NADPH-DEPENDENT ENZYME-CATALYZED REDUCTION OF ALDOPHOSPHAMIDE, THE PIVOTAL METABOLITE OF CYCLOPHOSPHAMIDE

One of the metabolites found in the urine of mammals given the prodrug cyclophosphamide is alcophosphamide, an alcohol. It is most probably generated from cyclophosphamide via aldophosphamide, an aldehyde which otherwise can directly give rise to phosphoramide mustard; the latter effects the cytotoxic action of cyclophosphamide and other oxazaphosp horines. It has already been demonstrated that horse liver alcohol deh ydrogenase catalyzes the reduction of aldophosphamide to alcophosphami de. Herein, we report that aldose reductase and aldehyde reductase pur ified from human placenta also catalyze this reaction. The K(m) values for aldose reductase- and aldehyde reductase-catalyzed reduction of a ldophosphamide to alcophosphamide were 0.15 and 1.6 mM, respectively. Aldose reductase and aldehyde reductase accounted for 94 and 6%, respe ctively, of total placental pyridine nucleotide-dependent enzyme-catal yzed aldophosphamide (160 muM) reduction. Aldose reductase-catalyzed r eduction of aldophosphamide appeared to be noncompetitively inhibited by sorbinil; the K(i) value was 0.4 muM. The in vivo significance of t hese observations is uncertain but could be of some magnitude since al cophosphamide is known to be only weakly cytotoxic.