Chi, Yu-Chou Lee, Shou-Lun Lee, Yung-Ping Lai, Ching-Long Yin, Shih-Jiun Modeling of Human Hepatic and Gastrointestinal Ethanol Metabolism with Kinetic-Mechanism-Based Full-Rate Equations of the Component Alcohol Dehydrogenase Isozymes and Allozymes Alcohol dehydrogenase (ADH) is the principal enzyme responsible for the metabolism of ethanol. Human ADH constitutes a complex family of isozymes and allozymes with striking variation in kinetic properties and tissue distribution. The liver and the gastrointestinal tract are the major sites for first-pass metabolism (FPM). The quantitative contributions of ADH isozymes and ethnically distinct allozymes to cellular ethanol metabolism remain poorly understood. To address this issue, kinetic mechanism and the steady-state full-rate equations for recombinant human class I ADH1A, ADH1B (including allozymes ADH1B1, ADH1B2, and ADH1B3), ADH1C (including allozymes ADH1C1 and ADH1C2), class II ADH2, and class IV ADH4 were determined by initial velocity, product inhibition, and dead-end inhibition experiments in 0.1 M sodium phosphate at pH 7.5 and 25 °C. Models of the hepatic and gastrointestinal metabolisms of ethanol were constructed by linear combination of the numerical full-rate equations of the component isozymes and allozymes in target organs. The organ simulations indicate that in homozygous <i>ADH1B*1/*1</i> livers, a representative genotype among ethnically distinct populations due to high prevalence of the allele, major contributors at 1 to 10 mM ethanol are ADH1B1 (45% to 24%) and the ADH1C allozymes (54% to 40%). The simulated activities at 1 to 50 mM ethanol for the gastrointestinal tract (total mucosae of <i>ADH1C*1/*1–ADH4</i> stomach and the <i>ADH1C*1/*1–ADH2</i> duodenum and jejunum) account for 0.68%–0.76% of that for the <i>ADH1B*1/*1–ADH1C*1/*1</i> liver, suggesting gastrointestinal tract plays a relatively minor role in the human FPM of ethanol. Based on the flow-limited sinusoidal perfusion model, the simulated hepatic <i>K</i><sub>m</sub><sup>app</sup>, <i>V</i><sub>max</sub><sup>app</sup>, and <i>C</i><sub>i</sub> at a 95% clearance of ethanol for <i>ADH1B*1/*1–ADH1C*1/*1</i> livers are compatible to that documented in hepatic vein catheterization and pharmacokinetic studies with humans that controlled for the genotypes. The model simulations suggest that slightly higher or similar ethanol elimination rates for <i>ADH1B*2/*2</i> and <i>ADH1B*3/*3</i> individuals compared with those for <i>ADH1B*1/*1</i> individuals may result from higher hepatocellular acetaldehyde. Allozymes Alcohol dehydrogenase;Kinetic-Mechanism-Based Full-Rate Equations;allozymes ADH 1B ADH 1B;ADH 1A ADH 1B;ADH 1B liver;ADH 1B individuals;50 mM ethanol;ADH 1C duodenum;Gastrointestinal Ethanol Metabolism;hepatic vein catheterization;V max app;0.1 M sodium phosphate;ADH 1C stomach;ethanol elimination rates;hepatic K m app;10 mM ethanol;full-rate equations;ADH 1B ADH 1C;allozymes ADH 1C;class IV ADH 4;ADH 1B livers;FPM;II;Component Alcohol Dehydrogenase Isozymes 2018-05-31
    https://acs.figshare.com/articles/journal_contribution/Modeling_of_Human_Hepatic_and_Gastrointestinal_Ethanol_Metabolism_with_Kinetic-Mechanism-Based_Full-Rate_Equations_of_the_Component_Alcohol_Dehydrogenase_Isozymes_and_Allozymes/6748493
10.1021/acs.chemrestox.8b00003.s001