EVALUATION OF THE DYSMORPHOGENIC EFFECTS OF PROCARBAZINE, BENZYLAZOXYPROCARBAZINE, AND METHYLAZOXYPROCARBAZINE IN WHOLE-EMBRYO CULTURE

Serum from procarbazine (PCZ)-treated rats is dysmorphogenic to rat embryos cultured in vitro, but PCZ is not effective when added directly to culture medium, even with an exogenous metabolizing system. Methylazoxyprocarbazine (MPCZ) is a metabolite which we have identified by HPLC in the dysmorphogenic serum of PCZ-treated rats. PCZ, MPCZ, and benzyl-azoxyprocarbazine (BPCZ, an isomer of MPCZ) were tested in rat whole embryo culture to determine their effects on embryo development. The parent compound, PCZ, produced no effect on embryo growth or development at concentrations up to 200 mu g/ml. MPCZ proved to be the most potent of the agents tested. There was significant embryo lethality at concentrations of greater than or equal to 10 mu g/ml while 25 mu g/ml had significantly reduced embryonic developmental score (DEVS), and 35 mu g/ml reduced DEVS, head length, and somite number. There was 89% embryo lethality at the 50 mu g/ml exposure level. At concentrations >5 mu g/ml, there were significant increases in anomalies, primarily, failure of neural tube closure, erratic neural seam, and microcephaly. In contrast, BPCZ produced embryo lethality and reductions in DEVS only at 100 mu g/ml. These data suggest that MPCZ, which has been identified in PCZ-treated rat serum, may be the proximate dysmorphogenic metabolite of PCZ. (C) 1994 Academic Press, Inc.