Abstract
A study was carried out to examine the possibility that altered mitochondrial function with aging might cause changes in hepatic rates of oxygen uptake and β-oxidation of fatty acids. Livers of 2–4 month and 20–25 month old CBA mice were perfused, and rates of respiration and ketogenesis were measured. Livers of old mice had significantly decreased rates of oxygen utilization (190 ± 16 vs 151 ± 9 μmol/gm/hr, p.05) and significantly lower rates of ketogenesis as indicated by rates of acetoacetate and β-hydroxybutyrate production (84 ± 8 vs 63 ± 7, p <.05). To determine whether NADPH supply, which is largely derived from β-oxidation of fatty acids in the fasted state, might be rate limiting for mixed-function oxidation in aged mice, rates of p-nitroanisole O-demethylation were measured in livers of young and old mice. Age had no effect on mixed-function oxidation of p-nitroanisole. Rates of glucuronidation of p-nitrophenol were also not affected by age; however, rates of sulfation of p-nitrophenol were significantly higher in livers of old (7.2 ±.6) than in young (3.5 ± 0.8) mice. This pilot study raises the possibility that the disposition of ingested fatty acids and xenobiotic compounds requiring sulfation may be significantly altered with aging. Moreover, it demonstrates that the perfused mouse livers can be used as a model in aging studies.
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Schmucker, D.L., Mooney, J.S., and Jones, A.L.: Sterological analysis of hepatic fine structure in the Fischer 344 rat: Influence of sublobular location and animal age. J. Cell Biol., 78: 319–337, 1978.
Pieri, C., Zs-Nagy, I., Mazzufferi, G., and Giuli, C.: The aging of rat livers as revealed by electron microscopic morphometry — I. Basic parameters. Exp. Gerontol., 10: 291–304, 1975.
Wilson, P.D. and Franks, L.M.: The effect of age on mitochondrial ultrastructure. Gerontologia, 21: 81–94, 1975.
Chen, J.C., Warshaw, J.B., and Sanadi, D.R.: Regulation of mitochondrial respiration in senescence. J. Cell Physiol., 80: 141–148, 1972.
Hansford, R.G.: Lipid oxidation by heart mitochondria from young adult and senescent rats. Biochem. J., 170: 285–295, 1978.
Abu-Erreigh, G.M., Neely, J.R., Whitmer, J.T., Whitman, V., and Sanadi, D.R.: Fatty acid oxidation by isolated perfused working hearts of aged rats. Am. J. Physiol., 232: E258–E262, 1977.
Danis, M., Kauffman, F.C., Evans, R.K., and Thurman, R.G.: Role of reducing equivalents from fatty acid oxidation in mixed-function oxidation: studies with 2-bromooctanoate in the perfused rat liver. J. Pharmacol. Exp. Ther., 219: 383–388, 1981.
Rothstein, M.: Biomedical Approaches to Aging. New York, Academic Press, 1982.
Brouwer, A., Van Bezooijen, C.F.A., and Knook, D.L.: Respiratory activities of hepatocytes isolated from rats of various ages: A brief note. Mech. Aging Dev., 6: 265–269, 1977.
Nohl, H., Breuninger, V., and Hegner, D.: Influence of mitochondrial radical formation on enery-linked respiration. Eur. J. Biochem., 90: 385–390, 1978.
Nohl, H.: Influence of age on thermotropic kinetics of enzymes involved in mitochondrial energy metabolism. Z. Gerontol., 12: 9–18, 1979.
Nohl, H.: Age dependent changes in the structure-function correlation of ADP/ATP — translocating mitochondrial membranes. Gerontol., 28: 354–359, 1982.
Kato, R. and Tanaka, A.: Effect of phenobarbital on electron transport system, oxidation and reduction of drugs in liver microsomes of rats of different age. J. Biochem., 63: 406–408, 1968.
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.
McMartin, D.N., O’Connor, J.A., Fasco, M.J., and Kaminsky, L.S.: Influence of ageing and induction on rat liver and kidney microsomal mixed function oxidase systems. Toxicol. Appl. Pharmacol., 54: 411–419, 1980.
Schmucker, D.L. and Wang, R.K.: Age-related changes in liver drug-metabolizing enzymes. Exp. Gerontol., 15: 321–329, 1980.
Rikans, L. and Notley, B.A.: Age-related changes in hepatic microsomal drug metabolism are substrate selective. J. Pharmacol. Exp. Ther., 220: 574–578, 1982.
Schmucker, D.L., Wang, R.K., and Kwong, P.: Age dependent alterations in rat liver microsomal NADPH cytochrome C (P-450) reductase. Liver and Aging — 1982, edited by Kitani, K., Amsterdam, Elsevier Biomedical Press, 1982, pp. 75–96.
Baird, M.B., Nicolosi, R.J., and Massie, H.R.: Microsomal mixed-function oxidase activity and senescence — I. Hexobarbital sleep time and induction of components of the hepatic microsomal enzyme system in rats of different ages. Exp. Gerontol., 10: 89–99, 1975.
Birnbaum, L.S. and Baird, M.B.: Induction of hepatic mixed function oxidases in senescent rodents — II. Effect of polychlorinated biphenyls. Exp. Gerontol., 13: 469–477, 1978.
Paterniti, J.R. Jr., Lin, C.I., and Beattie, D.S.: Regulation of heme metabolism during senescence: Activity of several heme-containing enzymes and heme oxygenase in the liver and kidney of ageing rats. Mech. Aging Dev., 12: 81–91, 1980.
Fujita, S., Uesugi, T., Kitagawa, H., Suzuki, T., and Kitani, K.: Hepatic microsomal mono-oxygenase and azoreductase activities in aging Fischer-344 rats — Importance of sex differences for aging studies, in Liver and Aging — 1982, edited by Kitani, K., Amsterdam, Elsevier Biomedical Press, 1982.
Rikans, L.E. and Notley, B.A.: Effects of methyltestosterone administration on microsomal drug metabolism in aging rats. Mech. Aging Dev., 25: 335–341, 1984.
Birnbaum, L.S.: Altered hepatic drug metabolism in senescent mice. Exp. Gerontol., 15: 259–267, 1980.
Kato, R., Tanaka, A., and Onoda, K.I.: Studies on age difference in mice for the activity of drug metabolizing enzymes of liver microsomes. Jap. J. Pharmacol., 20: 572–576, 1970.
Methods in Enzymology, Vol. 77. Detoxification and Drug Metabolism. Conjugation and Related Systems, edited by Jakoby, W.B. New York, Academic Press, 1981, pp. 197–218.
Singer, S.S. and Burns, L.: Enzymatic sulfation of steroids. VII. Hepatic cortisol sulfation and glucocorticoid sulfotransferases in old and young male rats. Exp. Gerontol., 13: 425–429, 1978.
Chen, L.J., Kane III, B., Bujanover, Y., and Thaler, M.M.: Development and regulation of bile salt sulfotransferase in rat liver. Biochem. Biophys. Acta, 713: 358–364, 1982.
Kirkpatrick, R.B. and Killenbeng, P.G.: Effects of ethinylestradiol on enzymes catalyzing bile acid conjugation and sulfation. J. Lipid Res., 21: 895–901, 1980.
Schimassek, H., Walli, A.K., Ferraudi, M., and Jost, U.: Relationship of different techniques for studying liver metabolism, in Alfred Benzon Symposium VI Regulation of Hepatic Metabolism, edited by Lundquist, F. and Tygstrup, N. New York, Academic Press, 1974, pp. 715–725.
Lindros, K.O.: The once-through perfusion technique — advantages and limitations, in Alfred Benzon Symposium VI Regulation of Hepatic Metabolism, edited by Lundquist, F. and Tygstrup, N. New York, Academic Press, 1974, pp. 778–786.
Harrison, D.E. and Archer, J.R.: Physiological assays for biological age in mice: relationship of collagen, renal function and longevity. Exp. Aging Res., 9: 245–251, 1983.
Scholz, R., Hansen, W., and Thurman, R.G.: Interaction of mixed-function oxidation with biosynthetic processes. I. Inhibition of gluconeogenesis by aminopyrine in perfused rat liver. Eur. J. Biochem., 38: 64–72, 1983.
Bergmeyer, H.V., ed. Methoden der Enzymatichen Analyse. Weinheim: Verlag Chemie, 1970.
Reinke, L.A., Kauffman, F.C., Belinsky, S.A., and Thurman, R.G.: Interaction between ethanol metabolism and mixed-function oxidation in perfused rat liver: Inhibition of p-nitroanisole O-demethylation. J. Pharmacol. Exp. Ther., 213: 70–78, 1980.
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Danis, M., Harrison, D.E. & Thurman, R.G. Effect of aging on oxidative metabolism and conjugation in perfused livers of an inbred strain of mice: A pilot study. AGE 8, 3–8 (1985). https://doi.org/10.1007/BF02431935
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DOI: https://doi.org/10.1007/BF02431935