Skip to main content
SpringerLink
Log in

Effects of age increase on hepatic expression and activity of cytochrome P450 in male C57BL/6 mice

  • Research Article
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Effects of aging on hepatic expression and activity of cytochrome P450 (CYP) isoforms were investigated in male mice aged 2, 6, 18, and 30 months. Microsomal protein, total CYP, cytochrome b5 and NADPH-dependent cytochrome P450 reductase contents in liver were fully expressed in young (2-month-old) mice. Neither Cyp1a1 nor Cyp2c was detected in any aged mice. And Cyp1a2 was maximally expressed at 2 months and decreased with age. Hepatic levels of Cyp2b10 and Cyp3a11 were decreased in 30-month-old mice. Hepatic Cyp2e1 levels were constantly maintained from 2-month to 30-month old mice. Hepatic activities of ethoxyresorufin–O-deethylase and methoxyresorufin–O-demethylase were gradually decreased after 6 months. The 30-month-old mice exhibited the lowest activity of midazolam 1′-hydroxylase. Pentoxyresorufin–O-depenthylase activity was decreased in 30-month-old mice, but not statistically significant. There were no significant differences in hepatic activities of chlorzoxazone 6-hydroxylase and midazolam 4-hydroxylase. The present study shows that increasing age, especially 30-month-old mice, leads to decrease in expression and activity of hepatic CYP isoforms, suggesting that aging mice exhibit poor hepatic drug-metabolizing capacity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Burke, M.D., S. Thompson, R.J. Weaver, C.R. Wolf, and R.T. Mayer. 1994. Cytochrome P450 specificities of alkoxyresorufin O dealkylation in human and rat liver. Biochemical Pharmacology 48: 923–936.

    Article  CAS  PubMed  Google Scholar 

  • Chen, J.J., G.S. Chen, and N.J. Bunce. 2003. Inhibition of CYP 1A2-dependent MROD activity in rat liver microsomes: an explanation of the hepatic sequestration of a limited subset of halogenated aromatic hydrocarbons. Environmental Toxicology 18: 115–119.

    Article  CAS  PubMed  Google Scholar 

  • Chovan, J.P., S.C. Ring, E. Yu, and J.P. Baldino. 2007. Cytochrome P450 probe substrate metabolism kinetics in Sprague-Dawley rats. Xenobiotica 37: 459–473.

    Article  CAS  PubMed  Google Scholar 

  • Cotreau, M.M., L.L. von Moltke, M.C. Beinfeld, and D.J. Greenblatt. 2000. Methodologies to study the induction of rat hepatic and intestinal cytochrome P450 3A at the mRNA, protein, and catalytic activity level. Journal of Pharmacological and Toxicological Methods 43: 41–54.

    Article  CAS  PubMed  Google Scholar 

  • Estabrook, R.W., and J. Werringloer. 1978. The measurement of difference spectra: application to the cytochromes of microsomes. Methods in Enzymology 52: 212–220.

    Article  CAS  PubMed  Google Scholar 

  • Imaoka, S., S. Fujita, and Y. Funae. 1991. Age-dependent expression of cytochrome P-450 s in rat liver. Biochimica et Biophysica Acta 1097: 187–192.

    Article  CAS  PubMed  Google Scholar 

  • Isabelle, L., I. Leclercq, Y. Horsmans, and J.P. Desager. 1998. Estimation of chlorzoxazone hydroxylase activity in liver microsomes and of the plasma pharmacokinetics of chlorzoxazone by the same high-performance liquid chromatographic method. Journal of Chromatography A 828: 291–296.

    Article  Google Scholar 

  • Kim, S.K., and R.F. Novak. 2007. The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression. Pharmacology & Therapeutics 113: 88–120.

    Article  CAS  Google Scholar 

  • Kitada, M., M. Taneda, K. Itahashi, and T. Kamataki. 1991. Four forms of cytochrome P-450 in human fetal liver: Purification and their capacity to activate promutagens. Japanese Journal of Cancer Research 82: 426–432.

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi, K., K. Urashima, N. Shimada, and K. Chiba. 2002. Substrate specificity for rat cytochrome P450 (CYP) isoforms: Screening with cDNA-expressed systems of the rat. Biochemical Pharmacology 63: 889–896.

    Article  CAS  PubMed  Google Scholar 

  • Liptrott, N.J., M. Penny, P.G. Bray, J. Sathish, S.H. Khoo, D.J. Back, and A. Owen. 2009. The impact of cytokines on the expression of drug transporters, cytochrome P450 enzymes, and chemokine receptors in human PBMC. British Journal of Pharmacology 156: 497–508.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lowry, O.H., N.G. Rosebrough, A.L. Farr, and R.J. Randall. 1951. Protein measurement with Folin phenol reagent. Journal of Biological Chemistry 193: 265–275.

    CAS  PubMed  Google Scholar 

  • Maeda, K., T. Kamataki, T. Nagai, and R. Kato. 1984. Postnatal development of constitutive forms of cytochrome P-450 in liver microsomes of male and female rats. Biochemical Pharmacology 33: 509–512.

    Article  CAS  PubMed  Google Scholar 

  • Martignoni, M., G.M. Groothuis, and R. de Kanter. 2006. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opinion on Drug Metabolism & Toxicology 6: 875–894.

    Article  Google Scholar 

  • Minn, A.L., H. Pelczar, C. Denizot, M. Martinet, J.M. Heydel, B. Walther, A. Minn, H. Goudonnet, and Y. Artur. 2006. Characterization of microsomal cytochrome P450-dependent monooxygenases in the rat olfactory mucosa. Drug Metabolism & Toxicology 6: 875–894.

    Google Scholar 

  • Omiecinski, C.J., C.A. Redlich, and P. Costa. 1990. Induction and developmental expression of cytochrome P450IA1 messenger RNA in rat and human tissues: detection by the polymerase chain reaction. Cancer Research 50: 4315–4321.

    CAS  PubMed  Google Scholar 

  • Omura, T., and R. Sato. 1964. The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature. Journal of Biological Chemistry 239: 2370–2378.

    CAS  PubMed  Google Scholar 

  • Schenkman, J.B., K.E. Thummel, and L.V. Favreau. 1989. Physiological and pathophysiological alterations in rat hepatic cytochrome P-450. Drug Metabolism Reviews 20: 557–584.

    Article  CAS  PubMed  Google Scholar 

  • Strobel, H.W., and J.D. Dignam. 1978. Purification and properties of NADPH-cytochrome P-450 reductase. Methods in Enzymology 52: 89–96.

    Article  CAS  PubMed  Google Scholar 

  • Tani, Y., H. Yamamoto, A. Kawaji, H. Mizuno, J. Fukushige, T. Hosokawa, and K. Doi. 1999. Hepatic cytochrome P450 and flavin-containing monooxygenase in male Nts: Mini rat, a transgenic rat carrying antisense RNA transgene for rat growth hormone. Toxicology Letters 106: 159–169.

    Article  CAS  PubMed  Google Scholar 

  • Wauthier, V., R.K. Verbeeck, and P.B. Calderon. 2007. The effect of ageing on cytochrome p450 enzymes: Consequences for drug biotransformation in the elderly. Current Medicinal Chemistry 14: 745–757.

    Article  CAS  PubMed  Google Scholar 

  • Yang, M.J., S. Sim, J.H. Jeon, E. Jeong, H.-C. Kim, Y.-H. Park, and I.-B. Kim. 2013. Mitral and tufted cells are potential cellular targets of nitration in the olfactory bulb of aged mice. PLoS ONE 8: e59673.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yun, K.U., S.J. Oh, J.M. Oh, K.W. Kang, C.S. Myung, G.Y. Song, B.H. Kim, and S.K. Kim. 2010. Age-related changes in hepatic expression and activity of cytochrome P450 in male rats. Archives of Toxicology 84: 939–946.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by a Grant from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare, & Family Affairs, Republic of Korea (A101836) and by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2013R1A1A2005981).

Author information

Authors and Affiliations

  1. College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 305-764, Republic of Korea

    Hui Chan Kwak & Sang Kyum Kim

  2. Bio-Evaluation Center, KRIBB, Chungbuk, Ochang, Republic of Korea

    Hyoung Chin Kim & Soo Jin Oh

Authors
  1. Hui Chan Kwak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyoung Chin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Soo Jin Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sang Kyum Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Soo Jin Oh or Sang Kyum Kim.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kwak, H.C., Kim, H.C., Oh, S.J. et al. Effects of age increase on hepatic expression and activity of cytochrome P450 in male C57BL/6 mice. Arch. Pharm. Res. 38, 857–864 (2015). https://doi.org/10.1007/s12272-014-0452-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-014-0452-z

Keywords

Search

Navigation