Comparison of the mutagenicity and teratogenicity of cyclophosphamide and its active metabolites, 4-hydroxycyclophosphamide, phosphoramide mustard, and acrolein

Hales, B.F.

Cancer Research 42(8): 3016-3021


ISSN/ISBN: 0008-5472
PMID: 7046914
Accession: 005014993

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Cyclophosphamide must be metabolically activated to have maximal mutagenic or teratogenic activity. The 1st step in this activation is hydroxylation to 4-hydroxycyclophosphamide; this metabolite breaks down to form 2 cytotoxic metabolites, phosphoramide mustard and acrolein. 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 NADP; phosphoramide mustard and 4-hydroperoxycyclophosphamide were mutagenic without activation, with the latter being the most potent. The 3rd 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 4 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; phosphoramide mustard produced only hydrocephaly and tail, forelimb and hindlimb defects. 4-Hydroperoxycyclophosphamide and its breakdown product, acrolein, were more potent as teratogens than cyclophosphamide or phosphoramide mustard. Cyclophosphamide produced malformations in both the injected and contralateral uninjected fetuses; the other 3 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.