Relationship between kinetics of liver alcohol dehydrogenase and alcohol metabolism

William F. Bosron, David W. Crabb, Li Ting-Kai Li

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Since alcohol dehydrogenase (ADH) catalyzes the rate-limiting step for ethanol metabolism, knowledge of the steady-state kinetics of ADH in liver is fundamental to the understanding of the pharmacokinetics of ethanol elimination. Accordingly, we have determined the kinetic properties of purified ADH isoenzymes in rat and human liver. At low ethanol concentrations, rat liver ADH obeys the Theorell-Chance mechanism and the equation predicts that activity in vivo is limited below Vmax mainly by NADH inhibition. At ethanol concentrations above 10mM, substrate inhibition, consistent with the formation a dead-end ADH-NADH-ethanol complex, also becomes a rate-limiting factor. ADH activity, calculated from this equation and the concentrations of substrates and products present in liver during ethanol oxidation, agrees well with ethanol elimination rates measured in vivo. With human liver ADH, large differences are observed in the kinetic properties of 5 homodimeric isoenzymes: γ1γ1 and γ2γ2 exhibit negative cooperativity for ethanol saturation, while αα, β1β1 and βIndβInd obey Michaelis-Menten kinetics. At pH 7.5, Km values for ethanol and Vmax values range from 0.048 mM and 9 min-1 for β1β1 to 64 mM and 560 min-1 for βIndβInd, respectively. Therefore, individuals with different ADH phenotypes shoudl display different ethanol elimination profiles.

Original languageEnglish (US)
Pages (from-to)223-227
Number of pages5
JournalPharmacology, Biochemistry and Behavior
Volume18
Issue numberSUPPL. 1
DOIs
StatePublished - 1983

Keywords

  • Alcohol dehydrogenase
  • Alcohol metabolism
  • Isoenzymes
  • Steady-state kinetics

ASJC Scopus subject areas

  • Biochemistry
  • Behavioral Neuroscience
  • Pharmacology

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