Abstract
Detoxification of cyclophosphamide is effected, in part, by hepatic class 1 aldehyde dehydrogenase (ALDH-1)-catalyzed oxidation of aldophosphamide, a pivotal aldehyde intermediate, to the nontoxic metabolite, carboxyphosphamide. This enzyme is found in erythrocytes as well. Detoxification of aldophosphamide may also be effected by enzymes, viz. certain aldo-keto reductases, that catalyze the reduction of aldophosphamide to alcophosphamide. Such enzymes are also found in erythrocytes. Not known at the onset of this investigation was whether the contribution of erythrocyte ALDH-1 and/or aldo-keto reductases to the overall systemic detoxification of circulating aldophosphamide is significant. Thus, NAD-linked oxidation and NADPH-linked reduction of aldophosphamide catalyzed by relevant erythrocyte enzymes were quantified. ALDH-1-catalyzed oxidation of aldophosphamide (160 μM) to carboxyphosphamide occurred at a mean (± SD) rate of 5.0 ± 1.4 atmol/min/rbc (red blood cell). Aldo-keto reductase-catalyzed reduction of aldophosphamide (160 μM) to alcophosphamide occurred at a much slower rate, viz. 0.3 ± 0.2 atmol/min/rbc. Thus, at a pharmacologically relevant concentration of aldophosphamide, viz. 1 μM, estimated aggregate erythrocyte ALDH-1-catalyzed aldophosphamide oxidation,viz. 2.0 μmol/min, was only about 3% of estimated aggregate hepatic enzyme-catalyzed aldophosphamide oxidation,viz. 72 μmol/min; however, this rate is greater than the estimated flow-limited rate of aldophosphamide delivery to the liver by the blood, viz. 1.5 μmol/min. These observations/considerations suggest an important in vivorole for erythrocyte ALDH-1 in systemic aldophosphamide detoxification. Erythrocyte ALDH-1-effected oxidation of other aldehydes to their corresponding acids, e.g. retinaldehyde to retinoic acid, may also be of pharmacological and/or physiological significance since a wide variety of aldehydes are known to be substrates for ALDH-1.
Footnotes
-
Send reprint requests to: N. E. Sladek, Department of Pharmacology, University of Minnesota, 3–249 Millard Hall, 435 Delaware Street S. E., Minneapolis, MN 55455. E-mail:slade001{at}maroon.tc.umn.edu.
-
Supported by USPHS Grant CA 21737, Bristol-Myers Squibb Company Grant 100-R220, and DOA DAMD 17–94-J-4057.
-
↵2 P. A. Dockham and N. E. Sladek, unpublished observations, 1991.
-
↵3 M.-O. Lee and N. E. Sladek, unpublished observations, 1992.
- Abbreviations used are::
- ALDH-1
- human cytosolic class 1 aldehyde dehydrogenase
- Hb
- hemoglobin
- pI
- isoelectric point
- rbc
- red blood cell
- AUC
- area under the plasma concentration curve
- Received May 19, 1997.
- Accepted August 13, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|