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Age-related changes in renal metabolism of acetaminophen in male Fischer 344 rats

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Abstract

Male Fischer 344 rats classified as young (2–4 months), middle age (12–15 months) and aged (22–25 months) were examined for changes in renal metabolism of acetaminophen. Renal microsomal cytochrome P-450 levels were 30% and 48% lower in middle age and aged animals, respectively, compared to young; however, no age-related changes were observed in NADPH-cytochrome c reductase activity. Renal mixed-function oxidase production of the reactive intermediate of acetaminophen was reduced 50% in aged rats. The deacetylation of acetaminophen to the nephrotoxic metabolite p-aminophenol by the renal 10,000 × g supernatant fraction was not changed by age. Thus, p-aminophenol becomes the proportionately greater nephrotoxic metabolite of acetaminophen produced by the aged rat kidney. Whole kidney reduced and oxidized glutathione content tended to be higher in aged rats, while glutathione S-transferase activity was 46% lower in aged animals. These results demonstrate that age alters several indices of renal metabolism of acetaminophen in male Fischer 344 rats.

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References

  1. Prescott, L.F., Wright, N., Roscoe, P., and Brown, S.S.: Plasma-paracetamol half-life and hepatic necrosis in patients with paracetamol overdose. Lancet, 1: 519–522, 1971.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Potter, W.Z., Davis, D.D., Mitchell, J.R., Jollow, D.J., Gillette, J.R., and Brodie, B.B.: Acetaminophen-induced hepatic necrosis. III. Cytochrome P-450-mediated covalent binding in vitro. J. Pharmacol. Exp. Ther., 187: 203–210, 1973.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  5. Rollins, D.E. and Buckpitt, A.R.: Liver cytosol catalyzed conjugation of reduced glutathione with a reactive metabolite of acetaminophen. Toxicol. Appl. Pharmacol., 47: 331–339, 1979.

    Article  PubMed  CAS  Google Scholar 

  6. Cobden, I., Record, C.O., Ward, M.K., and Kerr, D.N.S.: Paracetamol-induced acute renal failure in the absence of fulminant liver damage. Brit. Med. J., 284: 21–22, 1982.

    Article  CAS  Google Scholar 

  7. Gabriel, R., Caldwell, J., Hartley, R.B., Johnson, M.A., Copland, P., and Thom, S.: Acute renal failure following therapeutic doses of paracetamol (acetaminophen), in Acute Renal Failure, edited by Eliahou, H.E., London, John Libbey and Company Limited, 1982, pp. 125–128.

    Google Scholar 

  8. McMurtry, R.J., Snodgrass, W.R., and Mitchell, J.R.: Renal necrosis, glutathione depletion, and covalent binding after acetaminophen. Toxicol. Appl. Pharmacol., 46: 87–100, 1978.

    Article  PubMed  CAS  Google Scholar 

  9. Crowe, C.A., Yong, A.C., Calder, I.C., Ham, K.N., and Tange, J.D.: The nephrotoxicity of p-aminophenol. I. The effect of microsomal cytochromes, glutathione and covalent binding in kidney and liver. Chem.-Biol. Int., 27: 235–243, 1979.

    Article  CAS  Google Scholar 

  10. Newton, J.F., Yoshimoto, M., Bernstein, J., Rush, G.F., and Hook, J.B.: Acetaminophen nephrotoxicity in the rat. II. Strain differences in nephrotoxicity and metabolism of p-aminophenol, a metabolite of acetaminophen. Toxicol. Appl. Pharmacol., 69: 307–318, 1983.

    Article  PubMed  CAS  Google Scholar 

  11. Kato, R., Vassanelli, P., Frontino, G., and Chiesara, E.: Variation in the activity of liver microsomal drug-metabolizing enzymes in rats in relation to the age. Biochem. Pharmacol., 13: 1037–1051, 1964.

    Article  PubMed  CAS  Google Scholar 

  12. Guttman, D.: Patterns of legal drug use by older Americans. Addict. Dis., 3: 337–356, 1978.

    Google Scholar 

  13. Cohen, B.J., Anver, M.R., Ringler, D.H., and Adelman, R.C.: Age-associated pathological changes in male rats. Fed. Proceed., 37: 2848–2850, 1978.

    CAS  Google Scholar 

  14. McMartin, D.N., O’Connor, J.A., Fasco, M.J., and Kaminsky, L.S.: Influence of aging and induction of rat liver and kidney microsomal mixed function oxidase systems. Toxicol. Appl. Pharmacol., 54: 411–419, 1980.

    Article  PubMed  CAS  Google Scholar 

  15. Ioannides, C., Hall, D.E., Mulder, D.E., Steele, C.M., Spickett, J., Delaforge, M., and Parke, D.V.: A comparison of the protective effects of N-acetylcysteine and S-carboxymethyl-cysteine against paracetamol-induced hepatotoxicity. Toxicology, 28: 313–321, 1983.

    Article  PubMed  CAS  Google Scholar 

  16. Mitchell, J.R., Thorgeirsson, S.S., Potter, W.Z., Jollow, D.J., and Keiser, H.: Acetaminophen-induced hepatic injury: Protective role of glutathione in man and rationale for therapy. Clin. Pharmacol. Ther., 16: 676–684, 1974.

    PubMed  CAS  Google Scholar 

  17. Jones, D.P., Moldeus, P,, Stead, H., Ormstad, K., Jornvall, H., Orrenius, S.: Metabolism of glutathione and glutathione conjugate by isolated kidney cells. J. Biol. Chem., 254: 2787–2792, 1979.

    PubMed  CAS  Google Scholar 

  18. Moldeus, P., Jones, D.P., Ormstad, K., and Orrenius, S.: Formation and metabolism of a glutathione-S-conjugate in isolated rat liver and kidney cells. Biochem. Biophys. Res. Commun., 83: 195–200, 1978.

    Article  PubMed  CAS  Google Scholar 

  19. Prescott, L.F.: Glutathione: A protective mechanism against hepatotoxicity. Biochem. Soc. Trans. 10: 84–85, 1982.

    PubMed  CAS  Google Scholar 

  20. Miners, J.O., Drew, R., and Birkett, D.J.: Mechanism of action of paracetamol protective agents in mice in vivo. Biochem. Pharmacol., 33: 2995–3000, 1984.

    Article  PubMed  CAS  Google Scholar 

  21. Coleman, G.L., Barthold, S.W., Osbaldiston, G.W., Foster, S.J., and Jonas, A.M.: Pathological changes during aging in barrier-reared Fischer 344 male rats. J. Gerontology, 32: 258–278, 1977.

    CAS  Google Scholar 

  22. Schmucker, D.L. and Wang, R.K.: Qualitative changes in rat liver microsomal NADPH cytochrome c (P-450) reductase during aging. Age, 51: 105–110, 1982.

    Google Scholar 

  23. Gabius, H., Engelhardt, R., Deerberg, F., and Cramer, F.: Age-related changes in different steps of protein synthesis of liver and kidney of rats. FEBS Letters, 160: 115–118, 1983.

    Article  PubMed  CAS  Google Scholar 

  24. Schmucker, D.L., Mooney, J.S., and Jones, A.L.: Age-related changes in the hepatic endoplasmic reticulum: a quantitative analysis. Science, 197: 1005–1008, 1977.

    Google Scholar 

  25. Calder, I.C., Yong, A.C., Woods, R.A., Crowe, C.A., Ham, K.N., and Tange, J.D.: The nephrotoxicity of p-aminophenol. II. The effect of metabolic inhibitors and inducers. Chem.-Biol. Int., 27: 245–254, 1979.

    Article  CAS  Google Scholar 

  26. Grover, P.L.: Glutathione S-transferases in detoxification. Biochem. Soc. Trans., 10: 80–82, 1982.

    PubMed  CAS  Google Scholar 

  27. Stohs, S.J., Hassing, J.M., Al-Turk, W.A., and Masoud, A.: Glutathione levels in hepatic and extrahepatic tissues of mice as a function of age. Age, 3: 11–15, 1980.

    CAS  Google Scholar 

  28. Spearman, M.E. and Leibman, K.C.: Effects of aging on hepatic and pulmonary glutathione-S-transferase activities in male and female Fischer 344 rats. Biochem. Pharmacol. 33: 1309–1313, 1984.

    Article  PubMed  CAS  Google Scholar 

  29. Prohaska, J.R.: The glutathione peroxidase activity of glutathione S-tranferases. Biochem. Biophys. Acta, 611: 87–98, 1980.

    PubMed  CAS  Google Scholar 

  30. Burk, R.F., Trumble, M.J., and Lawrence, R.A.: Rat hepatic cytosolic glutathione-dependent enzyme protection against lipid peroxidation in the NADPH-microsomal lipid peroxidation system. Biochem. Biophys. Acta, 618: 35–41, 1980.

    PubMed  CAS  Google Scholar 

  31. Aikawa, K., Satoh, T., Kobayashi, K., and Kitagawa, H.: Effect of lipid peroxidation on covalent binding of active metabolite of acetaminophen to liver microsomal macromolecules in several animal species. J. Pharm. Dyn., 1: 22–27, 1978.

    CAS  Google Scholar 

  32. Zenser, T.V., Mattammal, M.B., and Davis, B.B.: Differential distribution of the mixed-function oxidase activities in rabbit kidney. J. Pharmacol. Exp. Ther., 207: 719–725, 1978.

    PubMed  CAS  Google Scholar 

  33. Habig, W.H., Pabst, M.J., and Jakoby, W.B.: Glutathione S-transferase; the first enzymatic step in mercapturic acid formation. J. Biol. Chem., 249: 7130–7139, 1974.

    PubMed  CAS  Google Scholar 

  34. Mohandas, J., Marshall, J.J., Duggin, G.G., Horvath, J.S., and Tiller, D.J.: Differential distribution of glutathione and glutathione-related enzymes in rabbit kidney. Possible implications in analgesic nephropathy. Biochem. Pharmacol., 33: 1801–1807, 1984.

    Article  PubMed  CAS  Google Scholar 

  35. Lowry, O.H., Rosebrough, N.J., Farr, A.L., and Randall, R.J.: Protein measurement with the folin phenol reagent. J. Biol. Chem., 193: 265–275, 1951.

    PubMed  CAS  Google Scholar 

  36. Orrenius, S., Ellin, A., Jakobsson, S., Thor, H., Cinti, D., Schenkman, J., and Estabrook, R.: The cytochrome P-450-containing mono-oxygenase system of rat kidney cortex microsomes. Drug Metab. Dispos., 1: 350–357, 1973.

    PubMed  CAS  Google Scholar 

  37. Williams, C.H. and Kamin, H.: Microsomal triphosphopyridine nucleotide-cytochrome C reductase of liver. J. Biol. Chem., 237: 587–595, 1962.

    PubMed  CAS  Google Scholar 

  38. Hissin, P.J. and Hilf, R.: A fluorometric method for determination of oxidized and reduced glutathione in tissues. Anal. Biochem., 74: 214–226, 1976.

    Article  PubMed  CAS  Google Scholar 

  39. Newton, J.F., Yoshimoto, M., Bernstein, J., Rush, G.F., and Hook, J.B.: Acetaminophen nephrotoxicity in the rat. I. Strain differences in nephrotoxicity and metabolism. Toxicol. App., Pharmacol., 69: 291–306, 1983.

    Article  CAS  Google Scholar 

  40. Mieyal, J. and Blumer, J.: Acceleration of autooxidation of human oxyhemoglobin by aniline and its relation to hemoglobin catalyzed aniline hydroxylation. J. Biol. Chem., 251: 3442–3446, 1976.

    PubMed  CAS  Google Scholar 

  41. Buckpitt, A.R., Rollins, D.E., Nelson, S.D., Franklin, R.B., and Mitchell, J.R.: Quantitative determination of the glutathione, cysteine, and N-acetyl cysteine conjugates of acetaminophen by high-pressure liquid chromatography. Anal. Biochem., 83: 168–177, 1977.

    Article  PubMed  CAS  Google Scholar 

  42. Howie, D., Adrianssens, P., and Prescott, L.F.: Paracetamol metabolism following overdose: Application of high performance liquid chromatography. J. Pharm. Pharmacol., 29: 235–237, 1977.

    PubMed  CAS  Google Scholar 

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  1. Department of Pharmacology and Toxicology, University of Maryland School of Pharmacy, 20 North Pine Street, Baltimore, Maryland, 21201

    William P. Beierschmitt & Myron Weiner

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  1. William P. Beierschmitt
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Beierschmitt, W.P., Weiner, M. Age-related changes in renal metabolism of acetaminophen in male Fischer 344 rats. AGE 9, 7–13 (1986). https://doi.org/10.1007/BF02431894

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