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Effect of age and gender on in vivo ethanol elimination, hepatic alcohol dehydrogenase activity, and NAD+ availability in F344 rats

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Research in Experimental Medicine

Summary

It has been reported that aging strikingly decreases in vivo ethanol metabolism in F344 rats without major effects on hepatic alcohol dehydrogenase (ADH) activity. Because hepatic ADH activity is not always rate limiting in the oxidation of ethanol, we measured in vivo ethanol elimination rate (EER), hepatic ADH activity, and the hepatic-cytoplasmic and mitochondrial redox states after acute ethanol application in 2- and 12-month-old F344 rats of both sexes. In male, but not in female, animals EER decreased with age significantly, by 28% (P<0.01). The body-to-liver weight ratio was significantly increased in male (39.4±1.5 vs 46.5±2.0;P<0.05), but not in female, animals with age. Specific activity of ADH was not significantly changed by age, while the activity was significantly reduced with age in male, but not female, rats when related to body weight (5.1±0.4 vs 3.9±0.3 μmoles/100 g b.wt./min;P<0.05). The cytoplasmic, but not the mitochondrial (NAD+) to (NADH), ratio was significantly decreased with age in male livers (317±48 vs 793±128,P<0.05), while this was not the case in female livers. In summary, the data show a sex dependence of the effect of age on ethanol metabolism. The observed reduction in in vivo EER with age in male animals is due at least in part to an increased body-to-liver weight ratio, decreased hepatic ADH activity, and reduced availability of NAD+, the cofactor of the ADH reaction. The cause of this may be decreased transport of reducing equivalents through the mitochondrial membrane due to a lack of shuttle systems or a change in the physicochemical properties of the mitochondrial membrane, or decreased reutilization of NADH as NADPH resulting from a reduction of microsomal ethanol oxidation with age.

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References

  1. Berry MN, Kun E (1978) Ethanol oxidation by isolated rat liver cells. Eur J Biochem 89:237–241

    Article  PubMed  CAS  Google Scholar 

  2. Bonnichsen RK, Brink NG (1955) Liver alcohol dehydrogenase. In: Colowick SP, Kaplan N (eds) Methods of enzymology, vol 1. Academic Press, New York, p 496

    Google Scholar 

  3. Bücher T, Czok R, Lamprecht W (1963) Pyruvate. In: Bergmeyer HU (ed) Methods of enzymatic analysis. Verlag Chemie, Weinheim/Academic Press, New York, p 253

    Google Scholar 

  4. Domschke S, Domschke W, Lieber CS (1974) Hepatic redox state: attenuation of the acute effects of ethanol induced by chronic ethanol consumption. Life Sci 15:1327–1334

    Article  PubMed  CAS  Google Scholar 

  5. Fujita S, Uesugi TU, Kitagawa H (1982) Hepatic microsomal monooxygenase and azoreductase in aging F344 rats. Importance of sex difference for aging studies. In: Kitani K (ed) Liver and aging, liver and drugs. Elsevier Biomedical Press, Amsterdam, pp 55

    Google Scholar 

  6. Fujita S, Tatsuno J, Kawai R (1985) Age associated alteration of lidocaine metabolism is positive selective. Biochem Biophys Res Commun 126:117–122

    Article  PubMed  CAS  Google Scholar 

  7. Gellert J, Geisbüsch B, Teschke R (1987) Quantitative Untersuchungen zur Entwicklung des Alkoholmetabolismus in vivo und in vitro in Abhängigkeit von Alter und Geschlecht (abstr). German J Gastroenterol 8:464

    Google Scholar 

  8. Hahn HJK, Burch RE (1983) Impaired ethanol metabolism with advancing age. Alcoholism Clin Exp Res 7:299–301

    CAS  Google Scholar 

  9. Hensgens LAM, Nieuwenhuis BJWM, Van der Meer R, Meijer AJ (1980) The role of hydrogen translocating shuttles during ethanol oxidation in hepatocytes from euthyroid and hyperthyroid rats. Eur J Biochem 108:39–45

    Article  PubMed  CAS  Google Scholar 

  10. Hohorst HJ (1963) Lactate. In: Bergmeyer HU (ed) Methods of enzymatic analysis. Verlag Chemie, Weinheim/Academic Press, New York, p 215

    Google Scholar 

  11. Kato R, Takanaka A (1968) Metabolism of drugs in old rats. I. Activities of NADPH-linked electron transport and drugmetabolizing enzyme systems in liver microsomes. Jpn J Pharmacol 18:381–388

    PubMed  CAS  Google Scholar 

  12. Kato R, Takanaka A (1968) Effects of phenobarbital on electron transport system, oxidation and reduction of drugs in liver microsomes of rats of different ages. J Biochem 63:406–408

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  14. Kao J, Hudson P (1980) Induction of hepatic cytochrome P-450 dependent monooxygenase system in young and geriatric rats. Biochem Pharmacol 291:1191–1194

    Article  Google Scholar 

  15. Kitakawa H, Fujita S, Suzuki T (1985) Disappearance of sex difference in rat liver drug metabolism in old age. Biochem Pharmacol 34:579–581

    Article  Google Scholar 

  16. Kitani F (1986) Hepatic drug metabolism in the elderly. Hepatology 6:316–319

    Article  PubMed  CAS  Google Scholar 

  17. Lieber CS (1985) Ethanol metabolism and pathophysiology of alcoholic liver disease. In: Seitz HK, Kommerell B (eds) Alcohol-related diseases in Gastroenterology Springer, Berlin Heidelberg New York, p 19

    Google Scholar 

  18. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275

    PubMed  CAS  Google Scholar 

  19. Makar AB, Mannering GJ (1970) Kinetics of ethanol metabolism in the intact rat and monkey. Biochem Pharmacol 19:2017–2022

    Article  PubMed  CAS  Google Scholar 

  20. Maly IP, Sasse D (1987) The intra-acinar distribution patterns of alcohol dehydrogenase activity in the liver of juvenile, castrated and testosterone treated rats. Biol Chem Hoppe Seyler 368:315–321

    PubMed  CAS  Google Scholar 

  21. Marquette BW, Schneider CW, Hartline RA (1984) Age differences in the oxidation of and neural response to ethanol in mice. Exp Aging Res 10:7–11

    PubMed  CAS  Google Scholar 

  22. Meijer AJ, Van Woerkom GM, Williamson JR, Tager JM (1975) Rate-limiting factors in the oxidation of ethanol by isolated rat liver cells. Biochem J 150:205–209

    PubMed  CAS  Google Scholar 

  23. Nordman R, Petit MA, Nordman J (1975) Role of the malate aspatate shuttle in the metabolism of ethanol in vivo. Biochem Pharmacol 24: 139–143

    Article  Google Scholar 

  24. Ott JF, Hunter BE, Walker DW (1985) The effect of age on ethanol metabolism and on the hypothermic and hypnotic responses to ethanol in the Fischer 344 rats. Alcoholism Clin Exp Res 9:59–65

    CAS  Google Scholar 

  25. Rachamin G, Mac Donald JA, Washid S, Clapp JJ, Khawna JM, Israel Y (1980) Modulation of alcohol dehydrogenase and ethanol metabolism by sex hormones in the spontaneously hypertensive rat. Biochem J 186:483–490

    PubMed  CAS  Google Scholar 

  26. Rikans LE (1989) Hepatic drup metabolism in female Fischer rats as a function of age. Drug Metab Dispos 17:114–116

    PubMed  CAS  Google Scholar 

  27. Rikans LE, Kling OR (1987) Effects of aging and testosterone administration on liver alcohol dehydrogenase activity in male F344 rats. Alcoholism Clin Exp Res 11:562–565 1987

    Article  CAS  Google Scholar 

  28. Rikans LE, Moore DR (1987) Effect of age and sex on allyl alcohol hepatoxicity in rats: role of liver alcohol and aldehyde dehydrogenase activities. J Pharmacol Exp Ther 243:20–26

    PubMed  CAS  Google Scholar 

  29. Rikans LE, Notley NA (1982) Age-related changes in hepatic microsomal drug metabolism are substrate specific. J Pharmacol Exp Ther 220:574–578

    PubMed  CAS  Google Scholar 

  30. Ritzmann RF, Springer A (1980) Age difference in brain sensitivity and tolerance to ethanol in mice. Age 3:15–17

    Article  CAS  Google Scholar 

  31. Scholz R, Nohl H (1976) Mechanism of the stimulatory effect of fructose on ethanol oxidation in perfused rat liver. Eur J Biochem 63:449–458

    Article  PubMed  CAS  Google Scholar 

  32. Seitz HK, Simanowski UA (1987) Metabolic and nutritional effects of alcohol. In: Hathcock JN (ed) Nutritional toxicology, vol II. Academic Press, New York, pp 63–104

    Google Scholar 

  33. Seitz HK, Veith S, Czygan P, Bösche J, Kommerell B, Gugler R (1984) In vivo interaction between H2-receptor antagonists and ethanol metabolism in man and in rats. Hepatology 4:1231–1234

    Article  PubMed  CAS  Google Scholar 

  34. Seitz HK, Meydani M, Ferschke I, Simanowski UA, Boesche J, Bogusz M, Hoepker WW, Blumberg JB, Russell RM (1989) Effect of aging on in vivo and in vitro ethanol metabolism and its toxicity in F344 rats. Gastroenterology 97:446–456

    PubMed  CAS  Google Scholar 

  35. Williamsson DH, Mellanby J (1963) 3-hydroxybutyrate/acetoacetate. In: Bergmeyer HU (ed) Methods of enzymatic analysis. Verlag Chemie, Weinheim/Academic Press, New York, p 454

    Google Scholar 

  36. Williamson DH, Lund P, Krebs HA (1967) The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondrial of rat liver. Biochem J 103:514–526

    PubMed  CAS  Google Scholar 

  37. Wiberg GS, Trenholm HL, Coldwell BB (1970) Increased ethanol toxicity in old rats: changes in LD50, in vivo and in vitro metabolism and liver alcohol dehydrogenase. Toxicol Appl Pharmacol 16:718–727

    Article  PubMed  CAS  Google Scholar 

  38. York L (1983) Increased responsiveness to ethanol with advancing age in rats. Pharmacol Biochem Behav 19:687–691

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Laboratory of Alcohol Research, Liver Disease and Nutrition, Department of Medicine, Salem Medical Center Heidelberg, Zeppelinstrasse 11-33, W-6900, Heidelberg, Federal Republic of Germany

    Helmut K. Seitz, Yin Xu, Ulrich A. Simanowski & Brigitte Osswald

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  1. Helmut K. Seitz
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  2. Yin Xu
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  3. Ulrich A. Simanowski
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  4. Brigitte Osswald
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Seitz, H.K., Xu, Y., Simanowski, U.A. et al. Effect of age and gender on in vivo ethanol elimination, hepatic alcohol dehydrogenase activity, and NAD+ availability in F344 rats. Res. Exp. Med. 192, 205–212 (1992). https://doi.org/10.1007/BF02576276

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  • DOI: https://doi.org/10.1007/BF02576276

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