Evaluation of the developmental toxicities of coumarin, 4-hydroxycoumarin, and 7-hydroxycoumarin using FETAX.
The developmental toxicities of coumarin and hydroxycoumarin metabolites were evaluated using FETAX. Young X. laevis embryos were exposed to coumarin, 4-hydroxycoumarin, and 7-hydroxycoumarin in each of two separate concentration-response experiments with and without an exogenous metabolic activation system (MAS) and/or inhibited MAS. The MAS was treated with carbon monoxide (CO), cimetidine (CIM), or ellipticine (ELL) to selectively modulate cytochrome P-450 activity. The MAS was also treated with cyclohexene oxide (CHO) to selectively modulate epoxide hydrolase activity. Without the MAS or inhibited MAS, coumarin and 7-hydroxycoumarin were nearly equitoxic, whereas 4-hydroxycoumarin was nearly 2-fold less developmentally toxic than coumarin on an equimolar basis. Addition of the MAS and CIM-MAS increased the developmental toxicities of coumarin and, particularly, 4-hydroxycoumarin. Addition of the CHO-MAS greatly increased the developmental toxicity of coumarin and, especially, 4-hydroxycoumarin. Addition of the ELL- or CO-inhibited MAS did not increase the developmental toxicity of coumarin. However, addition of the intact MAS did not alter the developmental toxicity of 7-hydroxycoumarin. Results from these studies suggested that P-450; specifically ELL-inhibited P-450 (arylhydrocarbon hydroxylase) may have been responsible for increasing the developmental toxicity of coumarin. Furthermore, the increased toxicity of coumarin or 4-hydroxycoumarin following co-incubation with CHO-treated microsomes indicated that highly toxic epoxide intermediates may be produced from oxidative P-450 metabolism and that epoxide hydrolase may play a role in detoxification of the reactive intermediates.
Fort
D J
DJ
STOVER GROUP, Stillwater, OK, USA.
Stover
E L
EL
Propst
T
T
Hull
M A
MA
Bantle
J A
JA
D015110:4-Hydroxycoumarins / Q000493:pharmacokinetics / Q000633:toxicity*; D000014:Abnormalities, Drug-Induced; D000818:Animals; D001711:Biotransformation; D003374:Coumarins / Q000493:pharmacokinetics / Q000633:toxicity*; D003520:Cyclophosphamide / Q000633:toxicity; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014468:Umbelliferones / Q000493:pharmacokinetics / Q000633:toxicity*; D014981:Xenopus / Q000196:embryology*
D015110:4-Hydroxycoumarins; D003374:Coumarins; D014468:Umbelliferones; C031477:7-hydroxycoumarin; D003520:Cyclophosphamide; C030123:coumarin; C068805:4-hydroxycoumarin