Rifampicin induces the bone form of alkaline phosphatase in humans
Nabil, Heba; Kummu, Outi; Lehenkari, Petri; Rysä, Jaana; Risteli, Juha; Hakkola, Jukka; Hukkanen, Janne (2021-12-29)
Nabil, H, Kummu, O, Lehenkari, P, et al. Rifampicin induces the bone form of alkaline phosphatase in humans. Basic Clin Pharmacol Toxicol. 2022; 130( S1): 81– 94. https://doi.org/10.1111/bcpt.13586
© 2021 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
https://creativecommons.org/licenses/by-nc/4.0/
https://urn.fi/URN:NBN:fi-fe202201122012
Tiivistelmä
Abstract
Pregnane X receptor (PXR) is a xenobiotic-sensing nuclear receptor that regulates drug metabolism in the liver and intestine. In our clinical trials on healthy volunteers to discover novel metabolic functions of PXR activation, we observed that rifampicin, a well-established ligand for human PXR, 600 mg daily for a week, increased the plasma alkaline phosphatase (ALP) significantly compared with the placebo. Further analysis with lectin affinity electrophoresis revealed that especially the bone form of ALP was elevated. To investigate the mechanism(s) of bone ALP induction, we employed osteoblast lineage differentiated from human primary bone marrow–derived mesenchymal stromal cells. Rifampicin treatment increased ALP activity and mRNA level of bone biomarker genes (ALP, MGP, OPN and OPG). PXR expression was detected in the cells, but the expression was very low compared with the human liver. To further investigate the potential role of PXR in the ALP induction, we treated mice and rats with a rodent PXR ligand pregnenolone 16α-carbonitrile (PCN). However, PCN treatment did not increase plasma ALP activity or bone ALP mRNA expression. In conclusion, rifampicin treatment induces the bone form of ALP in the serum of healthy human volunteers. Further studies are required to establish the mechanism of this novel finding.
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