Enhancement of rifampin teratogenicity in cultured rat embryos

The teratogenicity of the semisynthetic antibiotic rifampin (RIF) was investigated in rat embryos cultured from Days 10 to 11. Comparisons were made between the teratogenicity of RIF alone and RIF plus a rat liver fraction and cofactors for cytochrome P-450-mediated monooxygenation. Both groups were compared to vehicle controls. Rifampin without the metabolizing system caused significant retardation of growth but no significant increase in incidence of abnormalities (neural tube defects). Metabolism did not alter the growth-retarding action of the drug but did significantly increase the frequency of neural tube malformation. Exposure to RIF at concentrations from 12.5 to 100 micrograms/ml medium in the presence of the metabolizing system resulted in concentration-dependent decreases in embryo length, somite number, and protein content. The addition of metyrapone, an inhibitor of cytochrome P-450 activity, failed to prevent growth retardation but did reduce the incidence of malformations to a rate equal to that produced by the unmetabolized drug. No significant increases in malformation incidence or growth retardation were observed when embryos were cultured with the RIF metabolites, 3-formyl rifamycin, 25-deacetyl rifampin, or rifampin quinone.