Evaluation of the developmental toxicity of thalidomide using frog embryo teratogenesis assay-xenopus (FETAX): biotransformation and detoxification.
The developmental toxicity of thalidomide was evaluated using FETAX (Frog Embryo Teratogenesis Assay - Xenopus). Young X. Laevis embryos were exposed to this compound in each of two concentration-response experiments with and without differently induced exogenous metabolic activation systems (MASs) and/or inhibited MASs. Young male Sprague-Dawley rats were treated with either isoniazid or Aroclor 1254 to induce cytochrome P-450. Several of the rats were subsequently treated with diethyl maleate (DM) to deplete glutathione reserves. Specific aliquots of rat liver microsomes were treated with 3-amino-1,2,4-triazole (ATZ) or alpha-napthoflavone (alpha-N) to selectively inhibit P-450 activity. Bioactivation was indicated by increased developmental toxicity observed in MAS tests. Results obtained indicated that thalidomide was predominantly activated by P-450 isozyne CYP2E1, although weak cross-specificity between CYP1A1/A2 may have existed. Detoxification pathways for thalidomide were investigated by treatment of the MAS with cyclohexene oxide (CHO) and DM to inhibit the epoxide hydrolase and glutathione conjugation pathways, respectively. Results indicated that epoxide hydrolase was primarily responsible for the detoxification of bioactivated thalidomide. Teratogenesis Carcinog. Mutagen. 20:35-47, 2000.
Fort
D J
DJ
The Stover Group, Laboratory Services Division, Stillwater, Oklahoma 74074, USA. difort2@aol.com
Stover
E L
EL
Bantle
J A
JA
Finch
R A
RA
D000640:Amitrole / Q000494:pharmacology; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D001711:Biotransformation; D003510:Cyclohexanes / Q000494:pharmacology; D053138:Cyclohexenes; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000187:drug effects* / Q000378:metabolism; D047108:Embryonic Development; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005121:Extremities / Q000196:embryology / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D019055:No-Observed-Adverse-Effect Level; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens / Q000378:metabolism / Q000633:toxicity*; D013792:Thalidomide / Q000378:metabolism / Q000633:toxicity*; D018675:Toxicity Tests / Q000379:methods; D014982:Xenopus laevis / Q000196:embryology / Q000378:metabolism
D001571:Benzoflavones; D003510:Cyclohexanes; D053138:Cyclohexenes; D004791:Enzyme Inhibitors; D013723:Teratogens; C007193:cyclohexene oxide; D013792:Thalidomide; C011512:alpha-naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D000640:Amitrole