Skip to main content
SpringerLink
Log in

Oxidative Stress in Inherited Metabolic Diseases

  • Chapter
  • First Online:
Studies on Pediatric Disorders

  • 811 Accesses

Abstract

The major pathophysiologies of inherited metabolic diseases are explained by accumulated toxic substances such as phenylalanine, copper, ammonia, metabolites of free fatty acids, and lactate. Recently, enhanced oxidative stress and the resultant modifications of the clinical pictures have been implicated in several metabolic diseases. However, such information is insufficient. More studies must be conducted. To date, we have obtained details related to oxidative stress for several inherited metabolic diseases. In phenylketonuria, phenylalanine per se enhances oxidative stress directly. The status of oxidative stress in affected subjects appears to influence on the nitric oxide, cholesterol, oxysterol, and vitamin D metabolism. In aspartate/glutamate carrier isoform 2, namely citrin, deficiency presenting abnormalities in carbohydrate, urea cycle, and mitochondrial respiratory chain function, oxidative stress is enhanced consistently. The enhanced oxidative stress is expected to engender the development of adult-onset type II citrullinemia exhibiting prominent fatty liver and hyperammonemia. In Wilson’s disease presenting copper accumulation in the liver, brain, kidney, and many other organs and tissues, oxidative stress is enhanced as the accumulation of copper and the disease progress. Liver glutathione acting against oxidants is depleted completely in the progressed stage. Interestingly, the oxidative stress is closely related to fat deposition in the liver via peroxisome-proliferative activator receptors. Thus, oxidative stress is strongly associated with pathophysiologies and clinical pictures of inherited metabolic diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ADMA:

Asymmetric dimethylarginine

AGC2:

Aspartate/glutamate carrier isoform 2

CoQ10 :

Coenzyme Q10

CTLN2:

Adult-onset type II citrullinemia

DTNB:

5, 5-Dithibis [2-nitrobenzoic] acid

ELISA:

Enzyme-linked immunosorbent assay

GPx:

Glutathione peroxidase

GSH:

Reduced glutathione

GSSG:

Oxidized glutathione

MDA-LDL:

Malondialdehyde-modified low-density lipoprotein

NICCD:

Neonatal intrahepatic cholestasis caused by citrin deficiency

NO:

Nitric oxide

NOx:

Nitrite/nitrate

8-OHdG:

8-Hydroxy-2′-deoxyguanosine

PKU:

Phenylketonuria

PPAR:

Peroxisome proliferator-activated receptor

SOD:

Superoxide-dismutase

TAR:

Total antioxidant activity

TBARS:

Thiobarbituric acid-reactive species

WD:

Wilson’s disease

References

  1. Halliwell B (1994) Free radicals, antioxidants, and human disease: curiosity, cause, or consequence? Lancet 344:721–724

    Article  CAS  PubMed  Google Scholar 

  2. Reznick AZ, Packer L (1993) Free radicals and antioxidants in muscular neurological diseases and disorders. In: Poli G, Albano B, Dianzani MU (eds) Free radical: from basic science to medicine. Birkhauser, Basel, pp 425–437

    Chapter  Google Scholar 

  3. Przedborski S, Donaldson D, Jakowec M, Kish SJ, Guttman M, Rosoklija G, Hays AP (1996) Brain superoxide dismutase, catalase, and glutathione peroxidase activities in amyotrophic lateral sclerosis. Ann Neurol 39:158–165

    Article  CAS  PubMed  Google Scholar 

  4. Khan S, O’Brien PJ (1995) Modulating hypoxia-induced hepatocyte injury by affecting intracellular redox state. Biochim Biophys Acta 1269:153–161

    Article  PubMed  Google Scholar 

  5. Perlemuter G, Davit-Spraul A, Cosson C, Conti M, Bigorgne A, Paradis V, Corre MP, Prat L, Kuoch V, Basdevant A, Pelletier G, Oppert JM, Buffet C (2005) Increase in liver antioxidant enzyme activities in non-alcoholic fatty liver disease. Liver Int 25:946–953

    Article  CAS  PubMed  Google Scholar 

  6. Tsukahara H (2007) Biomarkers for oxidative stress: clinical application in pediatric medicine. Curr Med Chem 14:339–351

    Article  CAS  PubMed  Google Scholar 

  7. Crane FL (2001) Biochemical functions of coenzyme Q10. J Am Coll Nutr 20:591–598

    Article  CAS  PubMed  Google Scholar 

  8. Takayanagi R, Takeshige K, Minakimi S (1980) NADH- and NADPH-dependent lipid peroxidation in bovine heart submitchondrial particles. Dependent on the rate of electron flow in the respiratory chain and an antioxidant role for ubiquinol. Biochem J 192:853–860

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Moncada S, Palmer RM, Higgs EA (1991) Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43:109–142

    CAS  PubMed  Google Scholar 

  10. Karaa A, Kamoun WS, Clemens MG (2005) Oxidative stress disrupts nitric oxide synthase activation in liver endothelial cells. Free Radic Biol Med 39:1320–1331

    Article  CAS  PubMed  Google Scholar 

  11. Cooke JP (2005) ADMA: its role in vascular disease. Vasc Med 10:S11–S17

    Article  PubMed  Google Scholar 

  12. Sydow K, Munzel T (2003) ADMA and oxidative stress. Atheroscler Suppl 4:41–51

    Article  CAS  PubMed  Google Scholar 

  13. Sirtori LR, Dutra-Filho CS, Fitarelli D, Sitta A, Haeser A, Barschak AG, Wajner M, Coelho DM, Llesuy S, Belló-Klein A, Giugliani R, Deon M, Vargas CR (2005) Oxidative stress in patients with phenylketonuria. Biochim Biophys Acta 1740:68–73

    Article  CAS  PubMed  Google Scholar 

  14. Sitta A, Barschak AG, Deon M, de Mari JF, Barden AT, Vanzin CS, Biancini GB, Schwartz IV, Wajner M, Vargas CR (2009) L-carnitine blood level and oxidant stress in treated phenylketonuric patients. Cell Mol Neurobiol 29:211–218

    Article  CAS  PubMed  Google Scholar 

  15. Kotani K, Maekawa M, Kanno T, Kondo A, Toda N, Manabe M (1994) Distribution of immunoreactive malondialdehyde-modified low-density lipoprotein in human serum. Biochim Biophys Acta 1215:121–125

    Article  CAS  PubMed  Google Scholar 

  16. Artuch R, Colomé C, Sierra C, Brandi N, Lambruschini N, Campistol J, Ugarte D, Vilaseca MA (2004) A longitudinal study of antioxidant status in phenylketonuric patients. Clin Biochem 37:198–203

    Article  CAS  PubMed  Google Scholar 

  17. Tamura S, Tsukahara H, Ueno M, Maeda M, Kawakami H, Sekine K, Mayumi M (2006) Evaluation of a urinary multi-parameter biomarker set for oxidative stress in children, adolescents and young adults. Free Radic Res 40:1198–1205

    Article  CAS  PubMed  Google Scholar 

  18. Schulze F, Wesemann R, Schwedhelm E, Sydow K, Albsmeier J, Cooke JP, Böger RH (2004) Determination of asymmetric dimethylarginine (ADMA) using a novel ELISA assay. Clin Chem Lab Med 42:1377–1383

    Article  CAS  PubMed  Google Scholar 

  19. Summer KH, Eisenburg J (1985) Low content of hepatic reduced glutathione in patients with Wilson’s disease. Biochem Med 34:107–111

    Article  CAS  PubMed  Google Scholar 

  20. Tietze F (1969) Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem 27:502–522

    Article  CAS  PubMed  Google Scholar 

  21. Sies H, Summer KH (1975) Hydroperoxide-metabolizing systems in rat liver. Eur J Biochem 57:503–512

    Article  CAS  PubMed  Google Scholar 

  22. Gutteridge JM, Halliwell B (1990) The measurement and mechanism of lipid peroxidation in biological systems. Trend Biochem Sci 15:129–135

    Article  CAS  PubMed  Google Scholar 

  23. Will ED (1969) Lipid peroxide formation in microsomes. Biochem J 113:315–341

    Google Scholar 

  24. McCord JM, Fridovich I (1969) Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem 244:6049–6055

    CAS  PubMed  Google Scholar 

  25. Paglia DE, Valentine WN (1967) Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 70:158–169

    CAS  PubMed  Google Scholar 

  26. Jiménez I, Aracena P, Letelier ME, Navarro P, Speisky H (2002) Chronic exposure of HepG2 cells to excess copper results in depletion of glutathione and induction of metallothionein. Toxicol In Vitro 16:167–175

    Article  PubMed  Google Scholar 

  27. Scriver CR, Kaufman S (2001) Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Scriver CR, Beaudet al, Sly WS, Sly D (eds) The metabolic and molecular bases of inherited disease, 8th edn. McGraw-Hill, New York, pp 1667–1724

    Google Scholar 

  28. Hanley WB (2004) Adult phenylketonuria. Am J Med 117:590–595

    Article  CAS  PubMed  Google Scholar 

  29. Lee PJ, Amos A, Robertson L, Fitzgerald B, Hoskin R, Lilburn M, Weetch E, Murphy G (2009) Adults with late diagnosed PKU and severe challenging behaviour: a randomised placebo-controlled trial of a phenylalanine-restricted diet. J Neurol Neurosurg Psychiatry 80:631–635

    Article  CAS  PubMed  Google Scholar 

  30. Hargreaves IP (2007) Coenzyme Q10 in phenylketonuria and mevalonic aciduria. Mitochondrion 7(Suppl):S175–S180

    Article  CAS  PubMed  Google Scholar 

  31. Förstermann U, Münzel T (2006) Endothelial nitric oxide in vascular disease from marvel to menace. Circulation 113:1708–1714

    Article  PubMed  Google Scholar 

  32. Mori M, Gotoh T (2004) Arginine metabolic enzymes, nitric oxide and infection. J Nutr 134:2820–2825

    Google Scholar 

  33. Palmieri F (2008) Diseases caused by mitochondria transporters. Biochim Biophys Acta 1777:564–568

    Article  CAS  PubMed  Google Scholar 

  34. Yasuda T, Yamaguchi N, Kobayashi K, Nishi I, Horinouchi H, Jalil MA, Li MX, Ushikai M, Iijima M, Kondo I, Saheki T (2000) Identification of two novel mutations in the SLC25A13 gene and detection of seven mutations in 102 patients with adult-onset type II citrullinemia. Hum Genet 107:537–545

    Article  CAS  PubMed  Google Scholar 

  35. Yamaguchi N, Kobayashi K, Yasuda T, Nishi I, Iijima M, Nakagawa M, Osame M, Kondo I, Saheki T (2002) Screening of SLC25A13 mutations in early and late onset patients with citrin deficiency and in the Japanese population: identification of two novel mutations and establishment of multiple DNA diagnosis method for the nine mutations. Hum Mutat 19:122–130

    Article  CAS  PubMed  Google Scholar 

  36. Saheki T, Kobayashi K (2002) Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD). J Hum Genet 47:333–341

    Article  CAS  PubMed  Google Scholar 

  37. Ohura T, Kobayashi K, Tazawa Y, Abukawa D, Sakamoto O, Tsuchiya S, Saheki T (2007) Clinical pictures of 75 patients with neonatal intrahepatic cholestasis caused by citrin deficiency. J Inherit Metab Dis 30:139–144

    Article  CAS  PubMed  Google Scholar 

  38. Dimmock D, Kobayashi K, Iijima M, Tabata A, Wong LJ, Saheki T, Lee B, Scaglia F (2007) Citrin deficiency: a novel cause of failure to thrive that responds to a high-protein, low-carbohydrate diet. Pediatrics 119:773–777

    Article  Google Scholar 

  39. Tanzi RE, Petrukhin K, Chernov I, Pellequer JL, Wasco W, Ross B, Romano DM, Parano E, Pavone L, Brzustowicz LM, Devote M, Peppercorn J, Bush AI, Sternlieb I, Pirastu M, Gusella JF, Evgrafov O, Penchaszadeh GK, Honig B, Edelman IS, Soares MB, Sheinberg IH, Gilliam TC (1993) The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet 5:344–350

    Article  CAS  PubMed  Google Scholar 

  40. Scheinberg IH, Sternlieb I (1984) Wilson disease. In: Smith LH (ed) Major problems in internal medicine. Saunders, Philadelphia, PA, pp 1–179

    Google Scholar 

  41. Sokol RJ, Narkewicz MR (2001) Copper and iron disorders. In: Suchy FJ, Sokol RJ, Balistreli WF (eds) Liver disease in children. Lippincott Williams & Wilkins, Philadelphia, PA, pp 595–640

    Google Scholar 

  42. Hochstein P, Kumar KS, Forman SJ (1980) Lipid peroxidation and the cytotoxicity of copper. Ann N Y Acad Sci 355:240–248

    Article  CAS  PubMed  Google Scholar 

  43. Sokol RJ, Twedt D, McKim JM Jr, Devereaux MW, Karrer FM, Kam I, von Steigman G, Narkewicz MR, Bacon BR, Britton RS (1994) Oxidant injury to hepatic mitochondria in patients with Wilson’s disease and Bedlington terriers with copper toxicosis. Gastroenterology 107:1788–1798

    CAS  PubMed  Google Scholar 

  44. Strand S, Hofmann WJ, Grambihler A, Hug H, Volkmann M, Otto G, Wesch H, Marian SM, Hack V, Stremmel W, Krammer PH, Galle PR (1998) Hepatic failure and liver cell damage in acute Wilson’s disease involve CD95(APO-1/Fas) mediated apoptosis. Nat Med 4:588–593

    Article  CAS  PubMed  Google Scholar 

  45. Bedossa P, Poynard T (1996) An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 24:289–293

    Article  CAS  PubMed  Google Scholar 

  46. Tailleux A, Wouters K, Staels B (2012) Roles of PPARs in NAFLD: potential therapeutic targets. Biochim Biophys Acta 1821:809–818

    Google Scholar 

  47. Nagasawa T, Inada Y, Nakano S, Tamura T, Takahashi T, Maruyama K, Yamazaki Y, Kuroda J, Shibata N (2006) Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPAR delta agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet. Eur J Pharmacol 536:182–191

    Article  CAS  PubMed  Google Scholar 

  48. Lutchman G, Modi A, Kleiner DE, Promrat K, Heller T, Ghany M, Borg B, Loomba R, Liang TJ, Premkumar A, Hoofnagle JH (2007) The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hepatology 46:424–429

    Article  CAS  PubMed  Google Scholar 

  49. Enns GM, Kinsman SL, Perlman SL, Spicer KM, Abdenur JE, Cohen BH, Amagata A, Barnes A, Kheifets V, Shrader WD, Thoolen M, Blankenberg F, Miller G (2012) Initial experience in the treatment of inherited mitochondrial disease with EPI-743. Mol Genet Metab 105:91–102

    Article  CAS  PubMed  Google Scholar 

  50. Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Ryter SW, Kim HP, Hoetzel A, Park JW, Nakahira K, Wang X, Choi AM (2007) Mechanism of cell death in oxidative stress. Antioxid Redox Signal 9:49–89

    Article  CAS  PubMed  Google Scholar 

  52. Fernandes CG, Borges CG, Seminotti B, Amaral AU, Knebel LA, Eichler P, de Oliveira AB, Leipnitz G, Wajner M (2011) Experimental evidence that methylmalonic acid provokes oxidative damage and compromises antioxidant defenses in nerve terminal and striatum of young rats. Cell Mol Neurobiol 31:775–785

    Article  CAS  PubMed  Google Scholar 

  53. Kanaumi T, Takashima S, Hirose S, Kodama T, Iwasaki H (2006) Neuropathology of methylmalonic academia in a child. Pediatr Neurol 34:156–159

    Article  PubMed  Google Scholar 

  54. de Keyzer Y, Valayannopoulos V, Benoist JF, Batteux F, Lacaille F, Hubert L, Chrétien D, Chadefeaux-Vekemans B, Niaudet P, Touati G, Munnich A, de Lonlay P (2009) Multiple OXPHOS deficiency in the liver, kidney, heart, and skeletal muscle of patients with methylmalonic aciduria and propionic aciduria. Pediatr Res 66:91–95

    Article  PubMed  Google Scholar 

  55. Biancini GB, Sitta A, Wayhs CA, Pereira IN, Rockenbach F, Garcia SC, Wyse AT, Schwartz IV, Wajner M, Vargas CR (2011) Experimental evidence of oxidative stress in plasma of homocystinuric patients: a possible role for homocysteine. Mol Genet Metab 104:112–117

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Takarazuka City Hospital, 4-5-1 Kohama-cho, Takarazuka, 665-0827, Japan

    Hironori Nagasaka M.D.

  2. Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan

    Hirokazu Tsukahara M.D., Ph.D.

  3. Department of Clinical Laboratory Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    Takashi Miida M.D., Ph.D.

Authors
  1. Hironori Nagasaka M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hirokazu Tsukahara M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takashi Miida M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hironori Nagasaka M.D. .

Editor information

Editors and Affiliations

  1. Dentistry and Pharmaceutical Sciences Department of Pediatrics, Okayama University Graduate School of Medicine, Okayama, Japan

    Hirokazu Tsukahara

  2. Department of Pediatrics, Kansai Medical University, Osaka, Japan

    Kazunari Kaneko

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Nagasaka, H., Tsukahara, H., Miida, T. (2014). Oxidative Stress in Inherited Metabolic Diseases. In: Tsukahara, H., Kaneko, K. (eds) Studies on Pediatric Disorders. Oxidative Stress in Applied Basic Research and Clinical Practice. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0679-6_23

Download citation

Publish with us

Policies and ethics

Search

Navigation