title: Ethanol oxidation and the inhibition by drugs in human liver, stomach and small intestine: Quantitative assessment with numerical organ modeling of alcohol dehydrogenase isozymes.
abstract: Alcohol dehydrogenase (ADH) is the principal enzyme responsible for metabolism of ethanol. Human ADH constitutes a complex isozyme family with striking variations in kinetic function and tissue distribution. Liver and gastrointestinal tract are the major sites for first-pass metabolism (FPM). Their relative contributions to alcohol FPM and degrees of the inhibitions by aspirin and its metabolite salicylate, acetaminophen and cimetidine remain controversial. To address this issue, mathematical organ modeling of ethanol-oxidizing activities in target tissues and that of the ethanol-drug interactions were constructed by linear combination of the corresponding numerical rate equations of tissue constituent ADH isozymes with the documented isozyme protein contents, kinetic parameters for ethanol oxidation and the drug inhibitions of ADH isozymes/allozymes that were determined in 0.1 M sodium phosphate at pH 7.5 and 25 °C containing 0.5 mM NAD(+). The organ simulations reveal that the ADH activities in mucosae of the stomach, duodenum and jejunum with ADH1C*1/*1 genotype are less than 1%, respectively, that of the ADH1B*1/*1-ADH1C*1/*1 liver at 1-200 mM ethanol, indicating that liver is major site of the FPM. The apparent hepatic KM and Vmax for ethanol oxidation are simulated to be 0.093 ± 0.019 mM and 4.0 ± 0.1 mmol/min, respectively. At 95% clearance in liver, the logarithmic average sinusoidal ethanol concentration is determined to be 0.80 mM in accordance with the flow-limited gradient perfusion model. The organ simulations indicate that higher therapeutic acetaminophen (0.5 mM) inhibits 16% of ADH1B*1/*1 hepatic ADH activity at 2-20 mM ethanol and that therapeutic salicylate (1.5 mM) inhibits 30-31% of the ADH1B*2/*2 activity, suggesting potential significant inhibitions of ethanol FPM in these allelotypes. The result provides systematic evaluations and predictions by computer simulation on potential ethanol FPM in target tissues and hepatic ethanol-drug interactions in the context of tissue ADH isozymes.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, 161 Minchuan East Road Section 6, Taipei 11490, Taiwan.
authors.forename: Yu-Chou
authors.initials: YC
authors.lastname: Chi
authors.affiliation: Department of Biological Science and Technology, China Medical University, 91 Hsueh-Shih Road, Taichung 40402, Taiwan.
authors.forename: Shou-Lun
authors.initials: SL
authors.lastname: Lee
authors.affiliation: Department of Nursing, Chang Gung University of Science and Technology, 261 Wenhwa 1st Road, Kweishan Township, Taoyuan 33303, Taiwan.
authors.forename: Ching-Long
authors.initials: CL
authors.lastname: Lai
authors.affiliation: Department of Biochemistry, National Defense Medical Center, 161 Minchuan East Road Section 6, Taipei 11490, Taiwan.
authors.forename: Yung-Pin
authors.initials: YP
authors.lastname: Lee
authors.affiliation: Department of Dentistry, Tri-Service General Hospital, National Defense Medical Center, 325 Chenggong Road Section 2, Taipei 11490, Taiwan.
authors.forename: Shiao-Pieng
authors.initials: SP
authors.lastname: Lee
authors.affiliation: Department of Dermatology, Tri-Service General Hospital, National Defense Medical Center, 325 Chenggong Road Section 2, Taipei 11490, Taiwan.
authors.forename: Chien-Ping
authors.initials: CP
authors.lastname: Chiang
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, 161 Minchuan East Road Section 6, Taipei 11490, Taiwan; Department of Biochemistry, National Defense Medical Center, 161 Minchuan East Road Section 6, Taipei 11490, Taiwan. Electronic address: yinsj@ndmc.idv.tw.
authors.forename: Shih-Jiun
authors.initials: SJ
authors.lastname: Yin
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology; D000426:Alcohol Dehydrogenase / Q000378:metabolism*; D001241:Aspirin / Q000494:pharmacology; D002927:Cimetidine / Q000494:pharmacology; D000431:Ethanol / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D010084:Oxidation-Reduction / Q000187:drug effects; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D020156:Salicylic Acid / Q000494:pharmacology; D013270:Stomach / Q000187:drug effects; D013379:Substrate Specificity
chemical_list: D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D000082:Acetaminophen; D000431:Ethanol; D002927:Cimetidine; D000426:Alcohol Dehydrogenase; D020156:Salicylic Acid; D001241:Aspirin
keywords: Alcohol dehydrogenase; Aspirin, salicylate, acetaminophen and cimetidine; Ethanol–drug interaction; First-pass ethanol metabolism; Organ modeling and simulation; Tissue isozyme and allozyme