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1.
Sci Rep ; 14(1): 5440, 2024 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-38443482

RESUMEN

This study aims to evaluate the safety of MK-7 produced by fermentation process using a Bacillus subtilis var. natto strain for human ingestion via acute oral toxicity, repeated dose 90-day oral toxicity, 28-day recovery test, and genotoxicity tests. The acute oral toxicity test results indicated that all subjects survived at the dose of 5000 mg/kg with no toxic effects. For the repeated dose 90-day oral toxicity test, MK-7 was administered to rats at 500, 1500, and 4500 mg/kg for 90 d. No abnormal findings were detected in clinical observations or in clinical pathological and histopathological examinations. The no-observed-adverse-effect level(NOAEL) was determined to be 4500 mg/kg/d, the maximum dose tested. For the evaluation of genotoxicity, reverse mutation, chromosomal aberration, and micronucleus tests were performed. In the reversion mutation test, vitamin K2 did not induce reversion in bacterial strains, and no chromosomal abnormality was observed in the chromosomal abnormality test using Chinese hamster lung cells. In the micronucleus test, micronuclei were not induced using ICR mouse bone marrow cells. All the toxicity test results suggest that vitamin K2 produced by fermentation processes using Bacillus subtilis var. natto induced no toxicological changes under the experimental conditions.


Asunto(s)
Bacillus subtilis , Aberraciones Cromosómicas , Humanos , Ratones , Cricetinae , Animales , Ratas , Ratones Endogámicos ICR , Vitamina K 2/toxicidad , Mutación , Cricetulus
2.
Int J Mol Sci ; 20(10)2019 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-31137618

RESUMEN

The effective delivery of menahydroquinone-4 (MKH), an active form of menaquinone-4 (MK-4, vitamin K2(20)), to the skin is beneficial in the treatment of various skin pathologies. However, its delivery through the application of MK-4 to the skin is hampered due to the photoinstability and phototoxicity of MK-4. This study aimed to evaluate the potential of ester prodrugs of MKH for its delivery into the skin to avoid the abovementioned issues. The ester prodrugs, MKH 1,4-bis-N,N-dimethylglycinate hydrochloride (MKH-DMG) and MKH 1,4-bis-hemisuccinate (MKH-SUC), were prepared using our previously reported methods. Photostability was determined under artificial sunlight and multi-wavelength light irradiation, phototoxicity was determined by intracellular ROS formation and cell viability of UVA-irradiated human epidermal keratinocyte cells (HaCaT), and delivery of MKH into HaCaT cells was assessed by measuring menaquinone-4 epoxide (MKO) levels. MKH prodrugs showed higher photostability than MK-4. Although MK-4 induced cellular ROS and reduced cell viability after UVA irradiation, MKH prodrugs did not affect either ROS generation or cell viability. MKH prodrugs enhanced intracellular MKO, indicating effective delivery of MKH and subsequent carboxylation activity. In conclusion, these MKH prodrugs show potential for the delivery of MKH into the skin without photoinstability and phototoxicity.


Asunto(s)
Hidroquinonas/toxicidad , Queratinocitos/efectos de los fármacos , Profármacos/toxicidad , Vitamina K 2/análogos & derivados , Línea Celular , Humanos , Hidroquinonas/química , Queratinocitos/metabolismo , Profármacos/química , Especies Reactivas de Oxígeno/metabolismo , Vitamina K 2/química , Vitamina K 2/toxicidad
3.
Toxicol Mech Methods ; 21(7): 520-32, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21781006

RESUMEN

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.


Asunto(s)
Antifibrinolíticos/toxicidad , Vitamina K 2/análogos & derivados , Animales , Biomarcadores Farmacológicos/análisis , Biomarcadores Farmacológicos/sangre , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Femenino , Dosificación Letal Mediana , Masculino , Ratones , Ratones Endogámicos , Nivel sin Efectos Adversos Observados , Tamaño de los Órganos/efectos de los fármacos , Especificidad de Órganos , Ratas , Ratas Sprague-Dawley , Pruebas de Toxicidad Aguda , Pruebas de Toxicidad Subcrónica , Vitamina K 2/toxicidad
4.
Anticancer Res ; 21(4A): 2387-92, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11724297

RESUMEN

Vitamin K1, K2 and K3 were compared for their cytotoxic activity, radical generation and O2- scavenging activity. Among these compounds, vitamin K3 showed the highest cytotoxic activity against human oral tumor cell lines (HSC-2, HSG), human promyelocytic leukemic cell line (HL-60) and human gingival fibroblast (HGF). Vitamin K3 induced internucleosomal DNA fragmentation in HL-60 cells, but not in HSC-2 or HSG cells. The cytotoxic activity of vitamins K2 and K1 was one and two orders lower, respectively, than K3. Vitamin K2, but not vitamin K3, showed tumor-specific cytotoxic action. ESR spectroscopy showed that only vitamin K3 produced radical(s) under alkaline condition and most potently enhanced the radical intensity of sodium ascorbate and scavenged O2- (generated by hypoxanthine-xanthine oxidase reaction system); vitamin K2 was much less active whereas vitamin K1 was inactive. These data suggest that the cytotoxic activity of vitamin K3 is generated by radical-mediated oxidation mechanism and that this vitamin has two opposing actions (that is, antioxidant and prooxidant), depending on the experimental conditions.


Asunto(s)
Neoplasias de la Boca/tratamiento farmacológico , Vitamina K/toxicidad , Carcinoma de Células Escamosas/tratamiento farmacológico , Fragmentación del ADN/efectos de los fármacos , Espectroscopía de Resonancia por Spin del Electrón , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Depuradores de Radicales Libres/toxicidad , Encía/citología , Encía/efectos de los fármacos , Células HL-60/efectos de los fármacos , Humanos , Modelos Moleculares , Neoplasias de las Glándulas Salivales/tratamiento farmacológico , Relación Estructura-Actividad , Superóxidos/metabolismo , Células Tumorales Cultivadas , Vitamina K 1/toxicidad , Vitamina K 2/toxicidad , Vitamina K 3/toxicidad
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