Dicoumarol: A Drug which Hits at Least Two Very Different Targets in Vitamin K Metabolism

Abstract

Dicoumarol, a symmetrical biscoumarin can be considered as the "parent" of the widely used anticoagulant drug, warfarin. The discovery of dicoumarol's bioactive properties resulted from an investigation into a mysterious cattle disease in the 1940s. It was then developed as a pharmaceutical, but was superseded in the 1950s by warfarin. Both dicoumarol and warfarin antagonise the blood clotting process through inhibition of vitamin K epoxide reductase (VKOR). This blocks the recycling of vitamin K and prevents the γ-carboxylation of glutamate residues in clotting factors.VKOR is an integral membrane protein and our understanding of the molecular mechanism of action of dicoumarol and warfarin is hampered by the lack of a three dimensional structure. There is consequent controversy about the membrane topology of VKOR, the location of the binding site for coumarin inhibitors and the mechanism of inhibition by these compounds. Dicoumarol (and warfarin) also inhibit a second enzyme, NAD(P)H quinone oxidoreductase 1 (NQO1). This soluble, cytoplasmic enzyme may also play a minor role in the recycling of vitamin K. However, its main cellular roles as an enzyme appear to be detoxification and the prevention of the build-up of reactive oxygen species. NQO1 is well characterised biochemically and structurally. Consequently, structurebased drug design has identified NQO1 inhibitors which have potential for the development of anticancer drugs. Many of these compounds are structurally related to dicoumarol and some have reduced "off target" effects. Therefore, it is possible that dicoumarol will become the "parent" of a second group of drugs.

Warfarin and vitamin K epoxide reductase: a molecular accounting for observed inhibition

“…23,24 However, a recent study suggests that warfarin competitively inhibits VKOR by competing with vitamin K. 25 Several studies modeling warfarin's action within model structures of VKOR have identified residues that potentially interact with warfarin. 25,26 However, no direct interaction between warfarin and the experimentally supported TY 139 A warfarinbinding motif has been observed. It is worth noting that these modeling studies used a 4-TM topology model of human VKOR, derived from the crystal structure of Syn-VKOR, which appears to have a different topological structure from human VKOR.…”

Warfarin related acute kidney injury: A case report

“…Warfarin is mainly metabolized by CYP-2CP microsomal liver enzymes, which is affected by a multitude of different environmental factors, diet, drug interactions, and genetics, especially CYP2 complex mutations which can alter the pharmacokinetics and pharmacodynamics of warfarin metabolism leading to toxicity and prolonged international normalized ratio (INR). [1] The prothrombin time, standardized as the INR, is used to monitor warfarin anticoagulation. Warfarin-related nephropathy (WRN) is a recently reported clinical entity, secondary to a prolonged INR.…”

Targeting HIF-1α Function in Cancer through the Chaperone Action of NQO1

“…Importantly, the rate of this reductive half-reaction is strictly NADH-dependent, and thus, should be accelerated due to the HIF-mediated enhancement of aerobic glycolysis (raising cytosolic NADH levels, section 1.3.1); in a second and slower step (with a rate constant of 10 5 -10 6 M -1 •s -1 ), the oxidative half-reaction, the substrate binds and is reduced by the FADH2, thus releasing the reduced substrate and regenerating the holo-enzyme [76,79]. Dicoumarol, a potent anticoagulant and mitochondrial uncoupling agent, acts as a competitive inhibitor of NAD(P)H during the NQO1 cycle (Table A1) [87]. The high level of NQO1 expression in some cancer cells, coupled with its role in defence against ROS, has led to the suggestion that NQO1 inhibition may be a novel therapy for the disease.…”