Skip to main content
Log in

Effect of carrageenan-induced granuloma on hepatic cytochrome P-450 isozymes in rats

  • Original Articles
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Carrageenan-induced granuloma was used to study the apoprotein and RNA content, and catalytic activities of several cytochrome P-450 isozymes in liver. This model allowed discrimination between acute and chronic phases of experimental inflammation. The expression of most isozymes studied (CYP2D, CYP2E1, CYP3A1 and CYP4A) was reduced to 20% of the control level during the acute phase and partially recovered (30–60% of control group) during the chronic phase. CYP2B1 content was decreased to 65% of control during the acute and chronic phases of inflammation. RNA (CYP2B1 and CYP2E1) showed a strong depression during the acute phase and recovered during the chronic phase, without differences between isoenzymes. In most cases, there was a good correlation between the apoprotein content of isozymes and related activities. Our results show that the depletion of cytochrome P-450 induced by inflammation depends on the severity of the disease. Experimental inflammation equally affect the transcription of CYP2B1 and CYP2E1, so differences in apoprotein content and related activities between isozymes may due to differential posttranscriptional regulation.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Nelson, D. R., T. Kamataki, F. Waxman, F. P., Guengerich, R. W. Estabrook, R. Feyereisen, F. J. Gonzalez, M. J. Coon, I. C. Gunsalus, O. Gotoh, K. Okuda, andD. W. Nebert. 1993. The P450 superfamilly: Updated on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature.DNA Cell Biol. 8:1–51.

    Google Scholar 

  2. Nebert, D. W., andF. J. Gonzalez. 1982. P450 genes: structure, evolution and regulation.Annu. Rev. Biochem. 56:945–993.

    Google Scholar 

  3. Muntané, J., Y. Fernandez, S. Mitjavila, andM. T. Mitjavila. 1993. Hepatic changes during a carrageenan-induced granuloma in rats.Mediators Inflammation 2:79–83.

    Google Scholar 

  4. Beck, F. J., andM. W. Whitehouse. 1973. Effect of adjuvant disease in rats on cyclosphosphamide and isophosphamide metabolism.Biochem. Pharmacol. 22:2453–2468.

    PubMed  Google Scholar 

  5. Cawthorne, M. A., E. D. Palmer, andJ. Green. 1976. Adjuvant-induced arthritis and drug-metabolizing enzymes.Biochem. Pharmacol. 25:2683–2688.

    PubMed  Google Scholar 

  6. Morton, D. M., andD. H. Chatfield. 1970. The effect of adjuvant induced arthritis on the liver metabolism of drugs in rats.Biochem. Pharmacol. 19:473–481.

    PubMed  Google Scholar 

  7. Moreno, J. J., M. C. Castellote, andJ. Queralt. 1991. Effect of mycobacterium butyricum on the hepatic cytochrome P450 system of the mouse: Influence of anti-inflammatory drug.Comp. Biochem. Physiol. 99:7–10.

    Google Scholar 

  8. Adolfs, M. J. P., I. L.Bonta, and P. C.Bragt. 1979. Increased lipid peroxidation and decreased hepatic aminopyrine metabolism during carrageenin-induced granulomatous inflammation in the rat. Proceedings, Biochemical Pharmacology Symposium, 12–14 September, 123P–124P.

  9. Ishikawa, M., K. Sasaki, M. Ozaki, K. Watanabe, Y. Takayanagi, andK. Sasaki. 1991. Hepatic drug metabolizing activity in rats with carrageenan-induced inflammation.J. Pharmacobio-Dyn. 14:132–138.

    PubMed  Google Scholar 

  10. Sasaki, K., M. Ishikawa, Y. Takayanagi, andK. Sasaki. 1990. The effect of phenobarbital on the impairment of drug metabolism by carrageenan-induced inflammation in male rat.Res. Commun. Chem. Pathol. Pharmacol. 69:377–380.

    PubMed  Google Scholar 

  11. Bertini, R., P. G. Gervasi, V. Longo, andP. Ghezzi. 1992. Depression of hepatic drug metabolism in endotoxin-treated and sarcoma-bearing mice.Res. Commun. Chem. Pathol. Pharmacol. 76:223–231.

    PubMed  Google Scholar 

  12. Morgan, E. T. 1989. Suppression of constitutive cytochrome P-450 gene expression in livers of rats undergoing an acute phase response to endotoxin.Mol. Pharmacol. 36:699–707.

    PubMed  Google Scholar 

  13. Harrison, L. C., andI. L. Campbell. 1988. Cytokines: An expanding network of immunoinflammatory hormones.Mol. Endocrinol. 2:1151–1156.

    PubMed  Google Scholar 

  14. Poüs, C., J. P. Giroud, C. Damais, D. Raichvarg, andL. Chauvelot-Moachon. 1989. Effect of recombinant human interleukin-1β and tumor necrosis factorα on liver cytochrome P-450 and serumα-1-acid glycoprotein concentrations in the rat.Drug Metab. Disp. 18:467–470.

    Google Scholar 

  15. Wright, K., andE.T. Morgan. 1991. Regulation of cytochrome P450IIC12 expression by interleukin-1α, interleukin-6, and dexamethasone.Mol. Pharmacol. 39:468–474.

    PubMed  Google Scholar 

  16. Chen, Y. L., I. Florentin, A. M. Batt, L. Ferrari, J. P. Giroud, andL. Chauvelot-Moachon. 1992. Effects of interleukin-6 on cytochrome P450-dependent mixed function oxidases in the rat.Biochem. Pharmacol. 44:137–148.

    PubMed  Google Scholar 

  17. Ghezzi, P., B. Saccardo, P., Villa, V. Rossi, M. Bianchi, andC. A. Dinarello. 1986. Role of interleukin-1 in the depression of liver drug metabolism by endotoxin.Infect. Immun. 54:837–840.

    PubMed  Google Scholar 

  18. Fukuhara, M., andS. Tsurufuji. 1969. The effect of locally injected anti-inflammatory drugs on the carrageenin granuloma in rats.Biochem. Pharmacol. 18:475–484.

    PubMed  Google Scholar 

  19. Longo, V., L. Citti, andP. G. Gervasi. 1986. Metabolism of diethylnitrosamine by nasal mucosa and hepatic microsomes from hamster and rat: Species specificity of nasal mucosa.Carcinogenesis 7:1323–1328.

    PubMed  Google Scholar 

  20. Lowry, O. H., N. J. Rosebrough, A. L. Farr, andR. J. Randall. 1951. Protein measurement with the Folin phenol reagent.J. Biol. Chem. 193:265–275.

    PubMed  Google Scholar 

  21. Eliasson, E., I. Johansson, andM. Ingelman-Sundberg. 1988. Ligand-dependent maintenance of ethanol-inducible cytochrome P450 in primary rat hepatocyte cell cultures.Biochem. Biophys. Res. Commun. 150:436–443.

    PubMed  Google Scholar 

  22. Okoyama, H., M. Kawaichi, M. Brownstein, M. Lee, F. T. Yokota, andK. Arai. 1987. High-efficiency cloning of full-length cDNA; construction and screening of cDNA expression libraries for mammalian cells.Methods Enzymol. 154:3–28.

    PubMed  Google Scholar 

  23. Aitio, A. 1978. A simple and sensitive assay of 17-ethoxycoumarin deethylation.Anal. Biochem. 85:488–491.

    PubMed  Google Scholar 

  24. Lubet, R. A., R. T. Mayer, J.W. Cameron, R. W. Nims, M. D. Burke, T. Wolff, andF. P. Guengerich. 1985. Dealkylation of pentoxyresorufin: A rapid and sensitive assay for measuring induction of cytochrome(s) P450 by phenobarbital and other xenobiotics in the rat.Arch. Biochem. Biophys. 238:43–48.

    PubMed  Google Scholar 

  25. Tu, Y. Y., andC. S. Yang. 1983. High-affinity nitrosamine dealkylase system in rat liver microsomes and its induction by fasting.Cancer Res. 43:623–629.

    PubMed  Google Scholar 

  26. Ko, I. Y., S. S. Park, B. J. Song, C. Patten, Y. Tan, Y. C. Han, C. S. Yang, andH. V. Gelboin. 1987. Monoclonal antibodies to ethanol-induced rat liver cytochrome P450 that metabolizes aniline and nitrosamines.Cancer Res. 41:3101–3109.

    Google Scholar 

  27. Fujita, S., R. Morimoto, M. Chiba, K. Kitani, andT. Suzuki. 1989. Evaluation of the involvement of a male specific cytochrome P450 isozyme in senescence associated decline of hepatic drug metabolism in male rats.Biochem. Pharmacol. 38:3925–3931.

    PubMed  Google Scholar 

  28. Platt, K. L., E. Molitor, J. Dohmer, S. Dogra, andF. Oesch. 1989. Genetically engineered V79 Chinese hamster cell expression of purified cytochrome P450IIB1 monoxygenase activity.J. Biochem. Toxicol. 4:1–6.

    PubMed  Google Scholar 

  29. Reinke, L. A., S. H. Sexter, andL. E. Rikans. 1985. Comparison of ethanol and imidazole pretreatments on hepatic monooxygenase activities in the rat.Res. Commun. Chem. Pathol. Pharmacol. 47:97–106.

    PubMed  Google Scholar 

  30. Arlotto, M.-P., A. J. Sonderfan, C. D. Klassen, andA. Parkinson. 1987. Studies on the pregnenolone-16α-carbonitrile-inducible form of rat liver microsomal cytochrome P-450 and UDP-glucuronosyltransferase.Biochem. Pharmacol. 36:3859–3866.

    PubMed  Google Scholar 

  31. Guengerich, F. P., G. A. Dannan, S. T. Wright, H. V. Marrtin, andL. S. Kamisky. 1982. Purification and characterization of liver microsomal cytochromes P-450: Electrophoretic, spectral, catalytic and immunochemical properties and inductibility of eight isozymes isolated from rats treated with phenobarbital orβ-naphthoflavone.Biochemistry 21:6019–6030.

    PubMed  Google Scholar 

  32. Lubet, R. A., R. T. Mayer, J. W. Cameron, R. W. Nims, M. D. Burke, T. Wolf, andF. P. Guengerich. 1985. Dealkylation of pentoxyresorufin: A rapid and sensitive assay for measuring induction of cytochromes(s) P-450 by phenobarbital and other xenobiotic in rat.Arch. Biochem. Biophys. 238:43–48.

    PubMed  Google Scholar 

  33. Klotz, A. V., J. J. Stogeman, andC. Walsh. 1984. An alternative 7-ethoxyresorufinO-deethylase activity assay: A continuous visible spectrophotometric measurement of cytochrome P-450 monoxygenase activity.Anal. Biochem. 140:138–145.

    PubMed  Google Scholar 

  34. Wood, A. W., D. E. Ryan, P. E. Thomas, andW. Levin. 1983. Regio- and stereoselective metabolism of two C19 steroid by five highly purified and reconstituted rat hepatic cytochrome P-450 isozymes.J. Biol. Chem. 258:8839–8847.

    PubMed  Google Scholar 

  35. Waxman, D. J., A. Ko, andC. Walsh. 1983. Regioselectivity and stereoselectivity of androgen hydroxylations catalyzed by cytochrome P-450 isozymes purified from phenobarbital-induce rat liver.J. Biol. Chem. 258:11937–11947.

    PubMed  Google Scholar 

  36. Sonderfan, A. J., M. P. Arlotto, D. R. Dutton, S. K. McMillen, andA. Parkinson. 1987. Regulation of testosterone hydroxylation by rat liver microsomal cytochrome P-450.Arch. Biochem. Biophys. 255:27–41.

    PubMed  Google Scholar 

  37. Fukuda, Y., N. Ishida, T. Noguchi, A. Kappas, andS. Sassa. 1992. Interleukin-6 down regulates the expression of transcripts encoding cytochrome P450 IA1, IA2 and IIIA3 in human hepatoma cells.Biochem. Biophys. Res. Commun. 184:960–965.

    PubMed  Google Scholar 

  38. Williams, J. F., W. J. Bement, J. F. Sinclair, andP. R. Sinclair. 1991. Effect of interleukin 6 on phenobarbital induction of cytochrome P450IIB in cultured rat hepatocytes.Biochem. Biophys. Res. Commun. 178:1049–1055.

    PubMed  Google Scholar 

  39. Barker, C. W., J. B. Fagan, andD. S. Pasco. 1992. Interleukin-1β suppresses the induction of P4501A1 and P4501A2 mRNAs in isolated hepatocytes.J. Biol. Chem. 267:8050–8055.

    PubMed  Google Scholar 

  40. Eliasson, E., S. Mkrtchian, andM. Ingelman-Sundberg. 1992. Hormone- and substrate-regulated intracellular degradation of cytochrome P450 (2E1) involving MgATP-activated rapid proteolysis in the endoplasmic reticulum membranes.J. Biol. Chem. 267:15765–15769.

    PubMed  Google Scholar 

  41. Peterson, T. C., andK. W. Renton. 1986. Kupffer cell factor mediated depression of hepatic parenchymal cell cytochrome P-450.Biochem. Pharmacol. 35:1491–1497.

    PubMed  Google Scholar 

  42. Abel, S. M., D. J. Back, J. L. Maggs, andB. K. Park. 1993. Cortisol metabolism in vitro: II. Species difference.J. Steroid Biochem. Mol. Biol. 45:445–453.

    PubMed  Google Scholar 

  43. Butler, M. A., M. Iwasaki, F. P. Guengerich, andF. F. Kadlubar. 1989. Human cytochrome P-450PA (P-450IA2), the phenacetinO-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine andN-oxidation of carcinogen arylamines.Proc. Natl. Acad. Sci U.S.A. 86:7696–7700.

    PubMed  Google Scholar 

  44. Aoyama, T., S. Yamano, P. S. Guzelian, H. V. Gelboin, andF. Gonzalez. 1990. Five of 12 forms of vaccinia virus-expressed human hepatic cytochrome P450 metabolically activate aflatoxin B1.Proc. Natl. Acad. Sci. U.S.A. 87:4790–4793.

    PubMed  Google Scholar 

  45. Dahl, M. L., I. Johansson, M. P. Palmertz, M. Ingelman-Sundberg, andF. Sjöqvist. 1992. Analysis of the CYP2D6 gene in relation to debrisoquin and desipramine hydroxylation in a Swedish population.Clin. Pharmacol. Ther. 51:12–17.

    PubMed  Google Scholar 

  46. Pichard, L., I. Fabre, G. Fabre, J. Domergue, B. S. Aubert, G. Mourad, andP. Maurel. 1989. Cyclosporin A drug interactions. Screening for inducers and inhibitors of cytochrome P-450 (cyclosporin A oxidase) in primary cultures of human hepatocytes and in liver microsomes.Drug Metab. Disp. 18:595–606.

    Google Scholar 

  47. Pichard, L., G. Gillet, I. Fabre, I. Dalet-Beluche, C. Bonfils, J. P. Thenot, andP. Maurel. 1990. Identification of the rabbit and human cytochrome P-450IIIA as the major enzymes involved in theN-demethylation of diltiazem.Drug. Metab. Disp. 18:711–719.

    Google Scholar 

  48. Zhao, J., T. Leemann, andP. Dayer. 1992. In vitro oxidation of oxicam NSAIDs by a human liver cytochrome P450.Life Sci. 51:575–581.

    PubMed  Google Scholar 

  49. Martini, R., andM. Murray. 1993. Participation of P450 3A enzymes in rat hepatic microsomal retinoic acid 4-hydroxylation.Arch. Biochem. Biophys. 303:57–66.

    PubMed  Google Scholar 

  50. Ekström, G., andM. Ingelman-Sundberg. 1990. Lipid peroxidation dependent on ethanolinducible cytochrome P450 from rat liver.Biochem. Pharmacol. 97:582–589.

    Google Scholar 

  51. Adamson, G. M., andR. E. Billings. 1992. Tumor necrosis factor induced oxidative stress in isolated mouse hepatocytes.Arch. Biochem. Biophys. 294:223–229.

    PubMed  Google Scholar 

  52. Muntané, J., P. Puig-Parellada, Y. Fernandez, S. Mitjavila, andM. T. Mitjavila. 1993. Antioxidant defenses and its modulation by iron in carrageenan-induced inflammation in rats.Clin. Chim. Acta 214:185–193.

    PubMed  Google Scholar 

  53. Capdevila, J. H., J. R. Falck, andR. W. Estabrook. 1992. Cytochrome P450 and the arachidonate cascade.FASEB J. 6:731–736.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Additional information

At the time of the study, visiting scientists at the Department of Physiological Chemistry, Karolinska Institutet, S-10401 Stockholm, Sweden.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Muntané, J., Longo, V., Mitjavila, M.T. et al. Effect of carrageenan-induced granuloma on hepatic cytochrome P-450 isozymes in rats. Inflammation 19, 143–156 (1995). https://doi.org/10.1007/BF01534458

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01534458

Keywords

Navigation