Abstract
OBJECTIVES: Investigate the influence of large-dose warfarin (W) on tissue K1 and MK-4 distribution in rats fed a standard K1 diet, or enriched with MK4. METHODS: Male Wistar rats were fed a regular K1 (750 mcg K1/kg/diet; WK1) or enriched MK-4 (100 mg MK-4/kg/diet; WK1 + MK4) diet for 1 week after which they were administered 14 mg W/kg/day (in drinking water) and subcutaneous K1 (94 mg/kg, 3X/week; to maintain coagulation), for 12 weeks; diets were maintained throughout the experimental period. Respective diet controls (C and C + MK4) received subcutaneous saline and regular water. K1 and M-4 quinone and their epoxide forms (K1O and MK-4O) were assessed in serum, liver, heart, kidney, pancreas, adipose tissue and brain, by HPLC. Group differences were tested by one-way ANOVA, and by t-test for each K vitamer. RESULTS: In C group, K1 was the predominant K vitamer in serum, liver and heart, whereas MK-4 was found in relative higher concentrations in kidney, pancreas, brain, and adipose tissue. In MK-4 containing organs, W treatment was associated with significantly lower MK-4 concentration in pancreas, brain, and heart (P < 0.05) despite the local presence of K1, which suggests that W may block the production of MK-4 by UBIAD1. Compared to C group, K1 concentrations were significantly higher in all organs and serum in WK1 and WK1 + MK4 groups as a result of the subcutaneous administration. Interestingly, in WK1 animals who had received a MK-4 enriched diet (WK1 + MK4), K1 concentrations in naturally K1 rich tissues (i.e., liver, heart and serum) were significantly increased when compared to those from the WK1 group (P < 0.05), suggesting that dietary MK-4 may play a role in modulating the uptake of K1 in these tissues. Except in liver, W administration (WK1 and WK1 + MK4) was associated with higher tissue concentrations of K1 and MK-4 epoxide when compared to C group (P < 0.05). Noteworthy, in WK1 animals who had received a MK-4 enriched diet (WK1 + MK4), naturally rich MK-4 containing organs (i.e., kidney, pancreas, adipose tissue and brain) presented significantly higher concentration of MK-4 epoxide (relative to K1 epoxide), suggesting a preferential use of MK4 by these organs when available from the diet. CONCLUSIONS: In conclusion, results from this study point to modulatory roles of W and dietary MK-4 on tissue distribution of K1 and MK-4 in what appears to be a tissue specific manner. FUNDING SOURCES: CIHR.