Abstract
BackgroundSubtilisin QK is a serine protease in the subtilisin family, and is fermented by Bacillus subtilis QK02. The fibrinolytic activity of subtilisin QK was measured by detecting low molecular weight degradation products using a spectrophotometric method developed by Japan Bio Science Laboratory Co., Ltd. Subtilisin QK powder can maintain its fibrinolytic activity for more than 24 months when it is stored at room temperature and protected from light. Our previous results showed that subtlisin QK directly degraded cross-linked fibrins in the fibrin plate assay and effectively inhibited thrombosis in the mouse thrombus model. The aim of this study was to determine the acute toxicity, potential subchronic toxicity, and safety pharmacology of subtilisin QK in Sprague–Dawley (SD) rats.MethodsIn the acute toxicity study, a single oral dose of 100,000 FU/kg was administered to 10 female and 10 male SD rats. In the 28-day subchronic toxicity, 60 female and 60 male SD rats were randomly assigned to four experimental groups (daily oral dose of 0, 2500, 7500 and 25,000 FU/kg). In the safety pharmacology study, 20 female and 20 male SD rats were randomly assigned to four experimental groups (single oral dose of 0, 500, 1500 and 5000 FU/kg).ResultsNo death occurred and no adverse effects were observed in the acute toxicity study at a dose of 100,000 FU/kg. In the 28-day subchronic toxicity study, several hematological and blood biochemical parameters showed increases or decreases; however, due to the lack of a dose–response relationship, these differences were considered unrelated to treatment. In the safety pharmacology study, no adverse effects were observed on the central nervous of SD rats post-administration up to a dose of 5000 FU/kg subtilisin QK.ConclusionThe results showed that oral consumption of subtilisin QK is of low toxicological concern. No adverse effects were observed at doses of 2500, 7500, and 25,000 FU/kg in the 28-day subchronic toxicity, and the no-observed-adverse-effect level (NOAEL) of subtilisin QK was 25,000 FU/kg.
Highlights
Subtilisin QK is a serine protease in the subtilisin family, and is fermented by Bacillus subtilis QK02
Subtilisin QK is a serine protease produced by the fermentation of Bacillus subtilis QK02, and has better thrombolytic effects [15]
The results provide reliable toxicological data showing that subtilisin QK is a functional food or agent that may be used to prevent and treat Cardiovascular diseases (CVDs)
Summary
Subtilisin QK is a serine protease in the subtilisin family, and is fermented by Bacillus subtilis QK02. Volunteer experiments showed that a single oral dose of 2000 FU nattokinase had excellent thrombolysis and anticoagulation effects and no adverse effects [10, 11]. Nattokinase reportedly lowers blood pressure and reduces atherosclerosis in vivo [12, 13]. In another volunteer experiment, oral administration of 100 mg/day nattokinase for 8 weeks significantly reduced systolic and diastolic blood pressure [14]. Subtilisin QK is a serine protease produced by the fermentation of Bacillus subtilis QK02, and has better thrombolytic effects [15]
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