Page 623 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

588 SECTION | VIII Rodenticides

VetBooks.ir Anticoagulant rodenticides produce some biochemical Pathway II mediates the therapeutic effect of vitamin K 1
and resulting carboxylation in vitro (Wallin, 1986).
effect by interfering with the enzyme vitamin K 1 epoxide
Vitamin K and vitamin K 1 epoxide can be measured
reductase, resulting in the depletion of vitamin K 1
and, subsequently, impairing the synthesis of gamma- in serum (Bjornsson et al., 1979; Donnahey et al., 1979)
carboxylated clotting factors II, VII, IX, and X (Craciun and tissue. A number of vitamin K detection methods
et al., 1997, 1998). Clinical coagulopathy soon follows have been reported (Haroon et al., 1987; Haroon and
the depletion of vitamin K 1 . Since these clotting factors Hauschka, 1983; Haroon et al., 1980; Haroon et al., 1986,
have finite plasma half-lives of, e.g., 41, 6.2, 13.9, and Hart et al., 1984; Williams et al., 1972), including detec-
16.5 h in the dog, respectively, a lag time of 3 5days tion in human plasma (Langenberg and Tjaden, 1984) and
is commonly observed between ingestion of bait and serum (Lefevere et al., 1979) using HPLC with electro-
the onset of clinical signs (Jackson and Suttie, 1977; chemical detection (Takani and Suttie, 1983), or fluori-
Suttie, 1986; Murphy and Gerken, 1989). The interrela- metric detection in liver (Usui et al., 1989). The mode of
tionship of vitamin K, prothrombin, and gamma- action of vitamin K has been reviewed (Olson, 1966).
carboxyglutamic acid are reviewed in Stenflo (1978). Because anticoagulant rodenticides inhibit the
The interaction of warfarin and vitamin K reviewed in vitamin K 1 reductase reaction (Pelz et al., 2005) vita-
Suttie (1990). min K 1 epoxide is elevated and vitamin K 1 is reduced.
Microsomal vitamin K dependent carboxylase, vita- For example, diphenadione- (Mount and Kass, 1989)
min K epoxidase, vitamin K 1 epoxide reductase, and and warfarin-exposed dogs (Carlisle and Blaschke,
cytosolic vitamin K reductase (DT-diaphorase) are 1981) have elevated vitamin K 1 epoxide after SC vita-
involved in vitamin K reduction (Hildebrandt and Suttie, min K 1 administration.
1982). The physiologically important site of action of Also, vitamin K 1 concentrations are low-to-
the anticoagulant rodenticides has been reported to be nondetectable in rats 24 h after exposure to difenacoum
vitamin K 1 epoxide reductase (Hildebrandt and Suttie, (Winn et al., 1987). Measurement of the epoxide in serum
1982). Anticoagulant rodenticides act by inhibiting has been proposed as a method to detect surreptitious
vitamin K 1 -2,3 epoxide reductase and, consequently, exposure (Bechtold et al., 1983; Bechtold and Jahnchen,
the synthesis of clotting factors II, VII, IX and X. 1979). The disposition of vitamin K in anticoagulant
S-warfarin and difenacoum are more potent in complete rodenticide poisoning was examined some years ago
inhibition of clotting factor synthesis than racemic (Park et al., 1984).
warfarin, R-warfarin, or brodifacoum (Breckenridge Other mechanism of action: The anticoagulant rodenti-
et al., 1985). cides and oral anticoagulants are also of interest in cancer
The greater potency and duration of action of the research. In part, because catalyzing obligatory two-
long-acting or “superwarfarins” has been attributed to (1) electron reductions of quinones to hydroquinones, NAD
a greater affinity for vitamin K 1 -2,3-epoxide reductase, (P)H: quinone reductase (QR1) protects cells against the
(2) ability to inhibit the vitamin K 1 epoxide cycle at more deleterious effects of redox cycling of quinones and their
than one point, (3) hepatic accumulation, and (4) unusu- ability to deplete glutathione and produce neoplasia
ally long half-lives due to lipid solubility, enterohepatic (Dinkova and Talalay, 2000). DT-diaphorase and coen-
circulation, or both (Watt et al., 2005). The two diastereo- zyme Q appear to have both antioxidant and prooxidant
mers of brodifacoum may have different conformational functions in quinone metabolism (Cadenas, 1995; Beyer,
alignment with vitamin K epoxide reductase (Cort and 1994), and have recently been investigated as modulators
Cho, 2009). of inflammation.
As it turns out, rat liver has two pathways for vitamin
K reduction. One is responsible for the therapeutic effect
of vitamin K 1 therapy. This pathway is DT-diaphorase Metabolism
(EC.1.6.99.2) and a microsomal dehydrogenase that has Warfarin is metabolized by CYP 2C9 and 2C19 in
3.6 fold higher activity with NADH than with NADPH. It humans (Brandon et al., 2005; Goldstein, 2001). The CYP
is not a cytochrome P-450 or cytochrome-b5 reductase 2C9 enzyme has several inherited polymorphisms
(Wallin, 1986). Although dicoumarol, warfarin, and (Kirchheiner and Brockmoller, 2005). Chlorophacinone
diphenadione inhibit NADPH in rat liver in vitro, only elimination may be enhanced by phenobarbital adminis-
dicoumarol inhibited the enzyme in rats dosed in vivo tration (Burocoa et al., 1989; Lagrange et al., 1999), per-
(Schor et al., 1983). haps due to CYP induction. The effect of phenobarbitone
Pathway I is inactive in warfarin- and difenacoum- on vitamin K 1 metabolism (Wilson and Park, 1984) can
intoxicated rats. Vitamin K 1 epoxide reductase was be compared to that of the rabbit (Winn et al., 1988)
also inactive, so this may be part of Pathway I in vivo. (Fig. 46.1).