Hales B F
Teratology. 1981 Aug;24(1):1-11. doi: 10.1002/tera.1420240102.
Cyclophosphamide must be enzymatically activated to be either mutagenic or teratogenic. This activation is thought to be catalyzed by the cytochrome P-450 monooxygenase system. To study the relationship between the mutagenic and teratogenic metabolites of cyclophosphamide, the mutagenicity and teratogenicity of this drug were compared after activation by rats pretreated with chemicals (phenobarbital and beta-naphthoflavone) inducing different cytochromes P-450. Activation of cyclophosphamide to mutagenic metabolites by enzyme fractions from rats on day 13 of gestation was measured with the Ames test using Salmonella typhimurium TA1535. Teratogenicity was assessed in vivo by treatment of rats with cyclophosphamide on day 13 of gestation. Cyclophosphamide was activated to mutagenic metabolites to the same extent (on a tissue wet weight basis) by enzyme fractions from maternal liver, kidney and placenta, despite differences in cytochrome P-450 content. Fetal homogenates did not activate cyclophosphamide. Phenobarbital pretreatment increased the activation of cyclophosphamide to mutagenic metabolites by maternal liver microsomes 10-fold and liver cytochrome P-450 content 1.8 fold; however, this drug did not alter the activation of cyclophosphamide by maternal kidney, by placenta or by the fetus. Phenobarbital pretreatment increased the teratogenicity of cyclophosphamide in rats on day 13 of gestation (increased incidence of malformed embryos, decreased fetal weight). Pretreatment with beta-naphthoflavone did not induce liver cytochrome P-450 in the pregnant rat and did not change the activation of cyclophosphamide to mutagenic metabolites by liver, kidney, placenta or the fetus. Pretreatment with this polycyclic aromatic hydrocarbon had no effect or decreased the teratogenicity of cyclophosphamide. Thus, these experiments suggest that the mother, rather than the fetus, is the site of activation of cyclophosphamide; after phenobarbital pretreatment the predominant site of cyclophosphamide activation is the maternal liver. There appears to be a correlation between the teratogenicity and mutagenicity of cyclophosphamide after induction of the cytochromes P-450. We can speculate that the "proximate teratogen" of cyclophosphamide may also be the "proximate mutagen".
环磷酰胺必须经过酶促活化才能具有致突变性或致畸性。这种活化作用被认为是由细胞色素P - 450单加氧酶系统催化的。为了研究环磷酰胺的致突变和致畸代谢产物之间的关系，在用诱导不同细胞色素P - 450的化学物质（苯巴比妥和β - 萘黄酮）预处理的大鼠体内激活环磷酰胺后，比较了该药物的致突变性和致畸性。用鼠伤寒沙门氏菌TA1535的Ames试验测定妊娠第13天大鼠的酶组分将环磷酰胺活化为致突变代谢产物的情况。通过在妊娠第13天用环磷酰胺处理大鼠来评估其体内致畸性。尽管细胞色素P - 450含量存在差异，但母体肝脏、肾脏和胎盘的酶组分将环磷酰胺活化为致突变代谢产物的程度相同（以组织湿重为基础）。胎儿匀浆不能激活环磷酰胺。苯巴比妥预处理使母体肝脏微粒体将环磷酰胺活化为致突变代谢产物的能力提高了10倍，肝脏细胞色素P - 450含量增加了1.8倍；然而，这种药物并没有改变母体肾脏、胎盘或胎儿对环磷酰胺的活化作用。苯巴比妥预处理增加了妊娠第13天大鼠体内环磷酰胺的致畸性（畸形胚胎发生率增加，胎儿体重降低）。用β - 萘黄酮预处理未诱导孕鼠肝脏细胞色素P - 450，也未改变肝脏、肾脏、胎盘或胎儿将环磷酰胺活化为致突变代谢产物的能力。用这种多环芳烃预处理对环磷酰胺的致畸性没有影响或使其降低。因此，这些实验表明，环磷酰胺的活化部位是母体而非胎儿；苯巴比妥预处理后，环磷酰胺活化的主要部位是母体肝脏。细胞色素P - 450诱导后，环磷酰胺的致畸性和致突变性之间似乎存在相关性。我们可以推测，环磷酰胺的“直接致畸原”可能也是“直接致突变原”。
