Evaluation of acetaminophen-induced developmental toxicity using FETAX.
Potential mechanisms of acetaminophen-induced developmental toxicity were evaluated using FETAX (Frog Embryo Teratogenesis Assay-Xenopus). Early Xenopus laevis embryos were exposed to acetaminophen for 96-h in two definitive concentrations-response assays with and without an exogenous metabolic activation system (MAS). Two static renewal tests of acetaminophen and the MAS treated with carbon monoxide, cimetidine, ellipticine, diethyl maleate, and supplemented with glutathione were also performed. Addition of the MAS decreased the 96-h LC50 and EC50 (malformation) values of unactivated acetaminophen 3.9-fold and 7.1-fold, respectively. Addition of the carbon monoxide- and ellipticine-inhibited MAS, as well as the glutathione-supplemented MAS decreased the developmental toxicity of activated acetaminophen to levels near that of the unactivated parent compound. Cimetidine-inhibited MAS also reduced the developmental toxicity of acetaminophen, but not to the extent observed with the carbon monoxide- and ellipticine-inhibited, or glutathione-supplemented MAS. Addition of the diethyl maleate-treated MAS substantially increased the developmental toxicity of acetaminophen. Results indicate that a highly reactive intermediate formed as the result of MFO-mediated metabolism (possibly P-448) significantly increased the developmental toxicity of acetaminophen. Glutathione was also found to play a major role in intermediate detoxification in vitro.
Fort
D J
DJ
Stover Biometric Laboratories, Inc., Stillwater, Oklahoma 74076.
Rayburn
J R
JR
Bantle
J A
JA
D000014:Abnormalities, Drug-Induced; D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001681:Biological Assay; D001711:Biotransformation; D002248:Carbon Monoxide / Q000494:pharmacology; D002927:Cimetidine / Q000494:pharmacology; D004611:Ellipticines / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014981:Xenopus / Q000196:embryology
D004611:Ellipticines; C034192:ellipticine; D000082:Acetaminophen; D002248:Carbon Monoxide; D002927:Cimetidine; D005978:Glutathione