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Comparison of the Mutagenicity and Teratogenicity of Cyclophosphamide and Its Active Metabolites, 4-Hydroxycyclophosphamide, Phosphoramide Mustard, and Acrolein¹

Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada H3G 1Y6

Cyclophosphamide must be metabolically activated to have maximal mutagenic or teratogenic activity. The first step in this activation is hydroxylation to 4-hydroxycyclophosphamide; this metabolite breaks down to form two cytotoxic metabolites, phosphoramide mustard and acrolein. In this report, the mutagenicity and teratogenicity of cyclophosphamide, 4-hydroperoxycyclophosphamide (which forms 4-hydroxycyclophosphamide spontaneously in solution), phosphoramide mustard, and acrolein were compared. Mutagenicity was assessed using a Salmonella typhimurium TA 1535 test system; teratogenicity was studied in rats on Day 20 of gestation after intraamniotic injection of drug on Day 13. The activation of cyclophosphamide to mutagenic metabolites was dependent on the presence of liver microsomes and reduced nicotinamide adenine dinucleotide phosphate while both phosphoramide mustard and 4-hydroperoxycyclophosphamide were mutagenic without activation, with the latter being the most potent. The third metabolite, acrolein, was bacteriotoxic at low concentrations; it was not mutagenic in the absence and only very weakly mutagenic in the presence of liver microsomes. All four compounds tested were teratogenic. The malformations produced by cyclophosphamide, 4-hydroperoxycyclophosphamide, and acrolein included edema, hydrocephaly, open eyes, cleft palate, micrognathia, omphalocele, bent tail, and forelimb and hindlimb defects, whereas phosphoramide mustard produced only hydrocephaly and tail, forelimb, and hindlimb defects. 4-Hydroperoxycyclophosphamide and its breakdown product, acrolein, were more potent as teratogens than either cyclophosphamide or phosphoramide mustard. Cyclophosphamide produced malformations in both the injected and contralateral uninjected fetuses while the other three compounds all produced malformations only in the injected fetuses. Thus, the site of activation of cyclophosphamide to a teratogen is probably maternal. Because acrolein plays a major role in the teratogenicity of cyclophosphamide but is only weakly, if at all, mutagenic, the teratogenicity and mutagenicity of metabolites of this drug are dissociable.

¹ This work was supported by the Medical Research Council of Canada (Grant MA-7078) and the Conseil de la Recherche en Santé du Québec. Part of this material has been published previously in abstract form (20).

² Scholar of the Medical Research Council of Canada.

Received 12/28/81. Accepted 5/ 3/82.

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