This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Manthey, C. L. Articles by Sladek, N. E. Search for Related Content PubMed PubMed Citation Articles by Manthey, C. L. Articles by Sladek, N. E.

Identification of the Mouse Aldehyde Dehydrogenases Important in Aldophosphamide Detoxification¹

Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455

Aldophosphamide, the penultimate cytotoxic metabolite of cyclophosphamide, can be detoxified by an oxidation reaction catalyzed by certain aldehyde dehydrogenases. The selective toxicity of cyclophosphamide is due, at least in part, to a greater expression of the relevant aldehyde dehydrogenase activity in normal cells relative to that expressed in certain tumor cells. Not known at the onset of this investigation was which of the several known mouse aldehyde dehydrogenases catalyze this reaction. Twelve enzymes that catalyze the NAD(P)-linked oxidation of aldophosphamide, acetaldehyde, benzaldehyde, and/or octanal were chromatographically resolved from mouse liver. Four of these appear to be novel; four others were determined to be betaine aldehyde dehydrogenase, succinic semialdehyde dehydrogenase, glutamic -semialdehyde dehydrogenase, and xanthine oxidase (dehydrogenase). An additional aldehyde dehydrogenase, namely AHD-4, was semipurified from stomach. The stomach enzyme and nine of the hepatic enzymes catalyze the oxidation of aldophosphamide. K_m values for these reactions range from 16 µM to 2.5 mM. The relevant aldehyde dehydrogenase of major importance varies with the tissue. In the liver, the major cytosolic aldehyde dehydrogenase, namely AHD-2, accounts for >60% of total hepatic aldehyde dehydrogenase-catalyzed aldophosphamide (160 µM) detoxification. Succinic semialdehyde dehydrogenase (AHD-12) and three of the novel hepatic aldehyde dehydrogenases, namely AHD-8, AHD-10, and AHD-13, also contribute significantly to total hepatic aldehyde dehydrogenase-catalyzed aldophosphamide detoxification. In the stomach, AHD-4 and AHD-8 account for approximately 86% of total aldehyde dehydrogenasecatalyzed aldophosphamide (160 µM) detoxification. AHD-2 was not found in this tissue. Of all the aldehyde dehydrogenases examined, AHD-2 and AHD-8 were estimated to be the most efficient catalysts of aldophosphamide oxidation. Thus, these enzymes would seem most likely to be operative when tumor cells acquire aldehyde dehydrogenase-mediated cyclophosphamide resistance.

¹ Supported by USPHS Grant CA 21737. Descriptions of parts of this investigation have appeared in abstract form (49) and in the proceedings of a workshop (6).

² To whom requests for reprints should be addressed, at the Department of Pharmacology, University of Minnesota, 3-249 Millard Hall, 435 Delaware Street S. E., Minneapolis, MN 55455.

Received 10/ 6/89. Revised 4/16/90.

This article has been cited by other articles:

				Y. Alnouti and C. D. Klaassen Tissue Distribution, Ontogeny, and Regulation of Aldehyde Dehydrogenase (Aldh) Enzymes mRNA by Prototypical Microsomal Enzyme Inducers in Mice Toxicol. Sci., January 1, 2008; 101(1): 51 - 64. [Abstract] [Full Text] [PDF]

				J. S. Moreb, A. Gabr, G. R. Vartikar, S. Gowda, J. R. Zucali, and D. Mohuczy Retinoic Acid Down-Regulates Aldehyde Dehydrogenase and Increases Cytotoxicity of 4-Hydroperoxycyclophosphamide and Acetaldehyde J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 339 - 345. [Abstract] [Full Text] [PDF]

				T. Tabata, M. Katoh, S. Tokudome, M. Nakajima, and T. Yokoi IDENTIFICATION OF THE CYTOSOLIC CARBOXYLESTERASE CATALYZING THE 5'-DEOXY-5-FLUOROCYTIDINE FORMATION FROM CAPECITABINE IN HUMAN LIVER Drug Metab. Dispos., October 1, 2004; 32(10): 1103 - 1110. [Abstract] [Full Text] [PDF]

				E. Wagner, T. Luo, and U. C. Drager Retinoic Acid Synthesis in the Postnatal Mouse Brain Marks Distinct Developmental Stages and Functional Systems Cereb Cortex, December 1, 2002; 12(12): 1244 - 1253. [Abstract] [Full Text] [PDF]

				S. A. Ross, P. J. McCaffery, U. C. Drager, and L. M. De Luca Retinoids in Embryonal Development Physiol Rev, July 1, 2000; 80(3): 1021 - 1054. [Abstract] [Full Text] [PDF]

				S. Ren, T. F. Kalhorn, and J. T. Slattery Inhibition of Human Aldehyde Dehydrogenase 1 by the 4-Hydroxycyclophosphamide Degradation Product Acrolein Drug Metab. Dispos., January 1, 1999; 27(1): 133 - 137. [Abstract] [Full Text]

				P. A. Dockham, L. Sreerama, and N. E. Sladek Relative Contribution of Human Erythrocyte Aldehyde Dehydrogenase to the Systemic Detoxification of the Oxazaphosphorines Drug Metab. Dispos., December 1, 1997; 25(12): 1436 - 1441. [Abstract] [Full Text]

				K. D. Bunting and A. J. Townsend De Novo Expression of Transfected Human Class 1 Aldehyde Dehydrogenase (ALDH) Causes Resistance to Oxazaphosphorine Anti-cancer Alkylating Agents in Hamster V79 Cell Lines J. Biol. Chem., May 17, 1996; 271(20): 11884 - 11890. [Abstract] [Full Text] [PDF]

				K. L. Chambliss, D. L. Caudle, D. D. Hinson, C. R. Moomaw, C. A. Slaughter, C. Jakobs, and K. M. Gibson Molecular Cloning of the Mature NAD[IMAGE]-dependent Succinic Semialdehyde Dehydrogenase from Rat and Human J. Biol. Chem., January 6, 1995; 270(1): 461 - 467. [Abstract] [Full Text] [PDF]