Rifampicin induces the bone form of alkaline phosphatase in humans

• Published in: Basic & clinical pharmacology & toxicology Vol. 130; no. S1; pp. 81 - 94
• Main Authors: Nabil, Heba, Kummu, Outi, Lehenkari, Petri, Rysä, Jaana, Risteli, Juha, Hakkola, Jukka, Hukkanen, Janne
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.01.2022
• Subjects: Alkaline phosphatase; Alkaline Phosphatase - blood; Alkaline Phosphatase - genetics; Animals; Biomarkers; Biomedical materials; bone; Bone marrow; Clinical trials; Cross-Over Studies; Drug metabolism; Electrophoresis; Gene expression; Humans; Intestine; Ligands; Liver; Liver - drug effects; Liver - metabolism; Male; Mesenchyme; Metabolic rate; Mice; Mice, Inbred C57BL; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteoprotegerin; Phosphatase; pregnane X receptor; Pregnane X Receptor - drug effects; Pregnane X Receptor - metabolism; Pregnenolone; pregnenolone 16α‐carbonitrile; Pregnenolone Carbonitrile - pharmacology; Rats; Rats, Sprague-Dawley; Receptors; rifampicin; Rifampin; Rifampin - pharmacology; RNA, Messenger - genetics; Stromal cells; Xenografts; rifampicin; pregnenolone 16α-carbonitrile; alkaline phosphatase; bone; pregnane X receptor
• ISSN: 1742-7835; 1742-7843
• DOI: 10.1111/bcpt.13586

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.