of ethanol metabolism for the treatment of acute and chronic alcoholism it would be useful to inhibit liver alcohol dehydrogenase in vivo. Based on a knowledge of the three-dimensional structure of the horse enzyme, we designed activesite-directed inactivators [p-(XCH2CONH)C6H4(CH2)3CONH2I which bind to the enzyme-NAD or enzyme-NADH complex and alkylate methionine residue 306. In vitro, these reagents inactivated mouse, rat, horse and human liver alcohol dehydrogenases faster in the presence than in the absence of NAD or NADH, but with slightly different specificity. Mice and rats pretreated with the reagents eliminated ethanol in blood more slowly than those not treated, and the specific activity of alcohol dehydrogenase in liver homogenates of treated animals was decreased. It appears that the design of active-site-directed reagents is feasible, but these reagents must be improved so that they are more efficacious in vivo.
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References
Brändén, C.-I., Jörnvall, H., Eklund, H. and Furugren, B., 1975, Alcohol dehydrogenases, in: “The Enzymes,” 3rd. ed., P. D. Boyer, ed., Academic Press, New York.
Chen, W.-S. and Plapp, B. V., 1978, Ambivalent active-site-directed in-activators of liver alcohol dehydrogenase, Biochemistry, 17: 4916–4922.
Chen, W. S. and Plapp, B. V., 1980, Kinetics and control of alcohol oxidation in rats, in: “Alcohol and Aldehyde Metabolizing Systems,” R. G. Thurman et al., eds., in press.
Dworschack, R. T. and Plapp, B. V., 1977, Kinetics of native and activated enzymes of horse liver alcohol dehydrogenase, Biochemistry, 16: 111–116.
Fries, R. W., Bohlken, D. P. and Plapp, B. V., 1979, 3-Substituted pyrazole derivatives as inhibitors and inactivators of liver alcohol dehydrogenase, J. Med. Chem., 22: 356–359.
Guerri, C., Wallace, R. and Grisolia, S., 1978, The influence of prolonged ethanol intake on the levels and turnover of alcohol and aldehyde dehydrogenases and of brain (Na + K)-ATPase of rats, Eur. J. Biochem., 86: 581–587.
Lester, D. and Benson, G. D., 1970, Alcohol oxidation in rats inhibited by pyrazole, oximes, and amides, Science, 169: 282–284.
Li, T. K. and Theorell, H., 1969, Human liver alcohol dehydrogenase: Inhibition by pyrazole and pyrazole analogs, Acta Chem. Scand., 23: 892–902.
Lieber, C. S., Rubin, E., DeCarli, L. M., Misra, P. and Gang, H., 1970, Effects of pyrazole on hepatic function and structure, Lab. Invest., 22: 615–621.
Plapp, B. V., 1970, Enhancement of the activity of horse liver alcohol dehydrogenase by modification of amino groups at the active sites, J. Biol. Chem., 245: 1727–1735.
Plapp, B. V., 1975, Rate-limiting steps in ethanol metabolism and approaches to changing these rates biochemically, in: “Biochemical Pharmacology of Ethanol,” E. Majchrowicz, ed., Plenum Press, New York.
Rydberg, U. and.Neri, A., 1972, 4-Methylpyrazole as an inhibitor of ethanol metabolism: differential metabolic and central nervous effects, Acta Pharmacol. Toxicol., 31: 421–432.
Winer, A. D. and Theorell, H., 1960, Dissociation constants of ternary complexes of fatty acids and fatty acid amides with horse liver alcohol dehydrogenase-coenzyme complexes, Acta Chem. Scand., 14: 1729–1742.
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Chen, WS., Bohlken, D.P., Plapp, B.V. (1980). In Vivo Evaluation of Ambivalent Active-Site-Directed Inactivators of Liver Alcohol Dehydrogenase. In: Thurman, R.G. (eds) Alcohol and Aldehyde Metabolizing Systems-IV. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-1419-7_14
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DOI: https://doi.org/10.1007/978-1-4757-1419-7_14
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