The emerging threat of superwarfarins: history, detection, mechanisms, and countermeasures

Feinstein, Douglas L.; Akpa, Belinda S.; Ayee, Manuela A.; Boullerne, Anne I.; Braun, David; Brodsky, Sergey V.; Gidalevitz, David; Hauck, Zane; Kalinin, Sergey; Kowal, Kathy; Kuzmenko, Ivan; Lis, Kinga; Marangoni, Natalia; Martynowycz, Michael W.; Rubinstein, Israel; Breemen, Richard B. van; Ware, Kyle; Weinberg, Guy

doi:10.1111/nyas.13085

Cited by 56 publications

(49 citation statements)

References 79 publications

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“…In addition to those drugs, several derivatives of warfarin, called superwarfarins, have been developed to serve as rodenticide. Superwarfarins, such as bromadiolone and brodifacoum, have a much higher affinity to VKORC1, a tendency to accumulate in tissues and a very long half-life in vivo, compared to warfarin and other therapeutic vitamin K antagonists [ 61 ]. Whether VKORC1 and VKORC1L1 are equally sensitive to warfarin and other vitamin K antagonists was unknown, until a series of recent studies began to address this question using in vitro and cell based assays.…”

Section: Vkorc1l1 Is Less Sensitive To Warfarin Than Vkorc1 In VImentioning

confidence: 99%

VKORC1L1, An Enzyme Mediating the Effect of Vitamin K in Liver and Extrahepatic Tissues

Lacombe

Ferron

2018

Nutrients

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Vitamin K is an essential nutrient involved in the regulation of blood clotting and tissue mineralization. Vitamin K oxidoreductase (VKORC1) converts vitamin K epoxide into reduced vitamin K, which acts as the co-factor for the γ-carboxylation of several proteins, including coagulation factors produced by the liver. VKORC1 is also the pharmacological target of warfarin, a widely used anticoagulant. Vertebrates possess a VKORC1 paralog, VKORC1-like 1 (VKORC1L1), but until very recently, the importance of VKORC1L1 for protein γ-carboxylation and hemostasis in vivo was not clear. Here, we first review the current knowledge on the structure, function and expression pattern of VKORC1L1, including recent data establishing that, in the absence of VKORC1, VKORC1L1 can support vitamin K-dependent carboxylation in the liver during the pre- and perinatal periods in vivo. We then provide original data showing that the partial redundancy between VKORC1 and VKORC1L1 also exists in bone around birth. Recent studies indicate that, in vitro and in cell culture models, VKORC1L1 is less sensitive to warfarin than VKORC1. Genetic evidence is presented here, which supports the notion that VKORC1L1 is not the warfarin-resistant vitamin K quinone reductase present in the liver. In summary, although the exact physiological function of VKORC1L1 remains elusive, the latest findings clearly established that this enzyme is a vitamin K oxidoreductase, which can support γ-carboxylation in vivo.

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Section: Vkorc1l1 Is Less Sensitive To Warfarin Than Vkorc1 In VImentioning

confidence: 99%

VKORC1L1, An Enzyme Mediating the Effect of Vitamin K in Liver and Extrahepatic Tissues

Lacombe

Ferron

2018

Nutrients

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“…Detection of AR requires rapid, sensitive and specific methods. Warfarin and its metabolites are regularly analysed by gas chromatography or high-performance liquid chromatography, but owing to larger mass and lower volatility of some of the AR, liquid chromatography–mass spectrometry has been considered a more suitable method [ 17 ]. Several analytical methods for detection of AR have been published [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Quantitative method for analysis of six anticoagulant rodenticides in faeces, applied in a case with repeated samples from a dog

et al. 2018

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BackgroundAccidental poisoning with anticoagulant rodenticides is not uncommon in dogs, but few reports of the elimination kinetics and half-lives in this species have been published. Our objectives were to develop and validate a new method for the quantification of anticoagulant rodenticides in canine blood and faeces using reversed phase ultra-high performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS) and apply the method on a case of anticoagulant rodenticide intoxication.ResultsSample preparation was liquid–liquid extraction. Six anticoagulant rodenticides were separated using a UPLC® BEH C18-column with a mobile phase consisting of 5 mM ammonium formate buffer pH 10.2 and methanol. MS/MS detection was performed with positive electrospray ionization and two multiple reaction monitoring transitions. The limits of quantification were set at the levels of the lowest calibrator (1.5–2.7 ng/mL or ng/g). The method was successfully applied to a case from a dog accidentally poisoned with anticoagulant rodenticide. Coumatetralyl and brodifacoum concentrations were determined from serial blood and faecal samples. A terminal half-life of at least 81 days for coumatetralyl in blood was estimated, which is longer than previous reported in other species. A slow elimination of brodifacoum from the faeces was found, with traces still detectable in the faeces at day 513.ConclusionsThis study offers a new method of detection and quantification of six frequently used anticoagulant rodenticides in canine faeces. Such drugs might cause serious health effects and it is important to be able to detect these drugs, to initiate proper treatment. The very long elimination half-lives detected in our study is important to be aware of in assessment of anticoagulant rodenticide burden to the environment.

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“…Vitamin K-dependent proteins not only function in coagulation but also in the CNS, where they are involved in maintaining normal brain cells and homeostasis. 12 , 13 Glutamine carboxylase plays an important role in neurons and neuroglia cells. In the CNS, a lack of vitamin K may decrease the activities of glutamine carboxylase and carboxylases of protein in the brain, resulting in reduced synthesis of sulfatide, which is an important inherent structure of medullary sheath.…”

Section: Discussionmentioning

confidence: 99%

Effects of bromadiolone poisoning on the central nervous system

Wang¹,

Yang²,

Hou³

et al. 2017

NDT

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Cases of rodenticide poisoning (second-generation long-acting dicoumarin rodenticide, superwarfarin) have occasionally been reported. The main symptoms of bromadiolone poisoning are skin mucosa hemorrhage, digestive tract hemorrhage, and hematuresis. However, the symptoms of central nervous system toxicity have rarely been reported. Our case reports on a 41-year-old male who had no contact with bromadiolone. His main symptoms were dizziness, unsteady gait, and abnormal behavior. Laboratory test results revealed the presence of bromadiolone in his blood and urine, a longer prothrombin time, activated partial thromboplastin time, and a high international normalized ratio. Magnetic resonance imaging of the brain showed that the bilateral posterior limb of the internal capsule, splenium of corporis callosum, and bilateral centrum semiovale formed symmetrical patch distribution. The patient gradually recovered after treated with vitamin K1 and plasma transfusion. Our clinical study could pave the way to improve the detection of bromadiolone poisoning and avoid misdiagnosis.

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The emerging threat of superwarfarins: history, detection, mechanisms, and countermeasures

Cited by 56 publications

References 79 publications

VKORC1L1, An Enzyme Mediating the Effect of Vitamin K in Liver and Extrahepatic Tissues

VKORC1L1, An Enzyme Mediating the Effect of Vitamin K in Liver and Extrahepatic Tissues

Quantitative method for analysis of six anticoagulant rodenticides in faeces, applied in a case with repeated samples from a dog

Effects of bromadiolone poisoning on the central nervous system

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