Inactivation of liver alcohol dehydrogenases and inhibition of ethanol metabolism by ambivalent active-site-directed reagents

• Published in: Journal of medicinal chemistry Vol. 24; no. 2; pp. 190 - 193
• Main Authors: Chen, Wen-Sherng, Bohlken, David P, Plapp, Bryce V
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.02.1981
• Subjects: Alcohol Oxidoreductases - antagonists & inhibitors; Animals; Binding Sites - drug effects; Dose-Response Relationship, Drug; Ethanol - metabolism; Horses; In Vitro Techniques; Indicators and Reagents - pharmacology; Liver - enzymology; Male; Mice; Rats; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00134a012

Active-site-directed reagents, of the general structure omega-(BrCH2CONH)RCOY, where R = alkyl, aryl, or aralkyl, and Y = OH or NH2, inactivated horse, mouse, rat, and human liver alcohol dehydrogenases at widely different rates, reflecting differences in reagent specificity and in the structures of the enzymes. Treatment of mice and rats with either of two optimally specific reagents, p-(XCH2CONH)C6H4(CH2)3CONH2, where X = Br (7) or CH3SO3 (10), partially (20 to 40%) inactivated alcohol dehydrogenase in liver, inhibited ethanol metabolism, and prolonged the impairment of coordination produced by ethanol in these animals. Although the dose of 7 used (0.13 mmol/kg) approximated the LD50, 10 was effective at a dose of 0.48 mmol/kg that was not acutely toxic.