@article{0f65dc41bb5d4cd0807dc5ea072a4dd2,
title = "Vitamin K antagonism of coumarin intoxication in the rat",
abstract = "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 K1 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 K1 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.",
author = "R. Wallin and Patrick, {S. D.} and Ballard, {J. O.}",
note = "Funding Information: We thank the Projects teams at the Ontario Institute for Cancer Research, Canada. We also thank the patients for participating in this study. This work was funded in part by the National Cancer Institute (1R21CA152613, P30CA023100), the CIRM Highly Active Anti-Leukemia Stem Cell Therapy (HALT) team grant (DR1-01430), the National Institutes of Health Grant UL1TR000100 and the Government of Canada through Genome Canada and through the Canadian Institutes of Health Research (CSC-105367). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. PJS was supported by the UCSD Cancer Center Training Grant in Drug Development—the Cancer Therapeutics Training Program T32CA121938. This work was also supported by the Cancer Stem Cell Consortium with funding from the Government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-047), and through the Canadian Institutes of Health Research (CSC-105367). TJH and LM received Investigator Awards from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. Copy number arrays, exome sequencing data, targeted sequencing data, and methylation array raw data will be available through dbGaP accession phs000767: http://www.ncbi.nlm.nih.gov/projects/ gap/cgi-bin/study.cgi?study_id=phs000767.v1.p1.",
year = "1986",
doi = "10.1055/s-0038-1661528",
language = "English (US)",
volume = "55",
pages = "235--239",
journal = "Thrombosis and Haemostasis",
issn = "0340-6245",
publisher = "Georg Thieme Verlag",
number = "2",
}