RELATIVE CONTRIBUTION OF HUMAN ERYTHROCYTE ALDEHYDE DEHYDROGENASE TO THE SYSTEMIC DETOXIFICATION OF THE OXAZAPHOSPHORINES

Detoxification of cyclophosphamide is effected, in part, by hepatic cl ass 1 aldehyde dehydrogenase (ALDH-l)-catalyzed oxidation of aldophosp hamide, a pivotal aldehyde intermediate, to the nontoxic metabolite, c arboxyphosphamide, This enzyme is found in erythrocytes as well. Detox ification of aldophosphamide may also be effected by enzymes, viz, cer tain aldo-keto reductases, that catalyze the reduction of aldophospham ide to alcophosphamide. Such enzymes are also found in erythrocytes, N ot known at the onset of this investigation was whether the contributi on of erythrocyte ALDH-1 and/or aldo-keto reductases to the overall sy stemic detoxification of circulating aldophosphamide is significant. T hus, NAD-linked oxidation and NADPH-linked reduction of aldophosphamid e catalyzed by relevant erythrocyte enzymes were quantified. ALDH-1-ca talyzed oxidation of aldophosphamide (160 mu M) to carboxyphosphamide occurred at a mean (+/- SD) rate of 5.0 +/- 1.4 atmol/min/rbc (red blo od cell). Aldo-keto reductase-catalyzed reduction of aldophosphamide ( 160 mu M) to alcophosphamide occurred at a much slower rate, viz. 0.3 +/- 0.2 atmol/min/rbc. Thus, at a pharmacologically relevant concentra tion of aldophosphamide, vir. 1 mu M, estimated aggregate erythrocyte ALDH-1-catalyzed aldophosphamide oxidation, viz, 2.0 mu mol/min, was o nly about 3% of estimated aggregate hepatic enzyme-catalyzed aldophosp hamide oxidation, viz. 72 mu mol/min; however, this rate is greater th an the estimated flow-limited rate of aldophosphamide delivery to the liver by the blood, viz, 1.5 mu mol/min. These observations/considerat ions suggest an important in vivo role for erythrocyte ALDH-I in syste mic aldophosphamide detoxification, Erythrocyte ALDH-1-effected oxidat ion of other aldehydes to their corresponding acids, e.g. retinaldehyd e to retinoic acid, may also be of pharmacological and/or physiologica l significance since a wide variety of aldehydes are known to be subst rates for ALDH-1.