Analysis of the mechanism of isoniazid-induced developmental toxicity with frog embryo teratogenesis assay: Xenopus (FETAX).
The developmental toxicity of isoniazid (INH) and the metabolites acetylhydrazide (AH) and isonicotinic acid (INA) were examined with the frog embryo teratogenesis assay-Xenopus (FETAX). Late Xenopus laevis blastulae were exposed to INH, AH, and INA for 96 h in two separate static-renewal tests with and without the presence of three differently induced metabolic activation systems (MAS). The MAS consisted of uninduced, Aroclor 1254-induced, and INH-induced rat liver microsomes. Addition of the INH-induced MAS decreased the 96 h LC50 of INH and AH approximately 1.6-fold and 7.9-fold, respectively. The 96 h EC50 (malformation) of INH was virtually unaffected; however, the INH-MAS decreased the teratogenic index (TI) [96 h LC50/96 h EC50 (malformation)] nearly 1.8-fold. The 96 h EC50 (malformation) of AH increased approximately 2.0-fold, decreasing the teratogenic index value 15.8-fold. INA yielded a teratogenic index value of 2.5. Neither the uninduced MAS nor the Aroclor 1254-induced MAS had an effect on any of the compounds tested and none of the MAS affected the developmental toxicity of INA. Results from this study suggest that mixed functional oxidase metabolism may alter the developmental toxicity of INH in vitro by producing a more embryolethal, but less teratogenic metabolite(s) than INH or AH themselves. Results are indicative of the utility and versatility of FETAX in evaluating toxicological mechanisms of teratogenesis in vitro.
Fort
D J
DJ
Department of Zoology, Oklahoma State University, Stillwater 74078.
Bantle
J A
JA
D000818:Animals; D001711:Biotransformation; D001755:Blastocyst / Q000187:drug effects*; D004625:Embryo, Nonmammalian / Q000187:drug effects; D005260:Female; D006834:Hydrazines / Q000633:toxicity; D007538:Isoniazid / Q000633:toxicity*; D007539:Isonicotinic Acids / Q000633:toxicity*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013723:Teratogens; D014982:Xenopus laevis
D006834:Hydrazines; D007539:Isonicotinic Acids; D013723:Teratogens; C014949:acetylhydrazine; D007538:Isoniazid