Mutagenic activity of major mammalian metabolites of cyclophosphamide toward several genes ofEscherichia coli
- 31 October 1977
- journal article
- research article
- Published by Taylor & Francis in Journal of Toxicology and Environmental Health
- Vol. 3 (4), 637-650
- https://doi.org/10.1080/15287397709529598
Abstract
Representative intermediates of the major mammalian metabolic pathway of cyclophosphamide, a drug that is not mutagenic as such unless it is metabolically activated, were assayed for their direct mutagenic activity toward a bacterial indicator strain, Escherichia coli 343/113. The compounds tested were 4‐hydroperoxycyclophosphamide and the two urinary metabolites, carboxyphosphamide and 4‐ketocyclophosphamide. Further, the degradation products of 4‐hydroxycyclophosphamide, phosphoramide mustard, acrolein, and nornitrogen mustard, were also tested. The mutagenicity test systems were those used previously to demonstrate the liver enzyme‐mediated mutagenic activity of cyclophosphamide in E. coli 343/113: stationary cell suspensions were treated for 180 min at 37°C with different concentrations of the compound under test; the induction of forward mutations from 5‐methyltryptophan sensitivity to resistance (MTR) and from galRS 18 to gal+ as well as back mutations from argS6 to arg+ was measured by plating aliquots of the treated bacterial population on different selective mutation media. Except for acrolein, all cyclophosphamide metabolites tested are directly mutagenic toward E. coli 343/113. With all substances the highest induced mutation frequency is that of arg+ mutations, followed by gal+ and MTR mutations; this indicates that mostly base‐pair substitution type mutations are induced. The mutagenic potential, however, differs greatly between compounds at concentrations between 0.1 and 20 mM. The results show that the first step in the mammalian biodegradation of cyclophosphamide gives rise to compounds that are directly mutagenic, and that this mutagenicity is retained and even enhanced through all further metabolic steps to produce the compound of highest mutagenicity, nornitrogen mustard. Georges R. Mohn's present address is Department of Radiation Genetics and Chemical Mutagenesis, State University of Leiden, Wassenaarseweg 72, Leiden, The Netherlands.Keywords
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