Skip to main content
SpringerLink
Log in

Expression of genes encoding for drug metabolising cytochrome P450 enzymes and P-glycoprotein in the rat small intestine; comparison to the liver

  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Summary

The level of expression of genes encoding for nine major xenobiotic metabolising Cytochrome P450s (CYPs) and the P-glycoprotein (Pgp) was determined in three different regions of the small intestine of male and female Sprague Dawley rats and the expression was compared with that in the liver. A semi-quantitative RT-PCR method, using the total RNA from the tissues, was established for the determination of the level of gene expression.

Four of the CYP genes: the CYP2B1, CYP2C6, CYP2C11 and CYP2D1 and the Pgp were expressed at as high levels in the small intestine as in the liver. The expression of the other CYP genes was remarkably different in the two organs. The CYP1A2, CYP2A3, CYP2E1 and CYP3A1 showed a strong expression in the liver but only a comparatively weak or no expression in the small intestine. The CYP1A1 on the other hand exhibited a stronger expression in the small intestine than in the liver.

With the exception of the CYP2A3, none of the genes showed a clear regional distribution in their small intestinal expression. Furthermore, no obvious sex difference in the expression of the CYP and Pgp genes could be observed.

Our results indicate that several of the enzymes, central for drug metabolism are differently expressed in the liver and in the small intestine of the rat which should be taken into account when using rat as a model for the bioavailability and organ specific toxicity studies of orally administered xenobiotics. The apparently strong small intestinal expression of the CYP2C genes suggests that these enzymes could play a key role in the intestinal drug metabolism in rats and therefore affect the bioavailability of those orally used drugs which are substrates of the CYP2Cs. This possibility should be investigated in more detail both in rats and humans.

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

Similar content being viewed by others

References

  1. Porter T.D. and Coon M.J. (1991): Cytochrome P-450. J. Biol. Chem., 266, 13469–13472

    CAS  PubMed  Google Scholar 

  2. Borst P., Schinkel A.H., Smit J.J.M., Wagenaar E., van Deemter L., Smith A.J., Eijdems E.W.H.M., Baas F. and Zaman G.J.R., (1993) Classical and Novel Forms of Multidrug Resistance and the Physiological Functions of P-glycoproteins in Mammals. Pharmac. Ther., 60, 289–299)

    Article  CAS  Google Scholar 

  3. Salphati L. and Benet L.Z., (1998): Modulation of P-glycoprotein Expression by Cytochrome P450 3A Inducers in Male and Female Rat Liver. Biochem. Pharmacol., 55, 387–395

    Article  CAS  PubMed  Google Scholar 

  4. Wacher V.J., Silverman J.A., Zhang Y., Benet L.Z., (1998): Role of P-glycoprotein and Cytochrome P450 3A in Limiting Oral Absorption of Peptides and Peptidomimetics J. Pharm. Sci., 87, 1322–1330

    Article  CAS  PubMed  Google Scholar 

  5. Nelson D.R., Kamataki T., Wexman D.J., Guengerich F.P., Estabrook R.W., Feyereisen R., Gonzalez F.J., Coon M.J., Gunsalus I.C., Gotoh O., Okuda K., and Nebert D.W., (1993): The P450 Superfamily: Update on New Sequences, Gene Mapping, Accession Numbers, Early Trivial Names of Enzymes, and Nomenclature. DNA and Cell Biol., 12, 1–51

    Article  CAS  Google Scholar 

  6. Paine M.F., Shen D.D., Kunze K.L., Perkins J.D., Marsh C.L., McVicar J.P., Barr D.M., Gillies B.S. and Thummel K.E., (1996): First-pass Metabolism of Midazolam by the Human Intestine. Clin. Pharmacol. There., 60, 14–24

    Article  CAS  Google Scholar 

  7. Wu C-Y., Benet L.Z., Hebert M.F., Gupta S.K., Rowland M., Gomez D.Y. and Wacher V.J., (1995): Differentiation of Absorption and Firstpass Gut and Hepatic Metabolism in Humans: Studies with Cyclosporine. Clin. Pharmacol. Ther., 58, 492–497

    Article  CAS  PubMed  Google Scholar 

  8. Reg_rdh C.G., Edgar B., Olsson R., Kendall M., Collste P and Shansky C., (1989): Pharmacokinetics of Felodipine in Patients with Liver Disease. Eur. J. Clin. Pharmacol., 36, 473–479

    Article  Google Scholar 

  9. Fromm M.F., Busse D., Kroemer H.K., and Eichelbaum M. (1996): Differential Induction of Prehepatic and Hepatic Metabolism of Verapamil by Rifampin. Hepatology. 24, 796–801

    Article  CAS  PubMed  Google Scholar 

  10. Bai J.P.F. (1994): Distribution of Brush-Border Membrane Peptidases Along the Rat Intestine. Pharmaceutical Research, 11, 897–900

    Article  CAS  PubMed  Google Scholar 

  11. Traber P.G., McDonnell W.M., Wang W. and Florence R. (1992): Expression and Regulation of Cytochrome P-450I Genes (CYP1A1 and CYP1A2) in the Rat Alimentary Tract. Biochimicia et Biophysica Acta., 1171, 167–175

    CAS  Google Scholar 

  12. Zhang Q-Y., Wikoff J., Dunbar D. and Kaminsky L. (1996): Characterization of Rat Small Intestinal Cytochrome P450 Composition and Inducibility. Drug Metab. Dispos., 24, 322–328

    CAS  PubMed  Google Scholar 

  13. De Waziers I., Cugnenc P.H., Yang C.S., Leroux J-P., and Beaune P.H. (1990): Cytochrome P 450 Isoenzymes, Epoxide Hydrolase and Glutathione Transferases in Rat and Human Hepatic and Extrahepatic. Tissues J. Pharmacol. Exp. Ther., 253, 387–394

    Google Scholar 

  14. Kaminsky L.S. and Fasco M.J. (1991): Small Intestinal Cytochromes P450. Crit. Rev. Toxicol., 21, 407–422

    Article  CAS  PubMed  Google Scholar 

  15. Zhang J. and Ding X. (1998): Identification and Characterization of a Novel Tissue-specific Transcriptional Activating Element in the 5_-Flanking Region of the CYP2A3 Gene Predominantly Expressed in Rat Olfactory Mucosa. J. Biol. Chem., 273, 23454–23462

    Article  CAS  PubMed  Google Scholar 

  16. Gonzalez F.J. (1989): The Molecular Biology of Cytochrome P450s. Pharmacological Reviews, 40, 243–288

    Google Scholar 

  17. Honkakoski P., Mäenpää J., Leikola J., Pasanen M., Juvonen R., Lang M.A. Melkonen O., and Raunio H. (1993): Cytochrome P4502A-Mediated Counmarin 7-Hydroxylation and Testosterone Hydroxylation in Mouse and Rat Lung. Pharmacol. & Toxicol., 72, 107–112

    Article  CAS  Google Scholar 

  18. Béréziat J-C., Raffalli F., Schmezer P., Frei E., Geneste O. and Lang M.A. (1995): Cytochrome P450 2A of Nasal Epithelium: Regulation and Role in Carcinogen Metabolism. Mol. Carcinogenesis, 14, 130–139

    Article  Google Scholar 

  19. Godoy W., Albano R.M., Moraes E.G., Alves Pinho P.R., Nunes R.A., Saito E.H., Higa C., Filho I.M., Pinto Kruel C.D., Schirmer C.C., Gurski R., Lang M.A., and Ribeiro Pinto L.F. (2002): CYP2A6/2A7 and CYP2E1 Expression in Human Oesophageal Mucosa: Regional anf Inter-individual Variation in Expression and Relevance to Nitrosamine Metabolism. Carcinogenesis, 23, 611–616.

    Article  CAS  PubMed  Google Scholar 

  20. Iber H., Chen Q., Sewer M., and Morgan E.T. (1997): Regulation of Hepatic Cytochrome P450 2C11 by Glucocorticoids. Arch. Biochem. Biophys., 345, 305–310

    Article  CAS  PubMed  Google Scholar 

  21. Hiroi T., Imaoka S., Chow T. and Funae Y. (1998): Tissue Distribution of CYP2D1, 2D2, 2D3 and 2D4 mRNA in Rats Detected by RT-PCR. Biochimica et Biophysica Acta, 1380, 305–312

    CAS  PubMed  Google Scholar 

  22. Hakkak R., Korourian S., Ronis M.J.J., Ingelman-Sundberg M. and Badger T.M. (1996): Effects of Diet and Ethanol on the Expression and Localization of Cytochromes P450 2E1 and P450 2C7 in the Colon of Male Rats. Biochem. Pharmacol., 51, 61–69

    Article  CAS  PubMed  Google Scholar 

  23. Shimizu M., Lasker J.M., Tsutsumi M. and Lieber C.S. (1990): Immunohistochemical Localization of Ethanol-Inducible P450IIE1 in the Rat Alimentary Tract. Gastroenterology, 99, 1044–1053

    CAS  PubMed  Google Scholar 

  24. Kocarek T.A., Zangar R.C. and Novak R.F. (2000): Post-transcriptional Regulation of Rat CYP2E1 Expression: Role of CYP2E1 mRNA Untranslated Regions in Control of Translational Efficiency and Message Stability. Arch. Biochem. Biophys., 376, 180–190

    Article  CAS  PubMed  Google Scholar 

  25. Kolars J.C., Schmiedlin-Ren P., Dobbins III W.O., Schuetz J., Wrighton S.A., and Watkins, P.B. (1992): Heterogeneity of Cytochrome P450IIIA Expression in Rat Gut Epithelia. Gastroenterology, 102, 1186–1198

    CAS  PubMed  Google Scholar 

  26. Johnson T.N., Tanner M.S., and Tucker G.T., (2000): A Comparison of the Ontogeny of Enterocytic and Hepatic Cytochromes P450 3A in the Rat. Biochem. Pharmacol., 60, 1601–1610.

    Article  CAS  PubMed  Google Scholar 

  27. Makhey V.D., Guo A., Norris D.A., Hu P., Yan J. and Sinko P.J. (1998) Characterization of the Regional Intestinal Kinetics of Drug Efflux in Rat and Human Intestine and in Caco-2 Cells. Pharmaceutical Research, 15, 1160–1167

    Article  CAS  PubMed  Google Scholar 

  28. Mugford C.A., and Kedderis G.L. (1998): Sex-dependent Metabolism of Xenobiotics. Drug. Metabolism Reviews 30, 441–498

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Biosciences, Uppsala University, Sweden

    Monica Lindell & Matti Lang

  2. Department of Pharmacy, Uppsala University, Sweden

    Monica Lindell & Hans Lennernäs

Authors
  1. Monica Lindell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matti Lang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hans Lennernäs
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lindell, M., Lang, M. & Lennernäs, H. Expression of genes encoding for drug metabolising cytochrome P450 enzymes and P-glycoprotein in the rat small intestine; comparison to the liver. Eur. J. Drug Metab. Pharmacokinet. 28, 41–48 (2003). https://doi.org/10.1007/BF03190865

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03190865

Keywords

Search

Navigation