VKORC1L1, an Enzyme Rescuing the Vitamin K 2,3-Epoxide Reductase Activity in Some Extrahepatic Tissues during Anticoagulation Therapy

Abstract

Background: Effective involvement of VKORC1L1 in vitamin K epoxide reductase activity, target of vitamin K antagonists (VKAs), is still unclear. Results: VKORC1L1 is not inhibited by VKAs and catalyzes VKOR activity in extrahepatic tissues. Conclusion: During long term anticoagulation the limited unwanted side effects of VKAs are due to VKORC1L1. Significance: Potential pharmaco-toxicologic effects of specific VKORC1L1 inhibitors should be assessed.

Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis

“…The model predicted that whereas VKOR supported >90% of K 1 >O reductase activity in liver, kidney, and brain, VKORL1 supported >50% of the activity in testis and rat osteosarcoma cells, and >20% in lung ( 111 ). The authors hypothesized that this different tissue susceptibility to VKAs and rescue by VKORL1 may partly explain why it has been diffi cult to fi nd serious side effects of warfarin that are attributable to lack of VKD functions in extrahepatic tissues.…”

“…If true, this hypothesis that specifi cally relates to antioxidant protection of cell membranes would have farreaching consequences to current concepts of antioxidant mechanisms. An alternative hypothesis is that VKORL1 is important for the reduction of K>O to K in extrahepatic tissues and can serve to rescue the recycling function in some extrahepatic tissues during treatment with VKAs ( 111 ). Clearly further studies are needed to clarify the physiological role of VKORL1, not least because currently there are disparities regarding the ability of VKORL1 to reduce K>O and its sensitivity to warfarin ( 86,110,111 ).…”

“…Finally, Vkor Ϫ / Ϫ mice did show evidence of skeletal abnormalities characteristic of vitamin K defi ciency or VKA antagonism, which was obviously not prevented by VKORL1. It is worth mentioning that the relative expression of Vkorl1 mRNA was higher than for Vkor mRNA in brain, testis, and osteoblast-like cells ( 111 ), while previous data for MK-4 distribution shows that brain and bone (testis not measured) also have higher ratios of MK-4 to K 1 ( 51 ). Also, the lowest ratio by far of Vkorl1 to Vkor expression was found in the liver ( 111 ), which is also the organ with the lowest ratio of MK-4 to K 1 ( 51 ).…”

“…It is worth mentioning that the relative expression of Vkorl1 mRNA was higher than for Vkor mRNA in brain, testis, and osteoblast-like cells ( 111 ), while previous data for MK-4 distribution shows that brain and bone (testis not measured) also have higher ratios of MK-4 to K 1 ( 51 ). Also, the lowest ratio by far of Vkorl1 to Vkor expression was found in the liver ( 111 ), which is also the organ with the lowest ratio of MK-4 to K 1 ( 51 ). It might be worth investigating whether MK-4 is the favored substrate for VKORL1, although the relative in vitro affi nity data for K 1 >O and MK-4>O substrates does not support this ( 110 ).…”

“…Evidence that VKORL1 may indeed be important for recycling vitamin K in some extrahepatic tissues has recently emerged ( 111 ). To assess the functional properties of VKORL1, human and rat VKOR and VKORL1 were overexpressed in Pichia pastoris .…”