The teratogenicity of cytochalasin D and its inhibition by drug metabolism.
Pregnant rats received intraperitoneal injections of cytochalasin D (CD) on gestational days 7-11. Doses of 400 micrograms/kg were only minimally and nonsignificantly teratogenic, leading to 2 exencephalic fetuses among the 111 fetuses delivered. By contrast, embryos exposed to CD in vitro on day 10 showed significant frequencies of neural tube abnormalities when exposed to CD concentrations at or above 3.1 ng/ml. These embryos also exhibited significantly decreased protein, somite counts, and crown-rump lengths. In order to understand this apparent discrepancy between the teratogenicity of CD in vivo and in vitro we performed experiments to determine whether drug metabolism could inhibit the teratogenicity in vitro. Male rats were pretreated with a mixture of polychlorinated biphenyls as cytochrome P-450 inducers, and their livers were used to prepare a microsome-rich fraction (S-9). This S-9 fraction, plus a source of reducing equivalents (NADPH), significantly inhibited the teratogenicity of CD. The teratogenicity was restored by the omission of NADPH, and was partially restored with the addition of carbon monoxide. These results led us to conclude that the teratogenic effect of CD can be inhibited by drug metabolism in vitro; additionally, it is likely that some or all of this drug metabolism may depend on cytochrome P-450. We further speculate that CD may be inactivated in vivo by these same systems, explaining the discrepancy between the teratogenicity of CD in vivo and in vitro.
D000818:Animals; D001711:Biotransformation; D003572:Cytochalasins / Q000378:metabolism / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D013723:Teratogens; D013997:Time Factors
D003572:Cytochalasins; D013723:Teratogens; D003577:Cytochrome P-450 Enzyme System