Abstract
An increase in the susceptibility to drugs is known to occur with advanced age. Several possible explanations for this phenomenon exist, but the exact cause has not been determined. Aryl hydrocarbon hydroxylase (AHH), 7-ethoxycoumarin O-deethylase (ECD) and aniline hydroxylase activities of hepatic and extrahepatic tissues as well as hepatic cytochrome P-450 content of female Swiss Webster mice at 1, 3, 6, 9, 12, 15 and 18 months of age were examined. AHH activity in liver and intestine reached a maximum at 6 mo. of age and began to decline thereafter. No change in pulmonary AHH activity was observed with age. ECD activity in liver as well as lungs was maximal at 6 mo. of age and decreased thereafter. Hepatic aniline hydroxylase activity exhibited over a 700% increase between one to six mo. of age, and declined by approximately 52% by 15 mo. of age as compared to peak activity. Hepatic cytochrome P-450 content was highest at 3 mo. of age and significantly decreased by 12 mo. The results demonstrate that decreases in microsomal mixed function monooxygenase activities do occur with advanced age and may contribute to a decreased rate of metabolism and increased susceptibility to drugs and other foreign chemicals with age.
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References
Schmucker, D. L.: Age-related changes in drug disposition. Pharmacol. Rev., 30:445–456, 1979.
Gillette, J. R.: Biotransformation of drugs during aging. Fed. Proc., 38:1900–1909, 1979.
Netter, K. J.: Mechanisms of toxicity and metabolism, in Proceedings of the Sixth International Congress of Pharmacology, Vol., 6, edited by Tuomisto, J. and Paasoven, M. K. Academic Press, New York, 1976, pp. 3–16.
Iba, M. M., Soyka, L. F. and Schulman, M. P.: Characteristics of the liver microsomal and drug-metabolizing enzyme system of new-born rats. Mol. Pharmacol., 13:1092–1104, 1976.
Guenthner, T. M. and Mannering, G. J.: Induction of hepatic mono-oxygenase systems in fetal and neonatal rats with phenobarbital. Biochem. Pharmacol., 26:567–575, 1977.
Hospador, M. A., Grasso, L. S. and Manthei, R. W.: Influence of age and diet on the induction of microsomal enzymes in the mouse. Proc. Soc. Exptl. Biol. Med., 136:884–888, 1971.
Comfort, A., Youhototsky-Gore, I. and Pathmenthan, K.: Effect of ethoxyquin on the longevity of C3H mice. Nature, 229:254–255, 1971.
Walker, R., Rahim, A. and Parke, D. V.: The effects of antioxidants on enzyme induction in developing and aging rats. Proc. Roy. Soc. Med., 6:16, 1973.
Kato, R., Takanaka, A. and Onoda, K. T.: Studies on age difference in mice for activity of drug-metabolizing enzymes of liver microsomes. Jpn. J. Pharmacol., 20:572–576, 1970
Slanina, P. and Stalhandske, T.: In vitro metabolism of nicotine in livers of aging mice. Arch. Int. Pharmacodyn. Therap., 226:258–262, 1977.
Birnbaum, L. S.: Altered hepatic drug metabolism in senescent mice. Exptl. Gerontol., In press, 1980.
Kao, J. and Hudson, P.: Induction of the hepatic cytochrome P-450-dependent mono-oxygenase system in young and geriatric rats. Biochem. Pharmacol., 29:1191–1194, 1980.
Stohs, S. J., Hassing, J. M., AI-Turk, W.A. and Masoud, A. N.: Glutathione levels in hepatic and extrahepatic tissues of mice as a function of age. Age 3:11–14, 1980.
Orrenius, S. and Jones, D. P.: Functions of glutathione in drug metabolism, in Functions of Glutathione in Liver and Kidney, edited by Sies, H. and Wendel, A. Springer-Verlag, New York, 1978, pp. 164–175.
Baird, M. B., Nicolosi, R. J., Massie, H. R. and Samis, H. V.: Microsomal mixed-function oxidase activity and senescence. I. Hexabarbital sleep time and induction of components of the hepatic microsomal enzyme system in rats of different ages. Exptl. Gerontol., 10: 89–99, 1975.
Stohs, S. J., Reinke, L. A. and El-Olemy, M. M.: Metabolism in vitro of digitoxigenin by rat liver homogenates. Biochem. Pharmacol., 20:437–446, 1971.
Stohs, S. J., Grafström, R. C., Burke, M. D., Moldéus, P. W. and Orrenius, S.: The isolation of rat intestinal microsomes with stable cytochrome P-450 and their metabolism of benzo(a)pyrene. Arch. Biochem. Biophys., 177:105–116, 1976.
Capdevila, J., Jakobson, S W., Jernström, B., Helia, O. and Orrenius, S.: Characterization of a rat lung microsomal fraction obtained by sepharose 2B ultracentrifugation. Cancer Res., 35:2820–2829, 1975.
Al-Turk, W. A., Stohs, S. J. and Roche, E. B.: Effect of acute and chronic estrone, estradiol and estriol treatment on hepatic, pulmonary and intestinal mixed function monooxygenase activities in female rats. Drug Metab. Disp., 8:143–146, 1980.
Reinke, L. A., Stohs, S. J. and Rosenberg, H.: Altered activity of hepatic mixed function monooxygenase enzymes in streptozotocin-induced diabetic rats. Xenobiotica, 8:611–619, 1978.
Kato, R. and Gillette, J. R.: Effects of starvation on NADPH-dependent enzymes in liver microsomes of male and female rats. J. Pharmacol. Exptl. Therap., 150:279–284, 1965.
Omura, T. and Sato, R.: The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature. J. Biol. Chem., 239:2370–2378, 1964.
Lowry, O. H., Rosebrough, N. J., Farr, A. L. and Randall, R. J.: Protein measurement with folin phenol reagent. J. Biol. Chem., 193:265–275, 1951.
Meyers, J. L.: Fundamentals of Experimental Design, 3rd edition, Allyn and Bacon, Inc., Boston, 1978, pp. 90–91.
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Stohs, S.J., Al-Turk, W.A. & Hassing, J.M. Altered drug metabolism in hepatic and extrahepatic tissues in mice as a function of age. AGE 3, 88–92 (1980). https://doi.org/10.1007/BF02432265
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DOI: https://doi.org/10.1007/BF02432265