RT Journal Article
SR Electronic
T1 Anticonvulsant toxicity in vitro: possible role of arene oxides.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 386
OP 389
VO 217
IS 2
A1 Spielberg, S P
A1 Gordon, G B
A1 Blake, D A
A1 Mellits, E D
A1 Bross, D S
YR 1981
UL http://jpet.aspetjournals.org/content/217/2/386.abstract
AB Human lymphocytes incubated with a mouse hepatic microsomal drug metabolizing system were used to study the cytotoxicity of four anticonvulsants. In vitro toxicity assessed by trypan blue dye exclusion was significantly greater for compounds with relatively high clinical toxicity (mephenytoin and phenacemide) than those with only rare cytotoxic complications (phenytoin and phenobarbital). No toxicity occurred in the absence of microsomes and toxicity was enhanced by inhibitors of epoxide hydrolase suggesting that the cytotoxicity of the drugs may result from arene oxide metabolites. In vivo, the covalent binding of such metabolites to cell macromolecules could lead to cell death and, by acting as haptens, to secondary hypersensitivity reactions. The method may be useful in assessing the potential of a drug for toxicity, the mechanism of cell damage and individual differences in cell defenses within the human population.