Abstract
The pregnane X receptor (PXR) is the key regulator of our defense mechanism against foreign substances such as drugs, dietary nutrients, or environmental pollutants. Because of increased health consciousness, the use of dietary supplements has gradually increased, and most of them can activate PXR. Therefore, an analysis of the interaction between drugs and nutrients is important because altered levels of drug-metabolizing enzymes or transporters can remarkably affect the efficiency of a co-administered drug. In the present study, we analyzed the effect of vitamin K-mediated PXR activation on drug metabolism-related gene expression in intestine-derived LS180 cells via gene expression studies and western blotting analyses. We demonstrated that menaquinone 4 (MK-4), along with other vitamin Ks, including vitamin K1, has the potential to induce MDR1 and CYP3A4 gene expression. We showed that PXR knockdown reversed MK-4-mediated stimulation of these genes, indicating the involvement of PXR in this effect. In addition, we showed that the expression of MDR1 and CYP3A4 genes increased synergistically after 24 h of rifampicin and MK-4 co-treatment. Our study thus elucidates the importance of drug–nutrient interaction mediated via PXR.
Highlights
Vitamin K (VK) is a fat-soluble vitamin that plays a significant role in blood coagulation and bone formation
We found that multi-drug resistance 1 (MDR1) and CYP3A4 mRNA levels were significantly increased at each of the concentrations tested (2.5–10 μM) (Figure 1a,b)
We found that MDR1 mRNA levels were significantly increased by all forms of VK tested, whereas CYP3A4 mRNA levels were significantly increased only by MK-4
Summary
Vitamin K (VK) is a fat-soluble vitamin that plays a significant role in blood coagulation and bone formation. VK1 is predominantly contained in green leafy vegetables and vegetable oils, whereas VK2 is mainly produced by microorganisms, and it is found in fermented foods such as natto (fermented soybeans) and cheese. VK acts as a cofactor of γ-glutamyl carboxylase (GGCX), which modifies the reaction during carboxylation of the γ-position of specific glutamic acid residues of VK-dependent (VKD) proteins to produce γ-carboxy glutamic acid residue (Gla). The enzyme activity of GGCX is important for the activation of blood coagulation factors II, VII, IX, and X, protein S, protein C, and protein Z. VKD proteins such as osteocalcin, matrix Gla protein, and growth arrest-specific protein 6 play important roles in modulating bone metabolism, arterial calcification, and cell proliferation
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