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. 1985 Jan;51(1):67–75. doi: 10.1038/bjc.1985.10

Effects of the induction of hepatic microsomal metabolism on the toxicity of cyclophosphamide.

H L Gurtoo, S K Bansal, Z Pavelic, R F Struck
PMCID: PMC1976820  PMID: 3966972

Abstract

Cyclophosphamide (CP) administration to rats in a single i.p. dose (200 mg kg-1), while producing urinary bladder toxicity and 30-40% depression of the hepatic microsomal mixed function oxidase (MFO), failed to produce any depression of MFO activities in extrahepatic tissues such as lung, kidney and intestine. Phenobarbital pretreatment of the rats, which is known to enhance hepatic microsomal activation of CP, protected against CP-induced urinary bladder toxicity and the depression of hepatic MFO activities. This protection appears to be, at least in part, related to phenobarbital induction of hepatic cytochrome P-450 isozyme(s) that metabolizes CP to a new metabolite tentatively identified as didechlorodihydroxycyclophosphamide.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alberts D. S., van Daalen Wetters T. The effect of phenobarbital on cyclophosphamide antitumor activity. Cancer Res. 1976 Aug;36(8):2785–2789. [PubMed] [Google Scholar]
  2. Bagley C. M., Jr, Bostick F. W., DeVita V. T., Jr Clinical pharmacology of cyclophosphamide. Cancer Res. 1973 Feb;33(2):226–233. [PubMed] [Google Scholar]
  3. Bakke J. E., Feil V. J., Fjelstul C. E., Thacker E. J. Metabolism of cyclophosphamide by sheep. J Agric Food Chem. 1972 Mar-Apr;20(2):384–388. doi: 10.1021/jf60180a054. [DOI] [PubMed] [Google Scholar]
  4. Berrigan M. J., Marinello A. J., Pavelic Z., Williams C. J., Struck R. F., Gurtoo H. L. Protective role of thiols in cyclophosphamide-induced urotoxicity and depression of hepatic drug metabolism. Cancer Res. 1982 Sep;42(9):3688–3695. [PubMed] [Google Scholar]
  5. Brock N., Stekar J., Pohl J., Niemeyer U., Scheffler G. Acrolein, the causative factor of urotoxic side-effects of cyclophosphamide, ifosfamide, trofosfamide and sufosfamide. Arzneimittelforschung. 1979;29(4):659–661. [PubMed] [Google Scholar]
  6. Conney A. H. Pharmacological implications of microsomal enzyme induction. Pharmacol Rev. 1967 Sep;19(3):317–366. [PubMed] [Google Scholar]
  7. Cox P. J. Cyclophosphamide cystitis--identification of acrolein as the causative agent. Biochem Pharmacol. 1979 Jul 1;28(13):2045–2049. doi: 10.1016/0006-2952(79)90222-3. [DOI] [PubMed] [Google Scholar]
  8. Cox P. J., Phillips B. J., Thomas P. The enzymatic basis of the selective action of cyclophosphamide. Cancer Res. 1975 Dec;35(12):3755–3761. [PubMed] [Google Scholar]
  9. Field R. B., Gang M., Kline I., Venditti J. M., Waravdekar V. S. The effect of phenobarbital or 2-diethylaminoethyl-2,2-diphenylvalerate on the activation of cyclophosphamide in vivo. J Pharmacol Exp Ther. 1972 Feb;180(2):475–483. [PubMed] [Google Scholar]
  10. Fujii-Kuriyama Y., Mizukami Y., Kawajiri K., Sogawa K., Muramatsu M. Primary structure of a cytochrome P-450: coding nucleotide sequence of phenobarbital-inducible cytochrome P-450 cDNA from rat liver. Proc Natl Acad Sci U S A. 1982 May;79(9):2793–2797. doi: 10.1073/pnas.79.9.2793. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gelboin H. V. Benzo[alpha]pyrene metabolism, activation and carcinogenesis: role and regulation of mixed-function oxidases and related enzymes. Physiol Rev. 1980 Oct;60(4):1107–1166. doi: 10.1152/physrev.1980.60.4.1107. [DOI] [PubMed] [Google Scholar]
  12. Guengerich F. P., Crawford W. M., Jr, Domoradzki J. Y., Macdonald T. L., Watanabe P. G. In vitro activation of 1,2-dichloroethane by microsomal and cytosolic enzymes. Toxicol Appl Pharmacol. 1980 Sep 15;55(2):303–317. doi: 10.1016/0041-008x(80)90092-7. [DOI] [PubMed] [Google Scholar]
  13. Guengerich F. P., Dannan G. A., Wright S. T., Martin M. V., Kaminsky L. S. Purification and characterization of liver microsomal cytochromes p-450: electrophoretic, spectral, catalytic, and immunochemical properties and inducibility of eight isozymes isolated from rats treated with phenobarbital or beta-naphthoflavone. Biochemistry. 1982 Nov 9;21(23):6019–6030. doi: 10.1021/bi00266a045. [DOI] [PubMed] [Google Scholar]
  14. Guengerich F. P. Isolation and purification of cytochrome P-450, and the existence of multiple forms. Pharmacol Ther. 1979;6(1):99–121. doi: 10.1016/0163-7258(79)90057-3. [DOI] [PubMed] [Google Scholar]
  15. Guengerich F. P., Martin M. V. Purification of cytochrome P-450, NADPH-cytochrome P-450 reductase, and epoxide hydratase from a single preparation of rat liver microsomes. Arch Biochem Biophys. 1980 Dec;205(2):365–379. doi: 10.1016/0003-9861(80)90119-8. [DOI] [PubMed] [Google Scholar]
  16. Gurtoo H. L., Dahms R., Hipkens J., Vaught J. B. Studies on the binding of [3H-chloroethyl]-cyclophosphamide and 14[C-4] -cyclophosphamide to hepatic microsomes and native calf thymus DNA. Life Sci. 1978 Jan;22(1):45–52. doi: 10.1016/0024-3205(78)90410-1. [DOI] [PubMed] [Google Scholar]
  17. Gurtoo H. L., Marinello A. J., Struck R. F., Paul B., Dahms R. P. Studies on the mechanism of denaturation of cytochrome P-450 by cyclophosphamide and its metabolites. J Biol Chem. 1981 Nov 25;256(22):11691–11701. [PubMed] [Google Scholar]
  18. Gurtoo H. L., Parker N. B. Sex-dependent regulation of benzo[a]pyrene and zoxazolamine metabolism in rat tissues. Drug Metab Dispos. 1977 Sep-Oct;5(5):474–481. [PubMed] [Google Scholar]
  19. Hipkens J. H., Struck R. F., Gurtoo H. L. Role of aldehyde dehydrogenase in the metabolism-dependent biological activity of cyclophosphamide. Cancer Res. 1981 Sep;41(9 Pt 1):3571–3583. [PubMed] [Google Scholar]
  20. Jao J. Y., Jusko W. J., Cohen J. L. Phenobarbital effects on cyclophosphamide pharmacokinetics in man. Cancer Res. 1972 Dec;32(12):2761–2764. [PubMed] [Google Scholar]
  21. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  22. Mizukami Y., Sogawa K., Suwa Y., Muramatsu M., Fujii-Kuriyama Y. Gene structure of a phenobarbital-inducible cytochrome P-450 in rat liver. Proc Natl Acad Sci U S A. 1983 Jul;80(13):3958–3962. doi: 10.1073/pnas.80.13.3958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. OMURA T., SATO R. THE CARBON MONOXIDE-BINDING PIGMENT OF LIVER MICROSOMES. I. EVIDENCE FOR ITS HEMOPROTEIN NATURE. J Biol Chem. 1964 Jul;239:2370–2378. [PubMed] [Google Scholar]
  24. Porter C. W., Dworacyzk D., Gurtoo H. L. Biochemical localization of aryl hydrocarbon hydroxylase in the intestinal epithelium of the rat. Cancer Res. 1982 Apr;42(4):1283–1285. [PubMed] [Google Scholar]
  25. Santos G. W., Sensenbrenner L. L., Anderson P. N., Burke P. J., Klein D. L., Slavin R. E., Schacter B., Borgaonkar D. S. HL-A-identical marrow transplants in aplastic anemia, acute leukemia, and lymphosarcoma employing cyclophosphamide. Transplant Proc. 1976 Dec;8(4):607–610. [PubMed] [Google Scholar]
  26. Sladek N. E. Therapeutic efficacy of cyclophosphamide as a function of its metabolism. Cancer Res. 1972 Mar;32(3):535–542. [PubMed] [Google Scholar]
  27. Zincke H., Woods J. E. Donor pretreatment in cadaver renal transplantation. Surg Gynecol Obstet. 1977 Aug;145(2):183–188. [PubMed] [Google Scholar]

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