title: ABCC6 does not transport vitamin K3-glutathione conjugate from the liver: relevance to pathomechanisms of pseudoxanthoma elasticum.
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.
authors: Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary.
authors: Krisztina
authors: K
authors: Fülöp
authors: Qiujie
authors: Q
authors: Jiang
authors: Koen V D
authors: KV
authors: Wetering
authors: Viola
authors: V
authors: Pomozi
authors: Pál T
authors: PT
authors: Szabó
authors: Tamás
authors: T
authors: Arányi
authors: Balázs
authors: B
authors: Sarkadi
authors: Piet
authors: P
authors: Borst
authors: Jouni
authors: J
authors: Uitto
authors: András
authors: A
authors: Váradi
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D004285:Dogs; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D007313:Insecta / Q000166:cytology; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D011561:Pseudoxanthoma Elasticum / Q000378:metabolism*; D013379:Substrate Specificity; D024483:Vitamin K 3 / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D024483:Vitamin K 3; C102029:ABCC6 protein, human; C504743:Abcc6 protein, mouse