EXPRESSION PROFILES OF CYTOCHROME P450S FOLLOWING SWIMMING EXERCISE IN AGING RATS

Main Article Content

Bang sub Lee
Wi-Young So
Sang-Hoon Kim
Jin-Ho Yoon

Keywords

aging, cytochrome P450s, exercise, nuclear receptors, rat, swimming

Abstract

Background and Objective


Cytochrome P450s (CYPs) are the major drug-metabolizing enzymes responsible for the clearance of approximately 75% of all drugs in clinical use. Drug clearance may be reduced with aging, resulting in increased drug toxicity in the elderly. Here, we evaluated changes in CYP expression following exercise in an aging rat model.


Materials and Methods


Sixteen male Sprague-Dawley rats were grouped into control (n=5), short-term exercise (SE) (n=4), and long-term exercise (LE) (n=7) groups and changes in CYPs and nuclear receptors (NRs) were measured with aging.


Results


CYP2C22, CYP3A1, and CYP2C11 mRNAs were upregulated, whereas CYP26B1 was downregulated in the SE and LE groups compared with the control group. Moreover, mRNA levels of the NRs, constitutive androstane receptor, retinoid X receptor α, peroxisome proliferator-activated receptor, and pregnane X receptor, were significantly increased in the LE group compared with those in the control group. As an indicator of more long-term changes, protein levels of CYP2C11, CYP2B, CYP1A, CYP2C, and CYP2C22 were significantly upregulated in the LE group compared with the control group. Overall, our data show that CYP and NR expression increased in rats with forced long-term exercise during aging.


Conclusion


Therefore, we propose that regular swimming exercise may increase CYP levels, resulting in enhanced drug clearance and thereby reducing age-related drug toxicity in elderly individuals.

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References

1. Guengerich FP, Shimada T, Yun CH, et al. Interactions of ingested food, beverage, and tobacco components involving human cytochrome P4501A2, 2A6, 2E1, and 3A4 enzymes. Environ Health Perspect 1994;1029:49–53.
2. Stupans IMM, Kirlich A, Tuck KL, Hayball PJ. Inactivation of cytochrome P450 by the food-derived complex phenol oleuropein. Food Chem Toxicol 2001;39:1119–24.
3. Martignoni M, Groothuis G, de Kanter R. Comparison of mouse and rat cytochrome P450-mediated metabolism in liver and intestine. Drug Metab Dispos 2006;34:1047–54.
4. Smith DA, Abel SM, Hyland R, Jones BC. Human cytochrome P450s: selectivity and measurement in vivo. Xenobiotica 1998;28:1095–128.
5. Wang P, Mason PS, Guengerich FP. Purification of human liver cytochrome P-450 and comparison to the enzyme isolated from rat liver. Arch Biochem Biophys 1980;199:206–19.
6. Frenkl R, Gyore A, Szeberenyi S. The effect of muscular exercise on the microsomal enzyme system of the rat liver. Eur J Appl Physiol Occup Physiol 1980;44:135–40.
7. Ware WR. Nutrition and the prevention and treatment of cancer: association of cytochrome P450 CYP1B1 with the role of fruit and fruit extracts. Integr Cancer Ther 2009;8:22–8.
8. Takizawa D, Kakizaki S, Horiguchi N, et al. Constitutive active/androstane receptor promotes hepatocarcinogenesis in a mouse model of non-alcoholic steatohepatitis. Carcinogenesis 2011;32:576–83.
9. Cuciureanu M, Vlase L, Muntean D, et al. Grapefruit juice--drug interactions: importance for pharmacotherapy. Rev Med Chir Soc Med Nat Iasi 2010;114:885–91.
10. Schmucker DL, Ohta M, Kanai S, et al. Hepatic injury induced by bile salts: correlation between biochemical and morphological events. Hepatology 1990;12:1216–21.
11. Van Bezooijen RL, Wang RK, Lechner MC, Schmucker DL. Aging effects on hepatic NADPH cytochrome P450 reductase, CYP2B1&2, and polymeric immunoglobulin receptor mRNAs in male Fischer 344 rats. Exp Gerontol 1994;29:187–95.
12. Jorquera F, Almar MM, Pozuelo M, et al. Effects of aging on antipyrine clearance: predictive factors of metabolizing capacity. J Clin Pharmacol 1995;35:895–901.
13. Liptrott NJ, Penny M, Bray PG, et al. Owen A. The im-pact of cytokines on the expression of drug transporters, cytochrome P450 enzymes, and chemokine receptors in human PBMC. J Pharmacol 2009;156:497–508.
14. Staskin DR. Overactive bladder in the elderly: a guide to pharmacological management. Drugs Aging 2005;22:1013–28.
15. De Stefano F, Zambon S, Giacometti L, et al. Obesity, Muscular Strength, Muscle Composition and Physical Performance in an Elderly Population. J Nutr Health Aging 2015;19:785–91.
16. Wauthier V, Verbeeck RK, Calderon PB. The effect of ageing on cytochrome p450 enzymes: consequences for drug biotransformation in the elderly. Curr Med Chem 2007;14:745–57.
17. Kvernmo HD, Osterud B. The effect of physical conditioning suggests adaptation in procoagulant and fibrinolytic potential. Thromb Res 1997;87:559–69.
18. Frenkl R, Szeberenyi S. Enzyme inducing effect of muscular exertion in the rat. Acta Med Acad Sci Hung 1976;33:95–100.
19. Boel J, Andersen LB, Rasmussen B, et al. Hepatic drug metabolism and physical fitness. Clin Pharmacol Ther 1984;36:121–6.
20. Frenkl R, Gyore A, Meszaros J, Szeberenyi S. A study of the enzyme inducing effect of physical exercise in man. The “trained liver”. J Sports Med Phys Fitness 1980;20:371–6.
21. Villa JG, Cuadrado G, Bayón JE, González-Gallego J. The effect of physical conditioning on antipyrine clearance. Eur J Appl Physiol Occup Physiol 1998;77:106–11.
22. Paterson DH, Jones GR, Rice CL. Ageing and physical activity: evidence to develop exercise recommendations for older adults. Can J Public Health 2007;98: S69–108.
23. Lee CM, Kim BY, Li L, Morgan ET. Nitric oxide-dependent proteasomal degradation of cytochrome P450 2B proteins. J Biol Chem 2008;283:889–98.
24. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001;25:402–8.
25. Sato K, Iemitsu M. Exercise and sex steroid hormones in skeletal muscle. J Steroid Biochem Mol Biol 2015;145:200–5.
26. Fu ZD, Klaassen CD. Short-term calorie restriction feminizes the mRNA profiles of drug metabolizing enzymes and transporters in livers of mice. Toxicol Appl Pharmacol 2014;274:137–46.
27. Lee JS, Ward WO, Wolf DC, et al. Coordinated changes in xenobiotic metabolizing enzyme gene expression in aging male rats. Toxicol Sci 2008;106:263–83.
28. Testa B, Kramer SD. The biochemistry of drug metabolism--an introduction: Part 3. Reactions of hydrolysis and their enzymes. Chem Biodivers 2007;4:2031–122.
29. Testa B, Kramer SD. The biochemistry of drug metabolism- an introduction: Part 2. Redox reactions and their enzymes. Chem Biodivers 2007;4:257–405.
30. Piatkowski TS, Day WW, Weiner M. Increased renal drug metabolism in treadmill-exercised Fischer-344 male rats. Drug Metab Dispos. 1993;21:474–9.
31. Villa JG, Cuadrado G, Bayon JE, Gonzalez-Gallego J. The effect of physical conditioning on antipyrine clearance. Eur J Appl Physiol Occup Physiol 1998;77:106–11.
32. Fabbri A, Bianchi G, Zoli M, et al. Effect of physical exercise on one-sample antipyrine clearance. Ital J Gastroenterol 1991;23:74–6.
33. Makanae Y, Ogasawara R, Sato K, et al. Acute bout of resistance exercise increases vitamin D receptor protein expression in rat skeletal muscle. Exp Physiol 2015;100:1168–76.
34. Piatkowski TS, Day WW, Weiner M. Increased renal drug metabolism in treadmill-exercised Fischer-344 male rats. Drug Metab Dispos 1993;21:474–9.
35. Mauriz JL, Tabernero B, García-López J, et al. Physical exercise and improvement of liver oxidative metabolism in the elderly. Eur J Appl Physiol 2000;81:62–6.
36. Orioli S, Bandinelli I, Birardi A, et al. Hepatic antipyrine metabolism in athletes. J Sports Med Phys Fitness 1990;30:261–3.
37. Kochańska-Dziurowicz AA, Janikowska G, Bijak A, et al. The effect of maximal physical exercise on relation-ships between the growth hormone (GH) and insulin-like growth factor 1 (IGF-1) and transcriptional activity of CYP1A2 in young ice hockey players. J Sports Med Phys Fitness 2015;55:158–63.
38. Yun KU, Oh SJ, Oh JM, et al. Age-related changes in hepatic expression and activity of cytochrome P450 in male rats. Arch Toxicol 2010;84:939–46.
39. Warrington JS, Greenblatt DJ, von Moltke LL. Age-related differences in CYP3A expression and activity in the rat liver, intestine, and kidney. J Pharmacol Exp Ther 2004;309:720–9.
40. Vyskočilová E, Szotáková B, Skálová L, et al. Age-related changes in hepatic activity and expression of detoxification enzymes in male rats. Biomed Res Int 2013;2013:408573.
41. Wada T, Gao J, Xie W. PXR and CAR in energy metabolism. Trends Endocrinol Metab 2009;20:273–9.
42. Pinto PR, Rocco DD, Okuda LS, et al. Aerobic exercise training enhances the in vivo cholesterol trafficking from macrophages to the liver independently of changes in the expression of genes involved in lipid flux in macrophages and aorta. Lipids Health Dis 2015;14:109.
43. Habano W, Gamo T, Terashima J, et al. Involvement of promoter methylation in the regulation of Pregnane X receptor in colon cancer cells. BMC Cancer 2011;11:81.
44. Iemitsu M, Miyauchi T, Maeda S, et al. Aging-induced decrease in the PPAR-alpha level in hearts is improved by exercise training. Am J Physiol Heart Circ Physiol 2002;283: H1750–60.