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

Serum from procarbazine (PCZ)-treated rats is dysmorphogenic to rat em bryos cultured in vitro, but PCZ is not effective when added directly to culture medium, even with an exogenous metabolizing system. Methyla zoxyprocarbazine (MPCZ) is a metabolite which we have identified by HP LC in the dysmorphogenic serum of PCZ-treated rats. PCZ, MPCZ, and ben zyl-azoxyprocarbazine (BPCZ, an isomer of MPCZ) were tested in rat who le embryo culture to determine their effects on embryo development. Th e parent compound, PCZ, produced no effect on embryo growth or develop ment at concentrations up to 200 mu g/ml. MPCZ proved to be the most p otent 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 3 5 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, f ailure of neural tube closure, erratic neural seam, and microcephaly. In contrast, BPCZ produced embryo lethality and reductions in DEVS onl y at 100 mu g/ml. These data suggest that MPCZ, which has been identif ied in PCZ-treated rat serum, may be the proximate dysmorphogenic meta bolite of PCZ. (C) 1994 Academic Press, Inc.