Amazoniac
Member
- Vitamin E: Interactions with Vitamin K and Other Bioactive Compounds
"Although both nutrients were discovered in the early 1900s, and both were linked to coagulation, the interaction between vitamin E and vitamin K was only revealed in the early 1970s when vitamin E supplement use became widespread in the general population. In the form of a case report, the first clinical evidence of an interaction of vitamin E with vitamin K was in a patient treated with warfarin who was taking high amounts of vitamin E (800–1200 IU/d) and experienced signs of hemorrhage accompanied by reductions in vitamin K-dependent clotting factors. These outcomes improved when vitamin E supplementation was discontinued [10]. Since then, multiple case reports have been reported, but the underlying mechanism have yet to be elucidated, despite focused research efforts addressing differential potential mechanisms."
"Since the interaction of vitamin E with vitamin K is known to result in abnormal coagulation, initial studies to identify the purported mechanism focused on the carboxylation of clotting proteins. In rats treated with warfarin and given high doses of vitamin E (specific form unknown) intramuscularly, prothrombin (also known as Factor II) activation was reduced compared to rats given warfarin without vitamin E [11, 12]. Reduced prothrombin is indicative of impaired coagulation and reduced carboxylation of Glu residues due to vitamin K antagonism [3]. In chicks, a high α-tocopherol diet prolonged prothrombin time, which is a direct measure of anticoagulation. This was reversed by a high phylloquinone diet [13]. Based on these results, the focus shifted to a potential mechanism leveraging the structural similarities of vitamins E and K. Specifically, Dowd and Zheng tested the ability of α-tocopherol and the vitamin E quinone (a vitamin E metabolite) to inhibit the vitamin K-dependent γ-carboxylase using rat liver microsomes. Vitamin E quinone is structurally similar to the vitamin K hydroquinone (Figure 19.2- vitamin K cycle). They found the vitamin E quinone bound to the γ-carboxylase, thus impeding carboxylation, whereas α-tocopherol did not [14]. However, the relevance of this finding to the anticoagulation effects of vitamin E is uncertain because the physiological importance of vitamin E quinones has yet to be established [2, 15]."
"When the focus on structural similarities failed to support a plausible mechanism supporting the interaction, the research shifted to the common metabolic pathways shared by vitamins E and K. Emerging evidence suggests the same transport-protein-mediated processes are involved in their absorption into enterocytes [16]." "While the observed interaction of vitamin E with vitamin K at the level of intestinal absorption may have clinical implications for individuals taking ezetimibe and warfarin, these observations do not clarify how the interaction could be occurring at the level of absorption of these two nutrients [22]. The amounts of α-tocopherol and phylloquinone that are absorbed are not similar in magnitude in that the former is consumed in milligram doses, whereas the latter is consumed in microgram doses, and the circulating concentrations of α-tocopherol are up to 10,000-fold greater than that of phylloquinone [25]. Therefore, it is not clear how increasing vitamin E intakes through diet and/or supplements would have a threshold effect beyond which there was an adverse interaction [26–30]."
"After absorption, chylomicrons transport both vitamin E and vitamin K to the liver. In the liver, both undergo ω- then β-oxidation of their side chain as they are metabolized [31, 32]. Cytochrome P4F2 (CYP4F2) catalyzes the ω-oxidation step for both nutrients [33–36]. As hepatic vitamin E stores increase, CYP enzymes are upregulated to prevent vitamin E overaccumulation [31]. There is currently no evidence of a similar regulation for vitamin K in the liver given that the turnover of vitamin K is far more rapid. Vitamin E and vitamin K can both stimulate the pregnane X receptor (PXR), a nuclear receptor that regulates CYP expression [37–39]. It has been proposed that CYP enzyme upregulation in response to excess vitamin E could promote vitamin K catabolism, thereby reducing vitamin K liver stores and promoting anticoagulation [2]. However, α-tocopherol injection did not affect urinary vitamin K metabolite excretion in rats [40]. In this same experiment, CYP4F2 and CYP3A expression decreased in response to α-tocopherol. If excess α-tocopherol promoted vitamin K catabolism, an upregulation of these CYPs would have been expected [40]. In a kinetic experiment using insect microsomes expressing human CYP4F2, α-tocopherol incubation also did not increase vitamin K catabolism [41]. Based on the available evidence, the adverse effect of vitamin E on vitamin K and coagulation status does not appear to be due to increased vitamin K catabolism in the liver."
"An alternate mechanism through which vitamin E could interfere with vitamin K involves the conversion of phylloquinone to MK4. Menaquinone-4 appears to be the preferential form of vitamin K in some extrahepatic tissues [42–44]. MK4 can be converted from dietary phylloquinone, through what is thought to be a two-step process: (1) side chain removal from phylloquinone to form menadione in the intestine and (2) prenylation of menadione to form MK4 in peripheral tissues, catalyzed by the prenyltransferase enzyme UBIAD1 [45–47]. Vitamin E supplementation has been hypothesized to interfere with side chain removal of phylloquinone and/or conversion of menadione to MK4, either of which would reduce MK4 formation [2, 40, 48]. In male rats fed an α-tocopherol-supplemented diet for 12 weeks, MK4 concentrations in the kidney, testes, and brain were lower than in rats fed a vitamin E-restricted diet [49]. The brain and kidney phylloquinone concentrations responded similarly. However, α-tocopherol supplementation did not affect liver MK4 or phylloquinone, suggesting an overall effect of high α-tocopherol intakes on extrahepatic tissue vitamin K concentrations. To test whether vitamin E affected MK4 production by interfering with phylloquinone side chain removal, Farley et al. fed rats diets containing phylloquinone or menadione for 2.5 weeks and subcutaneously injected with α-tocopherol daily for the last 7 days [40]. Whether the diet contained phylloquinone or menadione, α-tocopherol reduced MK4 concentrations in the brain, lung, kidney, heart, and plasma. In a subsequent experiment using deuterium-labeled phylloquinone as the sole dietary source of vitamin K, α-tocopherol injection reduced total vitamin K (the sum of labeled and unlabeled MK4 and phylloquinone) in rat kidney, lung, and brain. However, the relative amount of labeled MK4 in each tissue did not change in response to α-tocopherol [50], which is a further indication that α-tocopherol affects overall vitamin K concentrations in extrahepatic tissues, but not the conversion of phylloquinone to MK4."
"The only tissue in which α-tocopherol appeared to influence the phylloquinone to MK4 conversion was the heart [50]. Phylloquinone is normally the primary vitamin K form in the heart [43, 44], so the importance of reducing the conversion of phylloquinone to MK4 in heart tissue is uncertain. An overall effect of α-tocopherol on extrahepatic tissue vitamin K was also found when rats were fed diets containing the same amount of phylloquinone, which was the only form of vitamin K in the diet, with varying amounts of α-tocopherol for 6 weeks. Phylloquinone concentrations in the kidney, brain, heart, lung, skeletal muscle, and testes all dose-dependently decreased as dietary α-tocopherol increased. MK4 in the kidney, heart, and brain also decreased in response to increasing α-tocopherol intake. However, when the diet contained MK4 instead of phylloquinone, the tissue vitamin K concentrations did not change in response to α-tocopherol [48]. Similar responses were noted when phylloquinone or MK4 were administered orally with α-tocopherol. Collectively, these experiments indicate high α-tocopherol intakes can reduce extrahepatic tissue vitamin K concentrations, but this is not limited to the conversion of phylloquinone to MK4. It is plausible the observed effect of vitamin E on phylloquinone and MK4 in extrahepatic tissues is due, in part, to an effect of vitamin E on vitamin K intestinal absorption. However, this needs to be tested in experiments designed to do so. Furthermore, the functional consequences of the apparent effect of vitamin E on extrahepatic tissue vitamin K have not been determined. Finally, the studies of vitamin K-vitamin E interaction to date have focused on α-tocopherol with phylloquinone. It is not known if α-tocopherol interacts with menaquinones, other than MK4. In one study, γ-tocopherol was not found to effect vitamin K in tissues to the same extent as α-tocopherol [48]. Therefore further research is needed to determine if other forms of vitamins E and K similarly interact, which may shed light on the mechanism underlying this interaction."
"While the preponderance of research on vitamin E interactions has focused on its interaction with vitamin K, there are also suggestions of interactions with other bioactives. For example, the hemorrhagic effects of high amounts of vitamin E may be exacerbated by consuming it with other dietary bioactives that have anticoagulant activity, like Ginkgo biloba and garlic [56]. The exact mechanisms are not known, and it is assumed that there is an additive anticoagulant effect with simultaneous consumption. Similar to warfarin, chamomile also contains coumarin derivatives, so an interaction between vitamin E and chamomile is biologically plausible. To date no case studies have been reported; hence this putative interaction is still speculative [57]. More recently, it has been reported that α-tocopherol inhibits the antibacterial properties of ursolic acid, a plant secondary bioactive [58]. This is based on in vitro studies; hence its application to humans is unclear."
"[..]although there have been some suggestions that vitamin E exacerbates the symptoms of selenium deficiency, a recent study in weanling rats indicated that vitamin E deficiency did not alter biomarkers of selenium status [68]."
"Since the interaction of vitamin E with vitamin K is known to result in abnormal coagulation, initial studies to identify the purported mechanism focused on the carboxylation of clotting proteins. In rats treated with warfarin and given high doses of vitamin E (specific form unknown) intramuscularly, prothrombin (also known as Factor II) activation was reduced compared to rats given warfarin without vitamin E [11, 12]. Reduced prothrombin is indicative of impaired coagulation and reduced carboxylation of Glu residues due to vitamin K antagonism [3]. In chicks, a high α-tocopherol diet prolonged prothrombin time, which is a direct measure of anticoagulation. This was reversed by a high phylloquinone diet [13]. Based on these results, the focus shifted to a potential mechanism leveraging the structural similarities of vitamins E and K. Specifically, Dowd and Zheng tested the ability of α-tocopherol and the vitamin E quinone (a vitamin E metabolite) to inhibit the vitamin K-dependent γ-carboxylase using rat liver microsomes. Vitamin E quinone is structurally similar to the vitamin K hydroquinone (Figure 19.2- vitamin K cycle). They found the vitamin E quinone bound to the γ-carboxylase, thus impeding carboxylation, whereas α-tocopherol did not [14]. However, the relevance of this finding to the anticoagulation effects of vitamin E is uncertain because the physiological importance of vitamin E quinones has yet to be established [2, 15]."
"When the focus on structural similarities failed to support a plausible mechanism supporting the interaction, the research shifted to the common metabolic pathways shared by vitamins E and K. Emerging evidence suggests the same transport-protein-mediated processes are involved in their absorption into enterocytes [16]." "While the observed interaction of vitamin E with vitamin K at the level of intestinal absorption may have clinical implications for individuals taking ezetimibe and warfarin, these observations do not clarify how the interaction could be occurring at the level of absorption of these two nutrients [22]. The amounts of α-tocopherol and phylloquinone that are absorbed are not similar in magnitude in that the former is consumed in milligram doses, whereas the latter is consumed in microgram doses, and the circulating concentrations of α-tocopherol are up to 10,000-fold greater than that of phylloquinone [25]. Therefore, it is not clear how increasing vitamin E intakes through diet and/or supplements would have a threshold effect beyond which there was an adverse interaction [26–30]."
"After absorption, chylomicrons transport both vitamin E and vitamin K to the liver. In the liver, both undergo ω- then β-oxidation of their side chain as they are metabolized [31, 32]. Cytochrome P4F2 (CYP4F2) catalyzes the ω-oxidation step for both nutrients [33–36]. As hepatic vitamin E stores increase, CYP enzymes are upregulated to prevent vitamin E overaccumulation [31]. There is currently no evidence of a similar regulation for vitamin K in the liver given that the turnover of vitamin K is far more rapid. Vitamin E and vitamin K can both stimulate the pregnane X receptor (PXR), a nuclear receptor that regulates CYP expression [37–39]. It has been proposed that CYP enzyme upregulation in response to excess vitamin E could promote vitamin K catabolism, thereby reducing vitamin K liver stores and promoting anticoagulation [2]. However, α-tocopherol injection did not affect urinary vitamin K metabolite excretion in rats [40]. In this same experiment, CYP4F2 and CYP3A expression decreased in response to α-tocopherol. If excess α-tocopherol promoted vitamin K catabolism, an upregulation of these CYPs would have been expected [40]. In a kinetic experiment using insect microsomes expressing human CYP4F2, α-tocopherol incubation also did not increase vitamin K catabolism [41]. Based on the available evidence, the adverse effect of vitamin E on vitamin K and coagulation status does not appear to be due to increased vitamin K catabolism in the liver."
"An alternate mechanism through which vitamin E could interfere with vitamin K involves the conversion of phylloquinone to MK4. Menaquinone-4 appears to be the preferential form of vitamin K in some extrahepatic tissues [42–44]. MK4 can be converted from dietary phylloquinone, through what is thought to be a two-step process: (1) side chain removal from phylloquinone to form menadione in the intestine and (2) prenylation of menadione to form MK4 in peripheral tissues, catalyzed by the prenyltransferase enzyme UBIAD1 [45–47]. Vitamin E supplementation has been hypothesized to interfere with side chain removal of phylloquinone and/or conversion of menadione to MK4, either of which would reduce MK4 formation [2, 40, 48]. In male rats fed an α-tocopherol-supplemented diet for 12 weeks, MK4 concentrations in the kidney, testes, and brain were lower than in rats fed a vitamin E-restricted diet [49]. The brain and kidney phylloquinone concentrations responded similarly. However, α-tocopherol supplementation did not affect liver MK4 or phylloquinone, suggesting an overall effect of high α-tocopherol intakes on extrahepatic tissue vitamin K concentrations. To test whether vitamin E affected MK4 production by interfering with phylloquinone side chain removal, Farley et al. fed rats diets containing phylloquinone or menadione for 2.5 weeks and subcutaneously injected with α-tocopherol daily for the last 7 days [40]. Whether the diet contained phylloquinone or menadione, α-tocopherol reduced MK4 concentrations in the brain, lung, kidney, heart, and plasma. In a subsequent experiment using deuterium-labeled phylloquinone as the sole dietary source of vitamin K, α-tocopherol injection reduced total vitamin K (the sum of labeled and unlabeled MK4 and phylloquinone) in rat kidney, lung, and brain. However, the relative amount of labeled MK4 in each tissue did not change in response to α-tocopherol [50], which is a further indication that α-tocopherol affects overall vitamin K concentrations in extrahepatic tissues, but not the conversion of phylloquinone to MK4."
"The only tissue in which α-tocopherol appeared to influence the phylloquinone to MK4 conversion was the heart [50]. Phylloquinone is normally the primary vitamin K form in the heart [43, 44], so the importance of reducing the conversion of phylloquinone to MK4 in heart tissue is uncertain. An overall effect of α-tocopherol on extrahepatic tissue vitamin K was also found when rats were fed diets containing the same amount of phylloquinone, which was the only form of vitamin K in the diet, with varying amounts of α-tocopherol for 6 weeks. Phylloquinone concentrations in the kidney, brain, heart, lung, skeletal muscle, and testes all dose-dependently decreased as dietary α-tocopherol increased. MK4 in the kidney, heart, and brain also decreased in response to increasing α-tocopherol intake. However, when the diet contained MK4 instead of phylloquinone, the tissue vitamin K concentrations did not change in response to α-tocopherol [48]. Similar responses were noted when phylloquinone or MK4 were administered orally with α-tocopherol. Collectively, these experiments indicate high α-tocopherol intakes can reduce extrahepatic tissue vitamin K concentrations, but this is not limited to the conversion of phylloquinone to MK4. It is plausible the observed effect of vitamin E on phylloquinone and MK4 in extrahepatic tissues is due, in part, to an effect of vitamin E on vitamin K intestinal absorption. However, this needs to be tested in experiments designed to do so. Furthermore, the functional consequences of the apparent effect of vitamin E on extrahepatic tissue vitamin K have not been determined. Finally, the studies of vitamin K-vitamin E interaction to date have focused on α-tocopherol with phylloquinone. It is not known if α-tocopherol interacts with menaquinones, other than MK4. In one study, γ-tocopherol was not found to effect vitamin K in tissues to the same extent as α-tocopherol [48]. Therefore further research is needed to determine if other forms of vitamins E and K similarly interact, which may shed light on the mechanism underlying this interaction."
"While the preponderance of research on vitamin E interactions has focused on its interaction with vitamin K, there are also suggestions of interactions with other bioactives. For example, the hemorrhagic effects of high amounts of vitamin E may be exacerbated by consuming it with other dietary bioactives that have anticoagulant activity, like Ginkgo biloba and garlic [56]. The exact mechanisms are not known, and it is assumed that there is an additive anticoagulant effect with simultaneous consumption. Similar to warfarin, chamomile also contains coumarin derivatives, so an interaction between vitamin E and chamomile is biologically plausible. To date no case studies have been reported; hence this putative interaction is still speculative [57]. More recently, it has been reported that α-tocopherol inhibits the antibacterial properties of ursolic acid, a plant secondary bioactive [58]. This is based on in vitro studies; hence its application to humans is unclear."
"[..]although there have been some suggestions that vitamin E exacerbates the symptoms of selenium deficiency, a recent study in weanling rats indicated that vitamin E deficiency did not alter biomarkers of selenium status [68]."
