The long-term effects of the rodenticide, brodifacoum, on blood coagulation and vitamin K metabolism in rats.
1. The long-term (30 days) effects of a single dose of brodifacoum (0.2 mg kg-1, orally) on blood clotting activity and on liver parameters of the vitamin K cycle were investigated in rats. Maximal effect on blood clotting activity was seen on day one. On day seven blood clotting activity had returned to normal. 2. Liver microsomal vitamin KO reductase activity was maximally suppressed (10% of control activity) on day one, steadily recovered to about 40% on day 15 to remain at that level. The same time course was seen for the number of microsomal warfarin binding sites. 3. The persistent inhibition of the vitamin K cycle was also verified in vivo; following vitamin K administration (10 mg kg-1, i.v.) on day 30, the brodifacoum-treated rats accumulated vitamin KO in the liver. 4. Although clotting factor synthesis was normal, brodifacoum-treated rats were highly sensitive to warfarin. 5. Brodifacoum rapidly accumulated in the liver until the saturation of the microsomal binding site. Brodifacoum binding to the target prevented its elimination from the liver; liver content on day 30 was not different from day 7. 6. The results show (1) an over capacity for the hepatocellular vitamin K cycle, (2) a dissociation of the vitamin K epoxidation and the vitamin K-dependent carboxylation, (3) the 'superwarfarin' rodenticides to be extremely persistent due to their binding to the target.
Mosterd
J J
JJ
Department of Pharmacology, University of Limburg, Maastricht, The Netherlands.
Thijssen
H H
HH
D015110:4-Hydroxycoumarins / Q000008:administration & dosage* / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D006899:Mixed Function Oxygenases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012378:Rodenticides / Q000008:administration & dosage* / Q000494:pharmacology; D013997:Time Factors; D014812:Vitamin K / Q000378:metabolism*; D064417:Vitamin K Epoxide Reductases
D015110:4-Hydroxycoumarins; D012378:Rodenticides; D014812:Vitamin K; C013418:bromfenacoum; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases