Effects of endurance training and exercise on tissue antioxidative capacity and acetaminophen detoxification


Both acute acetaminophen toxicity and physical exercise are accompanied by structural and functional damage to tissues. For acute acetaminophen toxicity, this damage occurs mainly in the liver. This damage, which is believed to be initially caused by oxidation and/or arylation, occurs only after depletion of liver glutathione (GSH). GSH normally protects against oxidation and/or arylation. Prolonged physical exercise also depletes GSH in the body. We hypothesized that with endurance training (repeated oxidant stress) tissues will develop mechanisms to prevent GSH depletion. Our results show that, for the same amount of submaximal exercise, trained rats are able to maintain their levels of GSH or their GSH redox status (in the liver, heart, skeletal muscle, and plasma) in contrast to their untrained counterparts. Also, upon administration of acetaminophen, trained rats show a less pronounced depletion in liver GSH than untrained rats. We also hypothesized that training may lead to improved maintenance of tissue GSH homeostasis because of inductions in the enzyme pathways of protection. We observe that training significantly increases (50–70%) glutathione peroxidase and reductase, glucose-6-phosphate dehydrogenase, and catalase activity in heart and skeletal muscle. Since GSH, in addition to providing cellular protection, also functions in other physiological processes including transport and metabolism, the training-induced benefits seen here may have more far-reaching consequences than ever before realized.

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  1. 1.

    Gilman A.G., Goodman L.S., Gilman A. (eds), Mayer S.E., Melmon KL. (assoc eds) (1980): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 6th edn. New York, MacMillan, pp. 701–705.

    Google Scholar 

  2. 2.

    Mitchell J.R., follow D.J., Potter W.Z., Gillette J.R., Brodie B.B. (1973): Aoetaminophen-induced hepatic necrosis. 1. Role of drug metabolism. J. Pharmacol. Exp. Ther., 187, 185–194.

    CAS  PubMed  Google Scholar 

  3. 3.

    Smith M.T., Orrenius S. (1984): Studies on drug metabolism and drug toxicity in isolated mammalian cells. In: Mitchell J.R, Homing M.G. (eds). Drug Metabolism and Drug Toxicity. New York, Raven Press, pp. 71–98.

    Google Scholar 

  4. 4.

    Miner D.J., Kissinger P.T. (1979): Evidence for the involvement of N-acetyl-p-quinoneimine in acetaminophen metabolism. Biochem. Pharmacol., 28, 3285–3290.

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Holme J.A., Dahlin D.C., Nelson S.D., Dybing E. (1984): Cytotoxic effects of N-acetyl-p-benzoquinone imine, a common arylating intermediate of paracetamol and N-bydroxyparacetamol. Biochem. Pharmacol., 33, 401–406.

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Mitchell J.R., follow D.J., Potter W.Z., Gillette J.R., Brodie B.B. (1973): Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J. Pharmacol. Exp. Ther., 187, 211–217.

    CAS  PubMed  Google Scholar 

  7. 7.

    Potter W.Z., Thorgeirsson S.S., follow J.D, Mitchell J.R. (1974): Acetaminophen-induced hepatic necrosis. V. Correlation of hepatic necrosis, covalent binding and glutathione depletion in hamsters. Pharmacology, 12, 129–143.

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Moldeus P. (1978): Paracetamol metabolism and toxicity in isolated hepatocytes from rat and mouse. Biochem. Pharmacol., 27, 2859–2863.

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Moore M., Thor H., Moore G. Nelson S., Moldéus P., Orrenius S. (1985): The toxicity of acetaminophen and N-acetyl-p-benzoquinone imine in isolated hepatocytes is associated with thiol depletion and increased cytosolic Ca2+. J. Biol. Chem., 260, 13035–13040.

    CAS  PubMed  Google Scholar 

  10. 10.

    Tee L.B.G., Davies D.S., Seddon C.E., Boobis A.R. (1987): Species differences in the hepatotoxicity of paracetamol are due to differences in the rate of conversion to its cytotoxic metabolite. Biochem. Pharmacol., 36, 1041–1052.

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Albano E., Rundgren M., Harrison P., Nelson S.D., Moldéus P. (1985): Mechanisms of N-aceryl-p-benzoqumone imine cytotoxicity. Mol. Pharmacol., 28, 306–311.

    CAS  PubMed  Google Scholar 

  12. 12.

    Tsokos-Kuhn J.O., Hughes H., Smith C.V., Mitchell J.R. (1988): Alkylation of the liver plasma membrane and inhibition of the Ca2+-ATPase by acetaminophen. Biochem. Pharmacol., 37, 2125–2131.

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Landon E.J., Naukam R.J., Rama Sastry B.V. (1986): Effects of calcium channel blocking agents on calcium and centrilobular necrosis in the liver of rats treated with hepatotoxic agents. Biochem. Pharmacol., 35, 697–705.

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Wendel A, Feuerstein S, Konz K.H. (1979): Acute paracetamol intoxication of starved mice leads to lipid peroxidation in vivo. Biochem. Pharmacol., 28, 2051–2055.

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Wendel A, Feuerstein S. (1981): Drug-induced lipid peroxidation in mice. I. Modulation by monooxygenase activity, glutathione and selenium status. Biochem. Pharmacol., 30, 2513–2520.

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Reiter R., Wendel A. (1983): Drug-induced lipid peroxidation in mice. IV. In vitro hydrocarbon evolution, reduction of oxygen and covalent binding of acetaminophen. Biochem. Pharmacol., 32, 665–670.

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Thelen M., Wendel, A. (1982): Drug-induced lipid peroxidation in mice. V. Ethane production and glutathione release in the isolated liver upon perfusion with acetaminophen. Biochem. Pharmacol., 32, 1701–1706.

    Article  Google Scholar 

  18. 18.

    Boyer T.D., Rouff S.L. (1971): Acetaminophen-induced hepatic necrosis and renal failure. JAMA, 218, 440–441.

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Boyd E, Bereczky G. (1966): Liver necrosis from paracetamol. Br. J. Pharmacol., 26, 606–614.

    CAS  Google Scholar 

  20. 20.

    Davidson D.G.D, Eastham W.N. (1966): Acute liver necrosis following overdose of paracetamol. Br. Med. J, 551, 497–499.

    Article  Google Scholar 

  21. 21.

    Vihko V, Rantamäki J, Salminen A. (1978): Exhaustive physical exercise and acid hydrolase activity in mouse skeletal muscle. A histochemical study. Histochemistry, 57, 237–249.

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Vihko V, Rantamäki J, Salminen A. (1979): Exhaustive exercise, endurance training and acid hydrolase activity in skeletal muscle. J. Appl. Physiol. Resp. Environ. Exercise Physiol., 47, 43–50.

    CAS  Google Scholar 

  23. 23.

    Altland P.D., Highman B. (1961): Effects of exercise on serum enzyme values and tissues of rats. Am. J. Physiol., 201, 393–395.

    CAS  PubMed  Google Scholar 

  24. 24.

    Kasperek G.J., Dohm G.L., Tapscott E.B., Powell T. (1980): Effect of exercise on liver protein loss and lysosomal enzyme levels in fed and fasted rats (40890). Proc. Soc. Exp. Biol. Med., 164, 430–434.

    CAS  PubMed  Google Scholar 

  25. 25.

    Loegering D.J., Bonin M.L., Smith J.J. (1975): Effect of exercise, hypoxia and epinephrine on lysosomes and plasma enzymes. Exp. Mol. Pathol., 22, 242–251.

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Davies K.J.A, Quintanilha A.T., Brooks G.A., Packer L. (1982): Free radicals and tissue damage caused by exercise. Biochem. Biophys. Res. Commun., 107, 1198–1205.

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Radeva-Domustchieva D., Russanov E. (1976): Effect of exhaustive swimming on the oxidative phosphorylation and the activity of some enzymes in rat liver mitochondria Acta Physiol. Pharmacol. Bulg., 2, 72–77.

    CAS  Google Scholar 

  28. 28.

    Bostrom S., Fahlen M. Hjalmarson A, Johansson R. (1974): Activities of rat muscle enzymes after acute exercise. Acta Physiol. Scand., 90, 544–554.

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Jones D.A., Jackson M.J., Edwards R.H.T. (1984): Experimental mouse muscle damage: The importance of external calcium. Clin. Sci., 66, 317–322.

    CAS  PubMed  Google Scholar 

  30. 30.

    Fitts R.H, Courtright J.B, Kim D.H., Witzmann F.A. (1982): Muscle fatigue with prolonged exercise: Contractile and biochemical alterations. Am. J. Physiol., 242, C65-C73.

    CAS  PubMed  Google Scholar 

  31. 31.

    Lew H., Pyke S., Quintanilha A. (1985): Changes in glutathione status of plasma, liver and muscle following exhaustive exercise in rats. FEBS Lett., 185, 262–266.

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Pyke S., Lew H., Quintanilha A. (1986): Severe depletion in liver glutathione during physical exercise. Biochem. Biophys. Res. Commun., 139, 926–931.

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Adams J.D., Lauterburg B.H., Mitchell J.R. (1983): Plasma glutathione and glutathione disulfide in the rat Regulation and response to oxidative stress. J. Pharmacol. Exp. Ther., 221, 749–754.

    Google Scholar 

  34. 34.

    Splittgerber A.G., Tappel A.L. (1979): Inhibition of glutathione peroxidase by cadmium and other metal ions. Arch. Biochem. Biophys, 197, 534–542.

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    Carlberg I., Marmervik B. (1977): Purification on affinity chromatography of yeast glutathione reductase, the enzyme responsible for the NADPH-dependent reduction of the mixed disulfide of coenzyme A and glutathione. Biochim. Biophys. Acta, 484, 268–274.

    CAS  PubMed  Google Scholar 

  36. 36.

    Lew H. (1989): The effects of physical exercise on tissue antioxidative capacity: The role of glutathione. PhD thesis, University of California at Berkeley.

  37. 37.

    Sun A.S., Aggarwal B.B., Packer L. (1975): Enzyme levels of normal human cells: Aging in culture. Arch. Biochem. Biophys., 170, 1–11.

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    Gornau A.G., Bardawill C.J., David M.M. (1949): Determination of serum proteins by means of the Biuret reaction. J. Biol. Chem., 177, 751–766.

    Google Scholar 

  39. 39.

    Aikawa K.M., Quintanilha A.T., de Lumen B.O., Brooks G.A., Packer L. (1984): Exercise endurance training alters vitamin E tissue levels and red blood cell hemolysis in rodents. Biosci. Rep., 4, 253–257.

    Article  CAS  PubMed  Google Scholar 

  40. 40.

    Brady P.S., Brady L.J., Ullrey D.E. (1979): Selenium, vitamin E and the response to swimming stress in the rat J. Nutr., 109, 1103–1109.

    CAS  PubMed  Google Scholar 

  41. 41.

    Gee D.X., Tappel A.L. (1981): The effect of exhaustive exercise on expired pentane as a measure of in vivo lipid peroxidation in the rat Life Sci., 28,2425–2429.

    Article  CAS  PubMed  Google Scholar 

  42. 42.

    Dillard C.J., Litov R.E., Savin W.M. Dumelin E.E., Tappel A.L. (1978): Effects of exercise, vitamin E and oxygen on pulmonary function and lipid peroxidation. J. Appl. Physiol. Respir. Environ. Exercise Physiol., 45, 927–932.

    CAS  Google Scholar 

  43. 43.

    Jackson M.J., Jones D.A., Edwards R.H.T. (1983): Vitamin E and skeletal muscle. In: Biology of Vitamin E (Ciba Foundation Symposium 101). London, Pitman Books, pp. 224–233.

    Google Scholar 

  44. 44.

    Kosower N.S., Kosower E.M. (1978): The glutathione status of cells. Int Rev. Cytol., 54, 109–160.

    Article  CAS  PubMed  Google Scholar 

  45. 45.

    Eklöw L, Moldéus P, Orrenius S. (1984): Oxidation of glutathione during hydroperoxide metabolism. A study using isolated hepatocytes and the glutathione reductase inhibitor BCNU (l,3-bis(2-chloroethyl)-l-nitrosourea). Eur. J. Biochem. 138, 459–463.

    Article  PubMed  Google Scholar 

  46. 46.

    Sies H., Graf P. (1985): Hepatic thiol and glutathione efflux under the influence of vasopressin, phenylephrine and adrenaline. Biochem. J., 226, 545–549.

    CAS  PubMed  Google Scholar 

  47. 47.

    Brooks G.A., Fahey T.D. (1984): Exercise physiology: Human Bioenergetics and its Applications, New York, John Wiley, pp. 163–188.

    Google Scholar 

  48. 48.

    Meister A. (1983): Selective modification of glutathione metabolism. Science, 220, 472–477.

    Article  CAS  PubMed  Google Scholar 

  49. 49.

    Smith M.T. (1985): Personal communication.

  50. 50.

    Bannai S., Tateishi N. (1986): Role of membrane transport in metabolism and function of glutathione in mammals. J. Membr. Biol, 89, 1–8.

    Article  CAS  PubMed  Google Scholar 

  51. 51.

    Kaplowitz N., Aw T.Y., Oohktens M. (1985): The regulation of hepatic glutathione. Annu. Rev. Pharmacol. Toxicol, 25, 715–744.

    Article  CAS  PubMed  Google Scholar 

  52. 52.

    Jenkins R.R., Friedland R., Howald H. (1982): The adaptation of the hydroperoxide enzyme system to increased oxygen use (Abstract). Med. Sei. Sports Exerc, 14,149.

    Google Scholar 

  53. 53.

    Kanter M.M. Hamlin R.L., Unverferth D.V., Davis H.W., Merola A.J. (1985): Effect of exercise training on antioxidant enzymes and cardiotoxicity of doxorubicin. J. Appl. Physiol., 59, 1298–1303.

    CAS  PubMed  Google Scholar 

  54. 54.

    Jenkins R.R., Friedland R., Howald H. (1984): The relationship of oxygen uptake to superoxide dismutase and catalase activity in human skeletal muscle. Int. J. Sports Med., 5, 11–14.

    Article  CAS  PubMed  Google Scholar 

  55. 55.

    Higuchi M., Cartier L.-J, Chen M., Holloszy J.O. (1985): Superoxide dismutase and catalase in skeletal muscle: Adaptive response to exercise. J. Gerontol, 40, 281–286.

    CAS  PubMed  Google Scholar 

  56. 56.

    Prescott L.F., Park J., Sutherland G.R., Smith I.J., Proudfoot A.T. (1976): Cysteamine, methionine and penicillamine in the treatment of paracetamol poisoning. Lancet, ii, 109–113.

    Article  Google Scholar 

  57. 57.

    Prescott L.F., Illingworth R.N., Critchley J.A.J.H, Stewart M.J., Adam R.D., Proudfoot A.T. (1979): Intravenous N-acetylcysteine: The treatment of choice for paracetamol poisoning. Br. Med. J., 2, 1097–1100.

    Article  CAS  PubMed  Google Scholar 

  58. 58.

    Meister A. (1984): New aspects of glutathione biochemistry and transport Selective alteration of glutathione metabolism. Fed. Proc., 43, 3031–3042.

    CAS  PubMed  Google Scholar 

  59. 59.

    Smith C.V., Mitchell J.R. (1985): Acetaminophen hepatotoxicity in vivo is not accompanied by oxidant stress. Biochem. Biophys. Res. Commun., 133, 329–336.

    Article  CAS  PubMed  Google Scholar 

  60. 60.

    Lauterburg B.H., Smith C.V., Hughes H., Mitchell J.R. (1984): Biliary excretion of glutathione and glutathione disulfide in the rat Regulation and response to oxidative stress. J. Clin. Invest., 73, 124–133.

    Article  CAS  PubMed  Google Scholar 

  61. 61.

    Yiamouviannis C.A., Sanders R.A., Watkins J.B. III, Martin B.J. (1990): Chronic physical exercise alters xenobiotic biotransformation (Abstract no 3461). FASEB J, 4, A863.

    Google Scholar 

  62. 62.

    Ramos C.L., Day W.W., Piatkowski T.S., Mei J., Chesky J.A., Weiner M. (1990): Differential effects of treadmill running and swimming on hepatic microsomal metabolism in middle-aged and aged Fischer-344 rats (Abstract no 3462). FASEB J., 4, A863.

    Google Scholar 

  63. 63.

    ‘Exercise and Cancer’, The New York Times, 10 April 1990, Science section, p B9.

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Lew, H., Quintanilha, A. Effects of endurance training and exercise on tissue antioxidative capacity and acetaminophen detoxification. European Journal of Drug Metabolism and Pharmacokinetics 16, 59–68 (1991). https://doi.org/10.1007/BF03189876

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  • Endurance training
  • oxidative stress
  • antioxidative enzymes
  • glutathione
  • acetaminophen