Original articles
Christina Ferrucci-Da Silva, Le Zhan, Jianliang Shen, Bo Kong, Michael J. Campbell, Naureen Memon, Thomas Hegyi, Lucy Lu, Grace L. Guo. Effects of total parenteral nutrition on drug metabolism gene expression in mice[J]. Acta Pharmaceutica Sinica B, 2020, 10(1): 153-158

Effects of total parenteral nutrition on drug metabolism gene expression in mice
Christina Ferrucci-Da Silvaa,i, Le Zhanb, Jianliang Shenc, Bo Kongd, Michael J. Campbelld, Naureen Memone, Thomas Hegyia, Lucy Luf, Grace L. Guod,g,h
a Division of Neonatology, Department of Pediatrics, Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA;
b Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA;
c Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ 08854, USA;
d Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA;
e MidAtlantic Neonatology Associates, Morristown, NJ 07960, USA;
f School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15260, USA;
g Environmental and Occupational Health Institute, Rutgers University, Piscataway, NJ 08854, USA;
h VA NJ Health Care Systems, East Orange, NJ 07018, USA
Parenteral nutrition-associated liver disease (PNALD) is a liver dysfunction caused by various risk factors presented in patients receiving total parenteral nutrition (TPN). Omega-6 rich Intralipid® and omega-3 rich Omegaven® are two intravenous lipid emulsions used in TPN. TPN could affect the hepatic expression of genes in anti-oxidative stress, but it’s unknown whether TPN affects genes in drug metabolism. In this study, either Intralipid-or Omegaven-based TPN was administered to mice and the expression of a cohort of genes involved in anti-oxidative stress or drug metabolism was analyzed, glutathione (GSH) levels were measured, and protein levels for two key drug metabolism genes were determined. Overall, the expression of most genes was downregulated by Intralipid-based TPN (Gstp1, Gstm1, 3, 6, Nqo1, Ho-1, Mt-1, Gclc, Gclm, Cyp2d9, 2f2, 2b10, and 3a11). Omegaven® showed similar results as Intralipid® except for preserving the expression of Gstm1 and Cyp3a11, and increasing Ho-1. Total GSH levels were decreased by Intralipid®, but increased by Omegaven®. CYP3A11 protein levels were increased by Omegaven®. In conclusion, TPN reduced the expression of many genes involved in anti-oxidative stress and drug metabolism in mice. However, Omegaven® preserved expression of Cyp3a11, suggesting another beneficial effect of Omegaven® in protecting liver functions.
Key words:    Total parenteral nutrition    Glutathione    Drug metabolism    Liver    Parenteral nutritionassociated liver disease   
Received: 2019-07-09     Revised: 2019-09-25
DOI: 10.1016/j.apsb.2019.10.012
Funds: This work was supported by grants from the National Institutes of Health (R01GM104037, R21ES029258, T32ES007148, and P3-ES005022, USA) and Department of Veterans Affairs (BX002741, USA).
Corresponding author: Grace L. Guo     Email:guo@eohsi.rutgers.edu
Author description:
PDF(KB) Free
Christina Ferrucci-Da Silva
Le Zhan
Jianliang Shen
Bo Kong
Michael J. Campbell
Naureen Memon
Thomas Hegyi
Lucy Lu
Grace L. Guo

1. Nandivada P, Cowan E, Carlson SJ, Chang M, Gura KM, Puder M. Mechanisms for the effects of fish oil lipid emulsions in the management of parenteral nutrition-associated liver disease. Prostag leukotr ess 2013;89:153-8.
2. Nandivada P, Carlson SJ, Chang MI, Cowan E, Gura KM, Puder M. Treatment of parenteral nutrition-associated liver disease: the role of lipid emulsions. Adv Nutr 2013;4:711-7.
3. Tillman EM, Helms RA. Omega-3 long chain polyunsaturated fatty acids for treatment of parenteral nutrition-associated liver disease: a review of the literature. J Pediatr Pharmacol Ther 2011;16:31-8.
4. Weinberger B, Watorek K, Strauss R, Witz G, Hiatt M, Hegyi T. Association of lipid peroxidation with hepatocellular injury in preterm infants. Crit Care 2002;6:521-5.
5. Lu SC. Regulation of glutathione synthesis. Mol Asp Med 2009;30: 42-59.
6. Wu G, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health. J Nutr 2004;134:489-92.
7. Ghobadloo SM, Yaghmaei B, Bakayev V, Goudarzi H, Noorinayer B, Rad FH, et al. GSTP1, GSTM1, and GSTT1 genetic polymorphisms in patients with cryptogenic liver cirrhosis. J Gastrointest Surg 2004;8: 423-7.
8. Maurizio P, Novo E. Nrf1 gene expression in the liver: a single gene linking oxidative stress to NAFLD, NASH and hepatic tumours. J Hepatol 2005;43:1096-7.
9. Qi X, Ng KT, Lian QZ, Liu XB, Li CX, Geng W, et al. Clinical significance and therapeutic value of glutathione peroxidase 3 (GPx3) in hepatocellular carcinoma. Oncotarget 2014;5:11103-20.
10. Qu K, Liu SS, Wang ZX, Huang ZC, Liu SN, Chang HL, et al. Polymorphisms of glutathione S-transferase genes and survival of resected hepatocellular carcinoma patients. World J Gastroenterol 2015;21:4310-22.
11. Dalton TP, Dieter MZ, Yang Y, Shertzer HG, Nebert DW. Knockout of the mouse glutamate cysteine ligase catalytic subunit (Gclc) gene: embryonic lethal when homozygous, and proposed model for moderate glutathione deficiency when heterozygous. Biochem Biophys Res Commun 2000;279:324-9.
12. Sikorski EM, Hock T, Hill-Kapturczak N, Agarwal A. The story so far: molecular regulation of the heme oxygenase-1 gene in renal injury. Am J Physiol Renal Physiol 2004;286:F425-41.
13. Wang RQ, Nan YM, Wu WJ, Kong LB, Han F, et al. Induction of heme oxygenase-1 protects against nutritional fibrosing steatohepatitis in mice. Lipids Health Dis 2011;10:31.
14. Davis SR, Cousins RJ. Metallothionein expression in animals: a physiological perspective on function. J Nutr 2000;130:1085-8.
15. Thirumoorthy N, Shyam Sunder A, Manisenthil Kumar K, Senthil Kumar M, Ganesh G, Chatterjee M. A review of metallothionein isoforms and their role in pathophysiology. World J Surg Oncol 2011; 9:54.
16. Dinkova-Kostova AT, Talalay P. NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector. Arch Biochem Biophys 2010; 501:116-23.
17. Jiang XL, Gonzalez FJ, Yu AM. Drug-metabolizing enzyme, transporter, and nuclear receptor genetically modified mouse models. Drug Metab Rev 2011;43:27-40.
18. Zhan L, Yang I, Kong B, Shen J, Gorczyca L, Memon N, et al. Dysregulation of bile acid homeostasis in parenteral nutrition mouse model. Am J Physiol Gastrointest Liver Physiol 2016;310:G93-102.
19. Kong B, Zhang M, Huang M, Rizzolo D, Armstrong LE, Schumacher JD, et al. FXR deficiency alters bile acid pool composition and exacerbates chronic alcohol induced liver injury. Dig Liver Dis 2019;51:570-6.
20. Copple BL, Jaeschke H, Klaassen CD. Oxidative stress and the pathogenesis of cholestasis. Semin Liver Dis 2010;30:195-204.
21. Yang CS, Lambert JD, Sang S. Antioxidative and anti-carcinogenic activities of tea polyphenols. Arch Toxicol 2009;83:11-21.
22. Vlaardingerbroek H, Ng K, Stoll B, Benight N, Chacko S, Kluijtmans LA, et al. New generation lipid emulsions prevent PNALD in chronic parenterally fed preterm pigs. J Lipid Res 2014; 55:466-77.
23. Calkins KL, Venick RS, Devaskar SU. Complications associated with parenteral nutrition in the neonate. Clin Perinatol 2014;41:331-45.
24. Zeng X, Li X, Xu C, Jiang F, Mo Y, Fan X, et al. Schisandra sphenanthera extract (Wuzhi Tablet) protects against chronic-binge and acute alcohol-induced liver injury by regulating the NRF2-ARE pathway in mice. Acta Pharm Sin B 2017;7:583-92.
25. Sokol RJ, Taylor SF, Devereaux MW, Khandwala R, Sondheimer NJ, Shikes RH, et al. Hepatic oxidant injury and glutathione depletion during total parenteral nutrition in weanling rats. Am J Physiol 1996; 270:G691-700.
26. Peng L, Piekos S, Guo GL, Zhong XB. Role of farnesoid X receptor in establishment of ontogeny of phase-I drug metabolizing enzyme genes in mouse liver. Acta Pharm Sin B 2016;6:453-9.
27. Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician 2007; 76:391-6.
28. Kluth D, Landes N, Pfluger P, Muller-Schmehl K, Weiss K, BumkeVogt C, et al. Modulation of Cyp3a11 mRNA expression by alphatocopherol but not gamma-tocotrienol in mice. Free Radic Biol Med 2005;38:507-14.
Similar articles:
1.Hong Lu.Crosstalk of HNF4α with extracellular and intracellular signaling pathways in the regulation of hepatic metabolism of drugs and lipids[J]. Acta Pharmaceutica Sinica B, 2016,6(5): 393-408