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Precision-cut liver slices from rats of different ages: basal cytochrome P450-dependent monooxygenase activities and inducibility

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Abstract

The biotransformation capacity – of the cytochrome P450 (CYP) system for example – is lower but inducibility is more pronounced in neonates than in adults. On the other hand, both enzyme activities and inducibility decline with senescence. Precision-cut rat liver slices are widely used as an in vitro tool for the examination of drug toxicity, xenobiotic metabolism or enzyme induction. The aim of the present study was to assess whether age-related changes in CYP activities and induction observed in vivo are also mirrored in vitro in liver slices. For this purpose, different CYP model reactions were measured in precision-cut liver slices from one-day-old, 40-day-old and one-year-old rats after in vitro exposure to various inducers. Similar to the in vivo situation, basal CYP activities were distinctly lower and inducibility was much more pronounced in liver slices from neonatal than in those from adult animals. Also, enzyme activities were mostly somewhat lower in liver slices from aged rats compared to those from 40-day-old rats. However, CYP inducibility was less pronounced than with younger animals too. Thus, precision-cut rat liver slices are a suitable in vitro tool for investigating age-related changes in CYP activities and induction as well as developmental differences in drug metabolism and toxicity.

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Abbreviations

BNF:

β-Naphthoflavone

CYP:

Cytochrome P450

DEX:

Dexamethasone

DMSO:

Dimethylsulfoxide

ECOD:

Ethoxycoumarin O-deethylation

EROD:

Ethoxyresorufin O-deethylation

PB:

Phenobarbital

PCN:

Pregnenolone 16α-carbonitrile

PROD:

Pentoxyresorufin O-depentylation

TH:

Testosterone hydroxylation

References

  1. Lerche-Langrand C, Toutain HJ (2000) Toxicology 153:221–253

    Article  CAS  Google Scholar 

  2. Groneberg DA, Grosse-Siestrup C, Fischer A (2002) Toxicol Pathol 30:394–399

    Article  CAS  Google Scholar 

  3. Gebhardt R, Hengstler JG, Müller D, Glöckner R, Buenning P, Laube B, Schmelzer E, Ullrich M, Utesch D, Hewitt N, Ringel M, Reder-Hilz B, Bader A, Langsch A, Koose T, Burger H-J, Maas J, Oesch F (2003) Drug Metab Rev 35:145–213

    Article  CAS  Google Scholar 

  4. Farkas D, Tannenbaum SR (2005) Curr Drug Metab 6:111–125

    Article  CAS  Google Scholar 

  5. Vermeir M, Annaert P, Mamidi RN, Roymans D, Meuldermans W, Mannens G (2005) Exp Opin Drug Metab 1:75–90

    Article  CAS  Google Scholar 

  6. de Graaf IA, Groothuis GM, Olinga P (2007) Expert Opin Drug Metab Toxicol 3:879–898

    Article  Google Scholar 

  7. Lum PY, Walker S, Ioannides C (1985) Toxicology 35:307–317

    Article  CAS  Google Scholar 

  8. Müller D, Greiling K, Greiling H, Klinger W (1985) Biomed Biochim Acta 44:1171–1179

    Google Scholar 

  9. Watanabe J, Asaka Y, Kanamura S (1993) J Histochem Cytochem 41:397–400

    CAS  Google Scholar 

  10. Rich KJ, Boobis AR (1997) Microsc Res Tech 39:424–435

    Article  CAS  Google Scholar 

  11. Tanaka E (1998) J Clin Pharm Ther 23:247–255

    Article  CAS  Google Scholar 

  12. Johnson TN, Tanner MS, Tucker GT (2000) Biochem Pharmacol 60:1601–1610

    Article  CAS  Google Scholar 

  13. Alcorn J, McNamara PJ (2002) Clin Pharmacokinet 41:1077–1094

    Article  CAS  Google Scholar 

  14. Blake MJ, Castro L, Leeder JS, Kearns GL (2005) Sem Fet Neonat Med 10:123–138

    Article  Google Scholar 

  15. Klinger W (2005) Eur J Drug Metab Pharmacokinet 30:3–17

    CAS  Google Scholar 

  16. Elbarbry FA, McNamara PJ, Alcorn J (2007) J Biochem Mol Toxicol 21:41–50

    Article  CAS  Google Scholar 

  17. Hines RN (2007) J Biochem Mol Toxicol 21:169–175

    Article  CAS  Google Scholar 

  18. Strolin Benedetti M, Whomsley R, Canning M (2007) Drug Discov Today 12:599–610

    Article  Google Scholar 

  19. Lee PC, Struve MF, Werlin SL (1994) Biochem Mol Biol Int 34:861–870

    CAS  Google Scholar 

  20. Birnbaum L, Baird M (1978) Exp Gerontol 13:299–303

    Article  CAS  Google Scholar 

  21. McMartin D, O’Connor J, Fasco M, Kaminsky L (1980) Toxicol Appl Pharmacol 54:411–419

    Article  CAS  Google Scholar 

  22. Kamataki T, Maeda K, Shimada M, Kitani K, Nagai T, Kato R (1985) J Pharmacol Exp Ther 233:222–228

    CAS  Google Scholar 

  23. Kinirons MT, O’Mahony MS (2004) Br J Clin Pharmacol 57:540–544

    Article  CAS  Google Scholar 

  24. Warrington JS, Greenblatt DJ, von Moltke L (2004) J Pharmacol Exp Ther 309:720–729

    Article  CAS  Google Scholar 

  25. Wauthier V, Verbeeck RK, Buc Calderon P (2004) Arch Toxicol 78:131–138

    Google Scholar 

  26. Wauthier V, Verbeeck RK, Buc Calderon P (2007) Curr Med Chem 14:745–757

    Article  CAS  Google Scholar 

  27. Schmucker DL (2001) Drugs Aging 18:837–851

    Article  CAS  Google Scholar 

  28. Olinga P, Meijer DKF, Slooff MJH, Groothuis GMM (1997) Toxicol in Vitro 12:77–100

    Article  Google Scholar 

  29. Glöckner R, Steinmetzer P, Drobner C, Müller D (1999) Toxicol in Vitro 13:531–535

    Article  Google Scholar 

  30. Martin H, Sarsat J-P, de Waziers I, Housset C, Balladur P, Beaune P, Albaladejo V, Lerche-Langrand C (2003) Pharmac Res 20:557–568

    Article  CAS  Google Scholar 

  31. Persson KP, Ekehed S, Otter C, Lutz ESM, McPheat J, Masimirembwa CM, Andersson TB (2006) Pharmac Res 23:56–69

    Article  CAS  Google Scholar 

  32. Olinga P, Merema M, Hof IH, de Jong KP, Slooff MJH, Meijer DKF, Groothuis GMM (1998) Drug Metab Dispos 26:5–11

    CAS  Google Scholar 

  33. Fisher RL, Gandolfi AJ, Brendel K (2001) Cell Biol Toxicol 17:179–189

    Article  CAS  Google Scholar 

  34. Vandenbranden M, Wrighton SA, Ekins S, Gillespie JS, Binkley SN, Ring BJ, Gadberry MG, Mullins DC, Strom SC, Jensen CB (1998) Drug Metab Dispos 26:1063–1068

    CAS  Google Scholar 

  35. Renwick AB, Watts PS, Edwards RJ, Barton PT, Guyonnet I, Price RJ, Tredger M, Pelkonen O, Boobis AR, Lake BG (2000) Drug Metab Dispos 28:1202–1209

    CAS  Google Scholar 

  36. Correia MA (1995) Rat and human liver cytochrome P450: substrate and inhibitor specificities and functional markers. In: Ortiz de Montellano PR (ed) Cytochrome P450: structure, mechanism and biochemistry. Plenum, New York London, pp 607–630

  37. Lake BG, Renwick AB, Cunninghame ME, Price RJ, Surry D, Evans DC (1998) Toxicology 131:9–20

    Article  CAS  Google Scholar 

  38. Lewis DFV (2001) Guide to cytochromes P450: Structure and function. Taylor & Francis, London

  39. Wauthier V, Verbeeck RK, Buc Calderon P (2004) Toxicol in Vitro 18:879–885

    Article  CAS  Google Scholar 

  40. Müller D, Glöckner R, Rost M, Steinmetzer P (1998) Exp Toxicol Pathol 50:507–513

    Google Scholar 

  41. Müller D (1990) Exp Pathol 39:187–194

    Google Scholar 

  42. Klinger W, Müller D (1974) Z Versuchstierk 16:146–153

    Google Scholar 

  43. Ribeiro V, Lechner MC (1992) Arch Biochem Biophys 293:147–152

    Article  CAS  Google Scholar 

  44. Borlakoglu JT, Scott A, Henderson CJ, Wolf CR (1993) Int J Biochem 25:1659–1668

    Article  CAS  Google Scholar 

  45. Lupp A, Lucas N, Lindström-Seppä P, Koponen K, Hänninen O, Danz M, Klinger W (1998) Exp Toxicol Pathol 50:41–51

    CAS  Google Scholar 

  46. Oinonen T, Lindros KO (1998) Biochem J 329:17–35

    CAS  Google Scholar 

  47. Hart A, Mattheyse FJ, Balinsky JB (1983) In Vitro Toxicol 19:841–852

    Article  CAS  Google Scholar 

  48. Iwai M, Tanaka S, Mori T, Harada Y, Muramatsu A, Morikawa T, Kashima K, Fushiki S (2002) Cell Biol Toxicol 18:147–156

    Article  CAS  Google Scholar 

  49. Verrill C, Davies J, Millward-Sadler H, Sundstrom L, Sheron N (2002) J Pharmacol Toxicol Meth 48:103–110

    Article  CAS  Google Scholar 

  50. Lupp A, Danz M, Müller D (2005) Toxicology 206:427–438

    Article  CAS  Google Scholar 

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Acknowledgements

We gratefully thank Mrs H. Guder and Mrs H. Stadler for excellent technical assistance.

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Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, Friedrich Schiller University Jena, Nonnenplan 4, 07743, Jena, Germany

    Amelie Lupp, Reinhild Glöckner, Joachim Etzrodt & Dieter Müller

  2. Department of General, Visceral and Vascular Surgery, Friedrich Schiller University Jena, Erlanger Allee 101, 07747, Jena, Germany

    Joachim Etzrodt

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  1. Amelie Lupp
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  2. Reinhild Glöckner
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  3. Joachim Etzrodt
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  4. Dieter Müller
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Correspondence to Amelie Lupp.

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Lupp, A., Glöckner, R., Etzrodt, J. et al. Precision-cut liver slices from rats of different ages: basal cytochrome P450-dependent monooxygenase activities and inducibility. Anal Bioanal Chem 392, 1173–1184 (2008). https://doi.org/10.1007/s00216-008-2253-z

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  • DOI: https://doi.org/10.1007/s00216-008-2253-z

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