Teratogenicity induced in cultured rat embryos by the serum of procarbazine treated rats.

Male rats were injected with single intraperitoneal doses of 50-200 mg/kg of procarbazine hydrochloride (P). Their undiluted serum was then used as the culture medium for 9.5-day-old embryos to evaluate its teratogenic and toxic potential in vitro. A 48-h exposure to this medium resulted in a variety of dysmorphogenic effects. Somite, limb bud and otic vesicle deformities were seen at all dose levels, and neural tube and optic vesicle abnormalities were frequently observed in the 150 and 200 mg/kg groups. Embryonic growth and differentiation were only moderately affected at any dose levels. In a second set of experiments, embryos were directly exposed to 100-150 micrograms/ml P combined with a liver enzymatic activating system. No abnormalities were detected but toxicity occurred within narrow concentration ranges; 125 micrograms/ml affected growth and differentiation slightly, and 150 micrograms/ml suppressed the embryonic development severely. Exposure to 125 micrograms/ml P without the liver enzymatic activating system had no effect on embryonic growth and differentiation, suggesting that the metabolites responsible for the toxic effect were generated by the liver enzymatic preparation. Our results indicate that stable metabolites of P, responsible for its teratogenic action, are formed only within body compartments, whereas the formation of these metabolites does not take place in vitro in the presence of hepatic enzyme preparations.