Role of Aldehyde Dehydrogenase (ALDH) in the Detoxication of Cyclophosphamide (CP) in Rat Embryos

  • Philip E. Mirkes
  • Aaron Ellison
  • Sally A. Little
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 284)


The carbonyl compound 4-hydroxynonenal is one of the major and most toxic products of the oxidative lipid breakdown of biological membranes. Its formation has been quantified in rat liver homogenates, microsomes and whole parenchymal cells under various conditions of enhanced lipid peroxidation (Benedetti, et al., 1980; Esterbauer, et al., 1982; Poli, et al., 1985,1986).


L1210 Cell Aldehyde Dehydrogenase Heart Cell ALDH Activity Mandibular Arch 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bradford, M. (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of dye binding. Anal. Biochem. 72:248–254.PubMedCrossRefGoogle Scholar
  2. Cox, P.J., P.B. Farmer, and M. Jarman (1975) The microsomal metabolism of some analogues of cyclophosphamide:4-methyl-cyclophosphamide and 6-methylcyclophosphamide. Biochem. Pharmacol. 24:599–606.PubMedCrossRefGoogle Scholar
  3. Domeyer, B.E. and N.E. Sladek (1980) Metabolism of 4-hydroxycyclophosphamide/aldophosphamide in vitro. Biochem. Pharmacol. 29:2903–2912.PubMedCrossRefGoogle Scholar
  4. Dunn, T.J., A.J. Koleske, R. Lindahl, and H.C. Pitot (1989) Phenobarbital-inducible aldehyde dehydrogenase in the rat. cDNA sequence and regulation of the mRNA by phenobarbital in responsible rats. J. Biol. Chem. 264:13057–13065.PubMedGoogle Scholar
  5. Erickson, L., and C. Zlotogorski (1984) Induction and repair of macromolecular damage by alkylating agents. Cancer Treat. Rep. II (supp. A):25–35.CrossRefGoogle Scholar
  6. Fantel, A.G., J.C. Greenaway, M.R. Juchau, and T.H. Shepard (1979) Teratogenic bioactivation of cyclophosphamide in vitro. Life Sci. 25:67–72.PubMedCrossRefGoogle Scholar
  7. Hempel, J., and R. Lindahl, M. (1989) Class III aldehyde dehydrogenase from rat liver: superfamily relationship to classes I and II and functional interpretations. In: Progress in Clinical and Biological Research: Enzymology and Molecular Biology of Carbonyl Metabolism 2, H. Weiner and T.G. Flynn, eds., Volume 290, pp. 3–17.Google Scholar
  8. Hill, D.L., W.R. Laster, Jr., M.C. Kirk, S. ElDareer, and R.F. Struck (1973) Metabolism of phosphamide (2-(2-chloroethylamino)-3(2-chloroethyl)-tetrahydro 2H-1, 3,2,-oxazaphosphorine 2-oxide) and production of a toxic phosphamide metabolite. Cancer Res. 33:1016–1022.PubMedGoogle Scholar
  9. Hilton, J. (1984) Role of aldehyde dehydrogenase ion cyclophosphamide-resistant L1210 leukemia. Cancer Res. 44:5156–5160.PubMedGoogle Scholar
  10. Lindahl, R. (1977) Aldehyde dehydrogenase in 2-acetamidofluorene-induced rat hepatomas. Ontogeny and evidence that the new isoenzymes are not due to normal gene de-repression. Biochem. J. 164:119–123.PubMedGoogle Scholar
  11. Mehta, J.M. Przybylski, and D. Ludlum (1980) Alkylation of guanosine and deoxyguanosine by phosphoramide mustard. Cancer Res. 40:4183–4186.PubMedGoogle Scholar
  12. Mirkes, P.E., A.G. Fantel, J.C. Greenaway, and T.H. Shepard (1981) Teratogenicity of cyclophosphamide metabolites: phosphoramide mustard, acrolein, and 4-ketocyclophosphamide in rat embryos cultured in vitro. Toxicol. Appl. Pharmacol. 58:322–330.PubMedCrossRefGoogle Scholar
  13. Mirkes, P.E. and J.C. Greenaway (1985) Uptake and binding of tritium from (chloroethyl 3H) cyclophosphamide by rat embryos in vitro. Teratology 31:373–380.PubMedCrossRefGoogle Scholar
  14. New, D.A.T. (1978) Whole embryo culture and the study of mammalian embryos during organogenesis. Biol. Rev, 53:81–122.PubMedCrossRefGoogle Scholar
  15. Russo, J. and J. Hilton (1988) Characterization of cytosolic aldehyde dehydrogenase from cyclophosphamide resistant L1210 cells. Cancer Res. 48:2963–2968.PubMedGoogle Scholar
  16. Russo, J., J. Hilton, and M. Colvin (1988) Aldehyde dehydrogenase (ALDH) activity confers resistance to cyclophosphamide (CP) in murine small intestine. Proc. Am. Assoc. Cancer. Res. 29:296.Google Scholar
  17. Zar, J.H. (1984) In: Biostatistical analysis, Prentice Hall, Englewood Cliffs, New Jersey, pp. 401–403.Google Scholar
  18. Zwelling, L., S. Michaels, H. Schwartz, P. Dobson and K. Kohn (1980) DNA crosslinking as an indicator of sensitivity and resistance of mouse L1210 Leukemia to cis-diamminedichloroplatinum (II) and L-phenyl-alanine mustard. Cancer Res. 40:640–649.Google Scholar

Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • Philip E. Mirkes
    • 2
  • Aaron Ellison
    • 1
  • Sally A. Little
    • 1
  1. 1.Division of Embryology, Teratology and Congenital Defects, Department of PediatricsUniversity of WashingtonSeattleUSA
  2. 2.Child Development and Mental Retardation CenterUniversity of WashingtonUSA

Personalised recommendations