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Thromb Haemost 1986; 55(02): 235-239
DOI: 10.1055/s-0038-1661528
Original Article
Schattauer GmbH Stuttgart

Vitamin K Antagonism of Coumarin Intoxication in the Rat

R Wallin
The Departments of Physiology and Medicine, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pennsylvania, USA
,
D Susan
The Departments of Physiology and Medicine, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pennsylvania, USA
,
D Patrick
The Departments of Physiology and Medicine, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pennsylvania, USA
,
J O Ballard
The Departments of Physiology and Medicine, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pennsylvania, USA
› Author Affiliations
Further Information

Publication History

Received 20 November 1985

Accepted 06 February 1986

Publication Date:
18 July 2018 (online)

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Summary

An in vitro system which expresses all enzyme activities related to vitamin K-dependent carboxylation of blood clotting factors was prepared from livers of rats overdosed with warfarin, difenacoum and dicumarol respectively. In this system, the activities of the two pathways that are known to produce active reduced vitamin K1 cofactor for the carboxylation reaction were measured. Also the ability of high concentrations of vitamin Kx to overcome inhibition of clotting factor synthesis was studied. In the systems prepared from livers of warfarin and difenacoum intoxicated rats, pathway I was inactive. Vitamin K epoxide reductase was also inactive which strongly suggests that this enzyme catalyzes the activity of pathway I in vivo. Reduction of vitamin by pathway II bypassed the inactive pathway I and resulted in carboxylation activity. This pathway therefore mediates the antidotic effect of vitamin K1 in the coumarin intoxicated liver. In the in vitro system prepared from dicumarol intoxicated livers the activity of pathway I was not significantly affected. Dicumarol however was a strong inhibitor when added to liver microsomes in vitro.

Key words

Coumarin - Vitamin K - Anticoagulants
 

  • References

  • 1 Suttie JW, Vitamin K. In The Fat-Soluble Vitamins, Handbook of Lipid Research. Volume 2 DeLuca HF. (ed.) Plenum Press; New York: 1978: 211-277
    Google Scholar
  • 2 Suttie JW, Jackson CM. Prothrombin structure, activation, and biosynthesis. Physiol Rev 1977; 57: 1-70
    CrossrefPubMedGoogle Scholar
  • 3 O’Reilly RA. Vitamin K and the oral anticoagulant drugs. Ann Rev Med 1976; 27: 245-261
    CrossrefPubMedGoogle Scholar
  • 4 Wallin R, Martin LF. Vitamin K-dependent carboxylation and vitamin K metabolism in liver; effects of warfarin. J Clin Invest 1985; 76: 1879-1884
    CrossrefPubMedGoogle Scholar
  • 5 Wallin R, Martin LF. Coumarin intoxication and vitamin K antagonism in rat and human liver; design of an in vitro system that mimics the in vivo situation. Submitted for publication 1985
    PubMedGoogle Scholar
  • 6 Fasco MJ, Principe LM. R- and S-warfarin inhibition of vitamin K and vitamin K2, 3-epoxide reductase activities in the rat. J Biol Chem 1982; 257: 4894-4901
    CrossrefPubMedGoogle Scholar
  • 7 Wallin R. Vitamin K antagonism and coumarin anticoagulant drugs. A study of an enzymatic pathway in rat liver that is responsible for the antagonistic effect. . Thromb Haemostas 1985; 54: 150
    PubMedGoogle Scholar
  • 8 Wallin R, Hutson S. Vitamin K-dependent carboxylation; evidence that at least two microsomal dehydrogenases reduce vitamin Kx to support carboxylation. J Biol Chem 1982; 257: 1583-1586
    PubMedGoogle Scholar
  • 9 O’Reilly RA, Aggeler PM. Convert anticoagulant ingestion: Study of 25 patients and review of world literature. Medicine 1976; 55: 389-399
    CrossrefPubMedGoogle Scholar
  • 10 Van Der Meer J, Hemker HC, Loeliger EA. Pharmacological aspects of vitamin Kj. A clinical and experimental study in man. Thrombos Diathes Haemorrh Suppl 1968; 19: 61-63
    PubMedGoogle Scholar
  • 11 Park BK, Leek JB. A comparison of vitamin K antagonism by warfarin, difenacoum and brodifacoum in the rabbit. Biochem Pharmacol 1982; 31: 3635-3639
    CrossrefPubMedGoogle Scholar
  • 12 Suttie JW, Hageman JW, Lehrman SR, Rich DH. Vitamin K-dependent carboxylase. Development of a peptide substrate. J Biol Chem 1976; 251: 5827-5830
    PubMedGoogle Scholar
  • 13 Esmon CT, Suttie JW. Vitamin K-dependent carboxylase. Solubilization and properties. J Biol Chem 1976; 251: 6238-6243
    PubMedGoogle Scholar
  • 14 Mayo Clinic Laboratory Manual of Hemostasis. Thomson-Didishein-Owen Bowie. (eds.) W B Saunders Company; Philadelphia, London, Toronto: 1971: 93-129
    Google Scholar
  • 15 Nelsestuen GL, Suttie JW. The carbohydrate of bovine prothrombin. J Biol Chem 1972; 247: 6096-6102
    PubMedGoogle Scholar
  • 16 Sadowski JA, Esmon CT, Suttie JW. Vitamin K-dependent carboxylase: Requirement of the rat liver microsomal enzyme system. J Biol Chem 1970; 251: 2770-2779
    PubMedGoogle Scholar
  • 17 Tishler M, Fieser LF, Wendler NL. Hydro oxido and other derivatives of vitamin Kx and related compounds. J Am Chem Soc 1940; 62: 2866-2871
    CrossrefPubMedGoogle Scholar
  • 18 Shah DV, Suttie JW. Vitamin K-dependent carboxylase: increased activity in a hypoprothrombinemia state. Arch Biochem Biophys 1978; 191: 571-577
    CrossrefPubMedGoogle Scholar
  • 19 Witlon DS, Sadowski JA, Suttie JW. Mechanism of coumarin action: Significance of vitamin K epoxide reductase inhibition. Biochemistry 1978; 17: 1371-1977
    CrossrefPubMedGoogle Scholar
  • 20 Hildebrandt EF, Suttie JW. Mechanism of coumarin action: sensitivity of vitamin K metabolizing enzymes of normal and warfarin-resistant rat liver. Biochemistry 1982; 27: 2406-2411
    PubMedGoogle Scholar
  • 21 Caldwell PT, Ren P, Bell RG. Warfarin and metabolism of vitaminK1 . Biochem Pharmacol 1974; 23: 3353-3362
    CrossrefPubMedGoogle Scholar
  • 22 Bell RG, Stark P. Inhibition of prothrombin synthesis and epoxida-tion of vitamin K2 by anticoagulants in vitro. Biochem Biophys Res Commun 1976; 72: 619-625
    CrossrefPubMedGoogle Scholar
  • 23 Leek JB, Park BK. A comparative study of the effects of warfarin and brodifacoum on the relationship between vitamin K, metabolism and clotting factor activity in warfarin-susceptible and warfarin-resistant rats. Biochem Pharmacol 1981; 30: 123-128
    CrossrefPubMedGoogle Scholar
  • 1 Ren P, Laliberte RE, Bell RG. Effects of warfarin, phenylin-danedione, tetrachloropyridinol, and chloro-vitamin Kj on prothrombin synthesis and vitamin K metabolism in normal and Warfarin-resistant rats. Mol Pharmacol 1974; 10: 373-380
    PubMedGoogle Scholar
  • 25 O’Reilly RA, Aggeler PM, Leong LS. Studies on the coumarin anticoagulant drugs: a comparison of the pharmacodynamics of dicumarol and warfarin in man. Thrombos Diathes Haemorrh 1964; 11: 1-22
    PubMedGoogle Scholar
  • 26 Zimmerman A, Matschiner JT. Biochemical basis of hereditary resistance to warfarin in the rat. Biochem Pharmacol 1974; 23: 1033-1040
    CrossrefPubMedGoogle Scholar
  • 27 Backmann UA, Sullivan TJ. Dispositional and pharmacodynamic characteristics of brodifacoum in warfarin-sensitive rats. Pharmacol 1983; 27: 281-288
    CrossrefPubMedGoogle Scholar
  • 28 Fasco MJ, Kaminisky LS. R- and S-warfarin and metabolites as probes of vitamin K1 epoxide reductase. In Vitamin K Metabolism and Vitamin K-Dependent-Proteins: Suttie J W (ed.). University Park Press 1979; 366-369
    PubMedGoogle Scholar
  • 29 Park BK, Leek JB. A comparison of vitamin K antagonism by warfarin, difenacoum and brodifacoum in the rabbit. Biochem Pharmacol 1982; 31: 3635-3639
    CrossrefPubMedGoogle Scholar
  • 30 Ernster L, Lind C, Rase B. A study of the DT-diaphorase activity in warfarin-resistant rats. Eur J Biochem 1972; 25: 198-206
    CrossrefPubMedGoogle Scholar