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.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
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.
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.
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.
Miner D.J., Kissinger P.T. (1979): Evidence for the involvement of N-acetyl-p-quinoneimine in acetaminophen metabolism. Biochem. Pharmacol., 28, 3285–3290.
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.
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.
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.
Moldeus P. (1978): Paracetamol metabolism and toxicity in isolated hepatocytes from rat and mouse. Biochem. Pharmacol., 27, 2859–2863.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Boyer T.D., Rouff S.L. (1971): Acetaminophen-induced hepatic necrosis and renal failure. JAMA, 218, 440–441.
Boyd E, Bereczky G. (1966): Liver necrosis from paracetamol. Br. J. Pharmacol., 26, 606–614.
Davidson D.G.D, Eastham W.N. (1966): Acute liver necrosis following overdose of paracetamol. Br. Med. J, 551, 497–499.
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.
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.
Altland P.D., Highman B. (1961): Effects of exercise on serum enzyme values and tissues of rats. Am. J. Physiol., 201, 393–395.
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.
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.
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.
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.
Bostrom S., Fahlen M. Hjalmarson A, Johansson R. (1974): Activities of rat muscle enzymes after acute exercise. Acta Physiol. Scand., 90, 544–554.
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.
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.
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.
Pyke S., Lew H., Quintanilha A. (1986): Severe depletion in liver glutathione during physical exercise. Biochem. Biophys. Res. Commun., 139, 926–931.
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.
Splittgerber A.G., Tappel A.L. (1979): Inhibition of glutathione peroxidase by cadmium and other metal ions. Arch. Biochem. Biophys, 197, 534–542.
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.
Lew H. (1989): The effects of physical exercise on tissue antioxidative capacity: The role of glutathione. PhD thesis, University of California at Berkeley.
Sun A.S., Aggarwal B.B., Packer L. (1975): Enzyme levels of normal human cells: Aging in culture. Arch. Biochem. Biophys., 170, 1–11.
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.
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.
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.
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.
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.
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.
Kosower N.S., Kosower E.M. (1978): The glutathione status of cells. Int Rev. Cytol., 54, 109–160.
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.
Sies H., Graf P. (1985): Hepatic thiol and glutathione efflux under the influence of vasopressin, phenylephrine and adrenaline. Biochem. J., 226, 545–549.
Brooks G.A., Fahey T.D. (1984): Exercise physiology: Human Bioenergetics and its Applications, New York, John Wiley, pp. 163–188.
Meister A. (1983): Selective modification of glutathione metabolism. Science, 220, 472–477.
Smith M.T. (1985): Personal communication.
Bannai S., Tateishi N. (1986): Role of membrane transport in metabolism and function of glutathione in mammals. J. Membr. Biol, 89, 1–8.
Kaplowitz N., Aw T.Y., Oohktens M. (1985): The regulation of hepatic glutathione. Annu. Rev. Pharmacol. Toxicol, 25, 715–744.
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.
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.
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.
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.
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.
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.
Meister A. (1984): New aspects of glutathione biochemistry and transport Selective alteration of glutathione metabolism. Fed. Proc., 43, 3031–3042.
Smith C.V., Mitchell J.R. (1985): Acetaminophen hepatotoxicity in vivo is not accompanied by oxidant stress. Biochem. Biophys. Res. Commun., 133, 329–336.
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.
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.
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.
‘Exercise and Cancer’, The New York Times, 10 April 1990, Science section, p B9.
About this article
Cite this article
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
- Endurance training
- oxidative stress
- antioxidative enzymes