1 research outputs found
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