Identification of menaquinone-4 metabolites in the rat.

Tadano, Kyoichi; Yuzuriha, Teruaki; Satô, Tadashi; Fujita, Takeshi; Shimada, Katsutoshi; Hashimoto, Kazunori; Satoh, Takashi

doi:10.1248/bpb1978.12.640

Cited by 20 publications

(14 citation statements)

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“…These results suggested that an increase in the level of superoxide in TYK-nu cells might be an early event in apoptosis and also that vitamin K 2 -induced apoptosis might not involve the accumulation of GGO as a byproduct of the cellular metabolism of vitamin K 2 . Indeed, vitamin K 2 is apparently metabolized by ω-oxidation and no GGO is detected among the metabolites of vitamin K 2 in intact rats [18].…”

Section: Apoptosis Was Induced By Vitamin K 2 Subsequent To An Increamentioning

confidence: 95%

Production of superoxide and dissipation of mitochondrial transmembrane potential by vitamin K2 trigger apoptosis in human ovarian cancer TYK-nu cells

et al. 2006

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We reported previously that vitamin K(2) selectively induces apoptosis in human ovary cancer cells (TYK-nu cells) and pancreatic cancer cells (MIA PaCa-2 cells) through a mitochondrion-dependent pathway. In the present study, we examined the details of the mechanism of vitamin K(2)-induced apoptosis in TYK-nu cells. We found that superoxide (O(2)(*-)) was produced by TYK-nu cells between 2 and 3 days after the start of treatment with vitamin K(2), whereas it was produced within 30 min after the start of treatment with geranylgeraniol. The vitamin K(2)-induced apoptosis was inhibited by anti-oxidants, such as alpha-tocopherol, Tiron and N-acetyl-L-cysteine (NAC). Furthermore, both the production of superoxide and the induction of apoptosis by vitamin K(2) were inhibited almost completely by cycloheximide, an inhibitor of protein synthesis, suggesting that the synthesis of enzymes for the production of superoxide might be required for these processes. In parallel with the production of superoxide, the mitochondrial transmembrane potential, as measured by staining with Mitotracker Red CMXRos, dissipated during treatment of TYK-nu cells with vitamin K(2) for 3 days. The vitamin K(2)-induced depolarization of mitochondrial membranes was completely inhibited by alpha-tocopherol and, to a lesser extent, by Tiron and NAC. Since alpha-tocopherol reacts with oxygen radicals, such as superoxide, within the hydrophobic environment of the mitochondrial membrane, we postulate that vitamin K(2)-induced oxidative stress in mitochondria might damage mitochondrial membranes, with subsequent release of cytochrome c, the activation of procaspase 3 and, eventually, apoptosis.

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Section: Apoptosis Was Induced By Vitamin K 2 Subsequent To An Increamentioning

confidence: 95%

Production of superoxide and dissipation of mitochondrial transmembrane potential by vitamin K2 trigger apoptosis in human ovarian cancer TYK-nu cells

et al. 2006

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“…Overall, it can be noted that MK-4 metabolism resembled that of phylloquinone (Tadano et al, 1989), which also is metabolised to carboxylic acids, with either a 5-or 7-carbon side chain (McBurney et al, 1980). Therefore, similar to vitamin K 1 , vitamin K 2 metabolite formation appears to proceed via a series of reactions, beginning with ω-methyl oxidation to form the MK-4 carboxylic acid (ω-COOH), followed by β-oxidative degradation of the alkyl side chain to yield vitamin K acids 1 and 2.…”

Section: Metabolic Fate and Biological Distributionmentioning

confidence: 86%

“…In order to examine MK-4 metabolism and excretion, groups of 3 male, bile duct-cannulated Wistar rats were treated with single oral or intravenous doses of 4 mg [ 14 C]-MK-4 (Tadano et al, 1989). Urine and faeces samples were collected every 24 hours for a total of 5 days.…”

Section: Metabolic Fate and Biological Distributionmentioning

confidence: 99%

Vitamin K2 added for nutritional purposes in foods for particular nutritional uses, food supplements and foods intended for the general population and Vitamin K2 as a source of vitamin K added for nutritional purposes to foodstuffs, in the context of Regu

2008

EFSA Journal

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“…In another study, again using menaquinone‐4 (30 mg/kg/day; 3× week), in sciatic neurectomised rats, Iwamoto et al found an attenuation of neurectomy‐induced cancellous bone loss and increased bone formation rate . As rats can break down vitamin K into carboxylic acid catabolites , it is, of course, possible that this attenuation of cancellous bone turnover is due to increased endogenous production of CAN7C.…”

Section: Discussionmentioning

confidence: 99%

Vitamin K catabolite inhibition of ovariectomy‐induced bone loss: Structure–activity relationship considerations

Soper

Oguz

Emery

et al. 2014

Molecular Nutrition Food Res

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Scope-The potential benefit of vitamin K as a therapeutic in osteoporosis is controversial and the vitamin K regimen being used clinically (45 mg/day) employs doses that are many times higher than required to ensure maximal gamma-carboxylation of the vitamin K-dependent bone proteins. We therefore tested the hypothesis that vitamin K catabolites, 5-carbon (CAN5C) and 7-carbon carboxylic acid (CAN7C) aliphatic side-chain derivatives of the naphthoquinone moiety exert an osteotrophic role consistent with the treatment of osteoporosis.Methods and results-Osteoblast-like MG63 cell cultures were challenged with lipopolysaccharide and the levels of interleukin-6, an osteoclastogenic cytokine, measured with and without catabolites; low concentrations of CAN7C significantly inhibited interleukin-6 release, but CAN5C did not. In models of bone loss induced by ovariectomy or sciatic neurectomy in C57BL/6 mice, we found that the rarer CAN7C catabolite markedly restricted ovariectomyinduced bone loss and possibly limited sciatic neurectomy-induced bone loss. CAN7C activity depends on a free carboxylic acid and its particular side-chain structure.Conclusion-These in vivo data indicate for the first time that the clinical utility of vitamin K for osteoporosis may reside in an unusual catabolite.

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Identification of menaquinone-4 metabolites in the rat.

Cited by 20 publications

References 7 publications

Production of superoxide and dissipation of mitochondrial transmembrane potential by vitamin K2 trigger apoptosis in human ovarian cancer TYK-nu cells

Production of superoxide and dissipation of mitochondrial transmembrane potential by vitamin K2 trigger apoptosis in human ovarian cancer TYK-nu cells

Vitamin K2 added for nutritional purposes in foods for particular nutritional uses, food supplements and foods intended for the general population and Vitamin K2 as a source of vitamin K added for nutritional purposes to foodstuffs, in the context of Regu

Vitamin K catabolite inhibition of ovariectomy‐induced bone loss: Structure–activity relationship considerations

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