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 benzylazoxyprocarbazine (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 micrograms/ml. MPCZ proved to be the most potent of the agents tested. There was significant embryo lethality at concentrations of > or = 10 micrograms/ml while 25 micrograms/ml had significantly reduced embryonic developmental score (DEVS), and 35 micrograms/ml reduced DEVS, head length, and somite number. There was 89% embryo lethality at the 50 micrograms/ml exposure level. At concentrations > 5 micrograms/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 micrograms/ml. These data suggest that MPCZ, which has been identified in PCZ-treated rat serum, may be the proximate dysmorphogenic metabolite of PCZ.
Andrews
J E
JE
Developmental Toxicology Division, USEPA, Research Triangle Park, North Carolina 27711.
Ebron-McCoy
M
M
Copeland
F
F
Glennon
J J
JJ
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004622:Embryo, Mammalian / Q000187:drug effects*; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009924:Organ Culture Techniques; D011344:Procarbazine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D011344:Procarbazine; C077958:benzylazoxyprocarbazine; C059318:methylazoxyprocarbazine