Elevated Warfarin Metabolism in Warfarin-Resistant Roof Rats (<i>Rattus rattus</i>) in Tokyo

Ishizuka, Mayumi; Okajima, Fumie; Tamada, Tsutomu; Min, Heewon; Tanaka, Kazuyuki; Sakamoto, Kentaro Q.; Fujita, Shoichi

doi:10.1124/dmd.106.011775

Cited by 61 publications

(75 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…One important hypothesis surrounding vkorc1 sequence polymorphisms in rodents posits a role for selection with anticoagulant rodenticides such as warfarin [7,10,11,17,30,31]. In particular, tests for selection on specific mutations that occur in a population may provide further support for their roles in mediating anticoagulant resistance.…”

Section: Resultsmentioning

confidence: 99%

“…coumadin) responsiveness in humans [9]. However, the physiological response to anticoagulants can also be affected or modified by other genes, including cytochrome P450 genes in roof rats from Japan [10] and in humans ( cytochrome P450 2C9 ) (e.g. [9]).…”

Section: Introductionmentioning

confidence: 99%

“…As for Norway rats and house mice, variation in tolerance towards rodenticides has been observed for the roof rat [e.g. [10,13]]. Geographic mapping of vkorc1 SNPs in this species across the globe is required, especially in areas where the roof rat is considered a nuisance species.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Analysis of vkorc1 polymorphisms in Norway rats using the roof rat as outgroup

et al. 2010

View full text Add to dashboard Cite

BackgroundCertain mutations in the vitamin K epoxide reductase subcomponent 1 gene (vkorc1) mediate rodent resistance to warfarin and other anticoagulants. Testing for resistance often involves analysis of the vkorc1. However, a genetic test for the roof rat (Rattus rattus) has yet to be developed. Moreover, an available roof rat vkorc1 sequence would enable species identification based on vkorc1 sequence and the evaluation of natural selection on particular vkorc1 polymorphisms in the Norway rat (R. norvegicus).ResultsWe report the coding sequence, introns and 5' and 3' termini for the vkorc1 gene of roof rats (R. r. alexandrinus and R. r. frugivorus) from Uganda, Africa. Newly designed PCR primers now enable genetic testing of the roof rat and Norway rat. Only synonymous and noncoding polymorphisms were found in roof rats from Uganda. Both nominal subspecies of roof rats were indistinguishable from each other but were distinct from R. losea and R. flavipectus; however, the roof rat also shares at least three coding sequence polymorphisms with R. losea and R. flavipectus. Many of recently published vkorc1 synonymous and non-synonymous single nucleotide polymorphisms (SNPs) in Norway rats are likely SNPs from roof rats and/or other Rattus species. Tests applied to presumably genuine Norway rat vkorc1 SNPs are consistent with a role for selection in two populations carrying the derived Phe63Cys and Tyr139Cys mutations.ConclusionGeographic mapping of vkorc1 SNPs in roof rats should be facilitated by our report. Our assay should be applicable to most species of Rattus, which are intermediate in genetic distance from roof and Norway rats. Vkorc1-mediated resistance due to non-synonymous coding SNPs is not segregating in roof rats from Uganda. By using the roof rat sequence as a reference vkorc1, SNPs now can be assigned to the correct rat species with more confidence. Sampling designs and genotyping strategies employed so far have helped detect candidate mutations underlying vkorc1-mediated resistance, but generally provided unsuitable data to test for selection. We propose that our understanding of vkorc1-mediated evolution of resistance in rodents would benefit from the adoption of sampling and genotyping designs that enable tests for selection on vkorc1.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Analysis of vkorc1 polymorphisms in Norway rats using the roof rat as outgroup

et al. 2010

View full text Add to dashboard Cite

show abstract

“…The resistance to AVKs was proposed to be supported by two major mechanisms in rodents 1/a metabolic resistance due to an accelerated detoxification system involving cytochrome P‐450 (Ishizuka et al., 2007; Sugano et al., 2001) and 2/a target resistance due to the inefficiency of AVKs to specifically inhibit the vitamin K epoxide reductase (VKOR) activity. This VKOR activity is involved in the recycling of vitamin K by allowing the reduction in vitamin K epoxide in vitamin K quinone.…”

Section: Introductionmentioning

confidence: 99%

Adaptative evolution of the Vkorc1 gene in Mus musculus domesticus is influenced by the selective pressure of anticoagulant rodenticides

Goulois

Lambert

Legros³

et al. 2017

Ecology and Evolution

View full text Add to dashboard Cite

Anticoagulant rodenticides are commonly used to control rodent pests worldwide. They specifically inhibit the vitamin K epoxide reductase (VKORC1), which is an enzyme encoded by the Vkorc1 gene, involved in the recycling of vitamin K. Therefore, they prevent blood clotting. Numerous mutations of Vkorc1 gene were reported in rodents, and some are involved in the resistant to rodenticides phenotype. Two hundred and sixty‐six mice tails were received from 65 different locations in France. Coding sequences of Vkorc1 gene were sequenced in order to detect mutations. Consequences of the observed mutations were evaluated by the use of recombinant VKORC1. More than 70% of mice presented Vkorc1 mutations. Among these mice, 80% were homozygous. Contrary to brown rats for which only one predominant Vkorc1 genotype was found in France, nine missense single mutations and four double mutations were observed in house mice. The single mutations lead to resistance to first‐generation antivitamin K (AVKs) only and are certainly associated with the use of these first‐generation molecules by nonprofessionals for the control of mice populations. The double mutations, probably obtained by genetic recombination, lead to in vitro resistance to all AVKs. They must be regarded as an adaptive evolution to the current use of second‐generation AVKs. The intensive use of first‐generation anticoagulants probably allowed the selection of a high diversity of mutations, which makes possible the genetic recombination and consequently provokes the emergence of the more resistant mutated Vkorc1 described to date.

show abstract

“…Pelz et al reported that the 139 tyrosine substitution to phenylalanine caused the greatest level of insensitivity of VKOR to warfarin when this mutated enzyme was expressed in HEK 293 cells [11]. More recently, an alternative mechanism of warfarin resistance has been suggested which involves the acceleration of warfarin excretion by the cytochrome P450 system in resistant black rats in Japan [3].…”

mentioning

confidence: 99%

A Novel Mutation in VKORC1 and Its Effect on Enzymatic Activity in Japanese Warfarin-Resistant Rats

Tanaka

Kawai

Ikenaka

et al. 2013

The Journal of Veterinary Medical Science

Self Cite

View full text Add to dashboard Cite

ABSTRACT. Warfarin is a rodenticide commonly used worldwide. It inhibits coagulation of blood by inhibiting vitamin K 2,3-epoxide reductase (VKOR) activity. An inadequate supply of vitamin K blocks the production of prothrombin and causes hemorrhage. Recently, warfarin-resistant brown rats (Rattus norvegicus) were found around the Aomori area of Japan. There is no significant difference in the metabolic activity of warfarin in sensitive and resistant brown rats. To clarify the mechanism underlying warfarin resistance, we cloned the VKORC1 gene from rats and identified a novel substitution of arginine to proline at position 33 of the VKORC1 amino acid sequence. Then, we determined the differences in kinetics of VKOR activity between warfarin-resistant and sensitive rats. Hepatic microsomal VKOR-dependent activity was measured over a range of vitamin K epoxide concentrations from 6.25 to 150 µM. The V max values of resistant rats (0.0029 ± 0.020 nmol/min/mg) were about one tenth of those of sensitive rats (0.29 ± 0.12 nmol/min/mg). The K m values of resistant rats (47 ± 32 µM) were similar to those of sensitive rats (59 ± 18 µM). Warfarin-sensitive rats exhibited enzyme efficiencies (V max /K m ) which were ten-fold greater than those observed in resistant rats. It may mean that VKOR activity of warfarin-resistant Aomori rats is almost lost, because their enzymatic efficiencies are very low even without warfarin. Further studies are needed to clarify how these rats can survive with a markedly reduced VKOR activity and how they simultaneously exhibit warfarin resistance.

show abstract

Elevated Warfarin Metabolism in Warfarin-Resistant Roof Rats (Rattus rattus) in Tokyo

Cited by 61 publications

References 21 publications

Analysis of vkorc1 polymorphisms in Norway rats using the roof rat as outgroup

Analysis of vkorc1 polymorphisms in Norway rats using the roof rat as outgroup

Adaptative evolution of the Vkorc1 gene in Mus musculus domesticus is influenced by the selective pressure of anticoagulant rodenticides

A Novel Mutation in VKORC1 and Its Effect on Enzymatic Activity in Japanese Warfarin-Resistant Rats

Contact Info

Product

Resources

About