The toxicity of niridazole in rat embryos in vitro.
The antischistosomal drug niridazole (NDZ) was found to be teratogenic in a concentration-dependent manner from 10 to 50 micrograms/ml (47-233 microM) in rat embryos cultured from day 10 to day 11. A striking malformation consisting of axial asymmetry in which the right side of the embryo showed severe necrosis was the predominant malformation. The drug showed significantly greater dysmorphogenic activity at low (5%) compared to high (20%) oxygen tensions in cultures. Coincubation of embryos and NDZ with an exogenous source of metabolic enzymes and cofactors (NADPH) failed to modify teratogenicity. Inclusion of CO in the culture atmosphere significantly reduced the malformation incidence as did preincubation of the drug with S-9 and cofactors in medium with low O2 tension. Treatment of gravida with NDZ up to and including the maternal-lethal dose failed to result in observable malformations despite the use of several routes of exposure. These data lead us to hypothesize that rat embryos are capable of performing the reductive activation of NDZ in a fashion analogous to the schistosome but that reductive extraembryonic metabolism may result in teratogenic bioinactivation.
D000818:Animals; D001711:Biotransformation; D002248:Carbon Monoxide / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000378:metabolism; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D005313:Fetal Death / Q000139:chemically induced; D066298:In Vitro Techniques; D008431:Maternal-Fetal Exchange; D009560:Niridazole / Q000378:metabolism / Q000633:toxicity*; D010100:Oxygen / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D013723:Teratogens / Q000378:metabolism
D013723:Teratogens; D002248:Carbon Monoxide; D009560:Niridazole; D010100:Oxygen