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. 2022 Sep 23:13:995597.
doi: 10.3389/fphar.2022.995597. eCollection 2022.

Simulation of the crosstalk between glucose and acetaminophen metabolism in a liver zonation model

Kazuhiro Maeda  1 , Shuta Hagimori  2 , Masahiro Sugimoto  3   4 , Yasuyuki Sakai  2 , Masaki Nishikawa  2
Affiliations

Simulation of the crosstalk between glucose and acetaminophen metabolism in a liver zonation model

Kazuhiro Maeda et al. Front Pharmacol. .

Abstract

The liver metabolizes a variety of substances that sometimes interact and regulate each other. The modeling of a single cell or a single metabolic pathway does not represent the complexity of the organ, including metabolic zonation (heterogeneity of functions) along with liver sinusoids. Here, we integrated multiple metabolic pathways into a single numerical liver zonation model, including drug and glucose metabolism. The model simulated the time-course of metabolite concentrations by the combination of dynamic simulation and metabolic flux analysis and successfully reproduced metabolic zonation and localized hepatotoxicity induced by acetaminophen (APAP). Drug metabolism was affected by nutritional status as the glucuronidation reaction rate changed. Moreover, sensitivity analysis suggested that the reported metabolic characteristics of obese adults and healthy infants in glucose metabolism could be associated with the metabolic features of those in drug metabolism. High activities of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphate phosphatase in obese adults led to increased APAP oxidation by cytochrome P450 2E1. In contrast, the high activity of glycogen synthase and low activities of PEPCK and glycogen phosphorylase in healthy infants led to low glucuronidation and high sulfation rates of APAP. In summary, this model showed the effects of glucose metabolism on drug metabolism by integrating multiple pathways into a single liver metabolic zonation model.

Keywords: acetaminophen; glucose; hepatocytes; mathematical model; metabolism; zonation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Network map of the constructed model. Schematic representation of the simulation model combining glucose (Glc), acetaminophen (APAP), and cysteine (Cys) metabolisms indicated by open blue, solid orange, and solid blue shapes, respectively. The definitions of the abbreviations are listed in the Supplementary Material. Glc, lactate, APAP, and Cys in the blood can be transported into the cytosol. The endoplasmic reticulum and mitochondria are shown on the background. The square boxes represent enzymes and transporters, whereas the circles represent substrates and metabolites.
FIGURE 2
FIGURE 2
Metabolite concentrations without acetaminophen administration. Hepatocytes were in a feeding state from 0 to 12 h and in a fasting state for the rest of the simulation time. The external (blood) glucose levels were set to 4 and 11 mM for the fasting and feeding states, respectively. The solid red lines and blue dotted lines indicate the periportal and pericentral regions, respectively. The definitions of the abbreviations are listed in Supplementary Material.
FIGURE 3
FIGURE 3
Metabolite reaction rates without acetaminophen administration. Hepatocytes were in a feeding state from 0 to 12 h and in a fasting state for the rest of the simulation time. The external (blood) glucose levels were set to 4 and 11 mM for the fasting and feeding states, respectively. The solid red lines and blue dotted lines indicate the periportal and pericentral regions, respectively. The definitions of the abbreviations are listed in Supplementary Material.
FIGURE 4
FIGURE 4
Validation of the constructed model. (A) Simulated glucose exchange rate by glucose transporter 2 in response to external (blood) glucose concentration. (B) Simulated glycogen concentrations over time. Hepatocytes were in a feeding state from 0 to 24 h and in a fasting state for the rest of the simulation time. The external (blood) glucose concentrations were set to 4 and 11 mM for the fasting and feeding states, respectively. The external lactose concentration was fixed at 1 mM in all simulations.
FIGURE 5
FIGURE 5
Simulation of acetaminophen (APAP) metabolism. APAP was administered for the initial 30 min of the simulation. The red and blue lines indicate the periportal and pericentral regions, respectively. The solid and dotted lines indicate moderate (0.5 mM/h) and excessive (6.0 mM/h) APAP administration, respectively. The definitions of the abbreviations are listed in Supplementary Material.
FIGURE 6
FIGURE 6
Visual representation of the results in Tables 1, 2, and 3. Acetaminophen (APAP) was administered for the initial 30 min at 0.5 mM/h (moderate dose) or 6.0 mM/h (overdose) under either 4 mM (fasting) or 11 mM (feeding) of blood glucose. The reaction rates of APAP metabolic pathways were integrated up to 5 h, and the results are shown as relative contributions to APAP metabolism in pie charts. In each chart, the outer and inner circles represent the results in the periportal and pericentral regions, respectively. The activities of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphate phosphatase (G6P) increased in obese adults compared with healthy adults. Furthermore, the glycogen synthase activity increased, and PEPCK and glycogen phosphorylase activities decreased in healthy infants compared with healthy adults. The modified enzymatic activities are highlighted in green on the network maps. Dashed squares (red to red and blue to blue) highlight the prominent differences in relative contributions of APAP metabolic pathways among three model cases.
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References

    1. Abdel-Misih S. R., Bloomston M. (2010). Liver anatomy. Surg. Clin. North Am. 90, 643–653. 10.1016/j.suc.2010.04.017 - DOI - PMC - PubMed
    1. Adeva-Andany M. M., Pérez-Felpete N., Fernández-Fernández C., Donapetry-García C., Pazos-García C. (2016). Liver glucose metabolism in humans. Biosci. Rep. 36, e00416. 10.1042/bsr20160385 - DOI - PMC - PubMed
    1. Ahn J., Ahn J. H., Yoon S., Nam Y. S., Son M. Y., Oh J. H. (2019). Human three-dimensional in vitro model of hepatic zonation to predict zonal hepatotoxicity. J. Biol. Eng. 13, 22. 10.1186/s13036-019-0148-5 - DOI - PMC - PubMed
    1. Ainscow E. K., Brand M. D. (1999). Internal regulation of ATP turnover, glycolysis and oxidative phosphorylation in rat hepatocytes. Eur. J. Biochem. 266, 737–749. 10.1046/j.1432-1327.1999.00856.x - DOI - PubMed
    1. Anundi I., Lähteenmäki T., Rundgren M., Moldeus P., Lindros K. O. (1993). Zonation of acetaminophen metabolism and cytochrome P450 2E1-mediated toxicity studied in isolated periportal and perivenous hepatocytes. Biochem. Pharmacol. 45, 1251–1259. 10.1016/0006-2952(93)90277-4 - DOI - PubMed

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