Safety and toxicological evaluation of a synthetic vitamin K2, menaquinone-7

Kresimir Pucaj, Henrik Rasmussen, Mona Møller, Tom Preston, Kresimir Pucaj, Henrik Rasmussen, Mona Møller, Tom Preston

Abstract

Menaquinone-7 (MK-7) is part of a family of vitamin K that are essential co-factors for the enzyme γ-glutamyl carboxylase, which is involved in the activation of γ-carboxy glutamate (Gla) proteins in the body. Gla proteins are important for normal blood coagulation and normality of bones and arteries. The objective of this study was to examine the potential toxicity of synthetic MK-7 in BomTac:NMRI mice and in Sprague-Dawley rats. In an acute oral toxicity test, mice were administered a single oral dose of 2000 mg/kg body weight (limit dose) and no toxicity was observed during the 14-day observation period. In the subchronic oral toxicity test in rats, animals were administered MK-7 for 90 days by gavage at the following doses: 0 (vehicle control, corn oil), 2.5, 5, and 10 mg/kg body weight/day. All generated data, including clinical observations, ophthalmology, clinical pathology, gross necropsy, and histopathology, revealed no compound-related toxicity in rats. Any statistically significant findings in clinical pathology parameters and/or organ weights noted were considered to be within normal biological variability. Therefore, under the conditions of this experiment, the median lethal dose (LD(50)) of MK-7 after a single oral administration in mice was determined to be greater than the limit dose level of 2000 mg/kg body weight. The no observed adverse effect level (NOAEL) of MK-7, when administered orally to rats for 90 days, was considered to be equal to 10 mg/kg body weight/day, the highest dose tested, based on lack of toxicity during the 90-day study period.

Figures

Figure 1
Figure 1
Body weight of Sprague-Dawley male rats as a function of time following administration of menaquinone-7 (MK-7) in the 90-day subchronic toxicity study. Each value represents the mean of 10 animals.
Figure 2
Figure 2
Body weight of Sprague-Dawley female rats as a function of time following administration of menaquinone-7 (MK-7) in the 90-day subchronic toxicity study. Each value represents the mean of 10 animals.
Figure 3
Figure 3
Histopathological pictures of major organs from control animals (A-D) and animals treated with high dose, 10 mg/kg/day menaquinone-7 (MK-7) (E-H). All photos are 10× magnification and all the tissues are considered to be without histopathological findings. Control male rats (10×): renal cortex (A), spleen (B), liver (C), and cerebral cortex (D). MK-7 10 mg/kg/day male rats (10×): renal cortex (E), spleen (F), liver (G), and cerebral cortex (H).

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