Off‑target effect of imatinib and nilotinib on human vitamin D3 metabolism
Lysann Kroschwald1, Meinolf Suttorp2, Josephine Tabea Tauer3
1Department of Dermatology, University Hospital Carl Gustav Carus, TU Dresden, D‑01307 Dresden, Germany.
Abstract:
Prolonged treatment with tyrosine kinase inhibitors (TKI) including imatinib (IMA) or nilotinib (NIL), induces severe disturbances of bone metabolism in patients with chronic myeloid leukaemia. As vitamin D3 (VD3) is involved in the complex cycle of bone remodelling, the present study investigated in vitro, the influence of IMA and NIL on VD3 metabolism i) in HaCaT cells and ii) in cultured outer root sheath keratinocytes (ORS‑KC) from hair follicles of IMA treated children. Cells were incubated in the presence of IMA or NIL. Concomitantly, specific inhibitors were applied to analyze the inhibition of the VD3 processing cytochrome P450 isoenzyme family by TKIs. In vitro, IMA and NIL significantly impaired the production of calcitriol in HaCaT and cultured ORS‑KC cells from hair follicles of IMA treated children. For NIL, this inhibitory effect demonstrated a 4‑fold increase. In HaCaT and ORS‑KC, application of specific CYP450 inhibitors revealed that CYP27B1 was impaired by IMA and NIL leading to an intracellular accumulation of calcidiol. However, during TKI treatment, KC of IMA treated children revealed no differences in calcidiol and calcitriol levels. In conclusion, IMA and NIL interfere with the vitamin D3 cascade due to their metabolism by CYP27B1.
Insights
Tyrosine kinase inhibitors like imatinib and nilotinib disrupt vitamin D3 metabolism by inhibiting CYP27B1. This leads to impaired calcitriol production, affecting bone health in chronic myeloid leukemia patients.
Area of Science:
- Biochemistry
- Pharmacology
- Dermatology
Background:
- Tyrosine kinase inhibitors (TKIs) such as imatinib (IMA) and nilotinib (NIL) are crucial in treating chronic myeloid leukemia (CML).
- Prolonged TKI therapy is linked to significant bone metabolism disturbances.
- Vitamin D3 (VD3) plays a vital role in bone remodeling processes.
Purpose of the Study:
- To investigate the in vitro effects of imatinib and nilotinib on vitamin D3 metabolism.
- To examine VD3 metabolism in HaCaT cells and outer root sheath keratinocytes (ORS-KC).
- To determine the role of specific cytochrome P450 enzymes in TKI-induced VD3 metabolism disruption.
Main Methods:
- Cells (HaCaT and ORS-KC) were incubated with imatinib or nilotinib.
- Specific CYP450 inhibitors were used to assess TKI interference with VD3 processing.
- Intracellular levels of calcidiol and calcitriol were measured.
Main Results:
- Both imatinib and nilotinib significantly impaired calcitriol production in HaCaT and ORS-KC cells.
- Nilotinib exhibited a 4-fold greater inhibitory effect on calcitriol production compared to imatinib.
- TKIs inhibited CYP27B1, leading to calcidiol accumulation, but no significant changes were observed in keratinocytes from TKI-treated children.
Conclusions:
- Imatinib and nilotinib interfere with the vitamin D3 metabolic cascade.
- The observed interference is primarily due to the metabolism of TKIs by CYP27B1.
- Understanding this interaction is crucial for managing bone health in CML patients undergoing TKI treatment.
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