ABCC6 does not transport vitamin K3-glutathione conjugate from the liver: relevance to pathomechanisms of pseudoxanthoma elasticum |
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Authors: | Fülöp Krisztina Jiang Qiujie Wetering Koen V D Pomozi Viola Szabó Pál T Arányi Tamás Sarkadi Balázs Borst Piet Uitto Jouni Váradi András |
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Affiliation: | aInstitute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary;bDepartment of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA;cThe Netherlands Cancer Institute, Division of Molecular Biology, Amsterdam, The Netherlands;dChemical Research Center, Hungarian Academy of Sciences, Budapest, Hungary;eMembrane Research Group, Hungarian Academy of Sciences, Budapest, Hungary |
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Abstract: | Vitamin K is a cofactor required for gamma-glutamyl carboxylation of several proteins regulating blood clotting, bone formation and soft tissue mineralization. Vitamin K3 is an important intermediate during conversion of the dietary vitamin K1 to the most abundant vitamin K2 form. It has been suggested that ABCC6 may have a role in transporting vitamin K or its derivatives from the liver to the periphery. This activity is missing in pseudoxanthoma elasticum, a genetic disorder caused by mutations in ABCC6 characterized by abnormal soft tissue mineralization. Here we examined the efflux of the glutathione conjugate of vitamin K3 (VK3GS) from the liver in wild type and Abcc6−/− mice, and in transport assays in vitro. We found in liver perfusion experiments that VK3GS is secreted into the inferior vena cava, but we observed no significant difference between wild type and Abcc6−/− animals. We overexpressed the human ABCC6 transporter in Sf9 insect and MDCKII cells and assayed its vitamin K3-conjugate transport activity in vitro. We found no measurable transport of VK3GS by ABCC6, whereas ABCC1 transported this compound at high rate in these assays. These results show that VK3GS is not the essential metabolite transported by ABCC6 from the liver and preventing the symptoms of pseudoxanthoma elasticum. |
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Keywords: | Abbreviations: ABC, ATP binding cassette GGCX, gamma-glutamyl carboxylase enzyme LTC4, leukotriene C4 MRM, multiple reaction monitoring PXE, pseudoxanthoma elasticum VK1, VK2 and VK3, vitamin K1, 2 and 3, respectively VK3GS, glutathione-mono-conjugate of vitamin K3 WT, wild type |
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