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  • Sabutoclax In conclusion we demonstrated phenoconversion of

    2020-02-14

    In conclusion, we demonstrated phenoconversion of CYP3A in stable kidney transplant recipients, and that higher plasma indoxyl sulfate concentrations in these subjects may be involved in the phenomenon. The present findings suggest that dose adjustment of drugs metabolized by CYP3A may be needed in patients with CYP3A5*1 allele and high plasma indoxyl sulfate levels.
    Funding This work was supported in part by Grant-in-Aid for The Research Foundation for Pharmaceutical Sciences, Grant-in-Aid for The Nakatomi Foundation, and Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (15K18926).
    Conflicts of interest
    Acknowledgments
    Introduction Vitamin D3 (VD3), is an important nutrient which can be either synthesized or absorbed from the diet. Traditional roles for VD3 are the maintenance of calcium and phosphate homeostasis. Mechanisms for regulating intestinal calcium Sabutoclax and renal reabsorption are well understood. In positive dietary calcium balance, VD3 mediates systemic calcium absorption through intestinal epithelial calcium channels expressed on the brush border membrane. Well-known examples include transient potential vanilloid type 6 (TRPV6) and calbindin-D9k channels. Serum calcium is largely responsible for the mineralization of bone matrix. In negative calcium balance, the osteoclast calcium reabsorption is repressed and bone calcium is released into the blood stream to rectify hypocalcemia. The VD3-facilitated transcellular transport processes of phosphate are similar to those of calcium, and are controlled by sodium-dependent phosphate co-transporters such as sodium-dependent phosphate co-transporter 2b (NPT2b)2, 3. Global vitamin D receptor (Vdr) knockout (KO) mice developed abnormalities including hypocalcemia, secondary hyperparathyroidism and hypophosphatemia after weaning due to the impaired 1α,25-dihydroxybvitamin D3 (1,25-D3)-dependent intestinal calcium transport. These symptoms were further resolved after the local knock-in of Vdr in intestinal epithelial cells. The kidney is another traditional target organ for VD3. Renal calcium reabsorption in the distal tubules and phosphate reabsorption in the proximal tubules are also regulated by 1,25-D31. Apart from the intestine and kidney, the direct functions of VD3 on bone are controversial. Although one perspective views of this signaling as “redundant”; another suggests that VD3 stimulates bone formation and mineralization in human osteoblasts via several cellular signaling pathways4, 5. In recent decades, pleiotropic functions of VD3 (including its active metabolites, collectively mentioned as VD3) in physiological and pathological conditions have been gradually revealed. This has occurred in part due to increased understanding of the nuclear receptor VDR. Expression profiling shows that VDR is present not only in classical VD3-target organs (intestine, kidney, bone, parathyroid glands, etc.) but also in many other cells with diverse derivations. Newly-discovered VD3 functions indicate its participation in the progression of diverse diseases including metabolic syndromes6, 7, infections, cardiovascular diseases, cancers10, 11, and even central nervous system disorders12, 13. VD3 exhibits diverse effects in animals and humans because it participates in a plethora of biological processes such as proliferation, inflammation, and metabolism1, 14. Moreover, the fundamental VDR-mediated pathway has become recognized in the regulation network of drug metabolism enzymes. Xenobiotic biotransformation mechanisms are critical for inactivation and disposal of both externally-ingested drugs as well as endogenous substances. Orally-administered drugs commonly undergo the processes of absorption, distribution, metabolism and excretion in vivo. Cytochrome P450 (CYP) enzymes, consisting of several subfamilies and further divided into isoforms, are responsible for the metabolism of most drugs. Human CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 participate in about 90% of known phase I drug metabolic reactions. Among these CYPs, CYP3A4 is the most abundant isoform in human liver and intestine, and plays significant roles in the biotransformation of the greatest number of endobiotics and xenobiotics. CYP3A4 expression and activity are strictly regulated by transcription factors and upstream nuclear receptors, among which the most extensively studies are pregnane X receptor (PXR) and constitutive androstane receptor (CAR). PXR and CAR ligands are largely exogenous compounds, indicating complex interaction between xenobiotics and the body. On the contrary, VDR, which regulated by levels of endogenous ligands including VD3, can control homeostatic CYP3A4 activity. Because VD3 can serve as both an endogenous signaling molecule and a nutrient, its bioavailability is subject to complex regulation, with further impaction for the transcriptional activities of CYP3A genes.