Production of cyclophosphamide metabolites by primary hepatocyte cultures from male and pregnant rats: Effect of Aroclor 1254 pretreatment

Abstract In a previous paper (VanAerts et al., Toxicology in Vitro 1993, 7 , 769–775) we have shown that the embryotoxicity of Cyclophosphamide was greatly enhanced when Cyclophosphamide had been added to a primary hepatocyte culture derived from Aroclor 1254-pretreated male rats (M A ) and the medium from this culture was added to a post-implantation rat embryo culture. However, when medium from hepatocytes that had been derived from untreated male rats (M C ), untreated pregnant rats (P C ) or Aroclor 1254-pretreated pregnant rats (P A ) was used embryotoxicity was low. We now present data on the concentrations of 4-ketocyclophosphamide, carboxyphosphamide and nornitrogen mustard in the primary hepatocyte culture media. 4-Ketocyclophosphamide was absent in media from P C or P A and present in low concentrations in media from M C and M A . Carboxyphosphamide and nornitrogen mustard were present in all media, but their concentrations were several times higher in medium from M A than in media from other sources. This indicates that Aroclor 1254 pretreatment enhances Cyclophosphamide metabolism much more in male rats than in pregnant rats. It is suggested that both a greater inducibility of CYP2B1 and augmented stabilization of 4-hydroxycyclophosphamide by glutathione conjugation may be processes that contribute to the observed differences in metabolite concentrations.