Potentiating effects of nonactive/active vitamin D analogues and ketoconazole in parathyroid cells.

Abstract

BACKGROUND AND OBJECTIVE:

1,25-dihydroxyvitamin D(3)[1alpha,25(OH)(2)D(3), calcitriol], and its less calcaemic synthetic analogues have therapeutic potential in several diseases, including hyperparathyroidism (HPT). We have suggested that non-1alpha-hydroxylated (nonactive) vitamin D analogues may present an alternative in tumour cells expressing 25-hydroxyvitamin D(3) 1alpha-hydroxylase (1alpha-hydroxylase). The aim of this study was to investigate biological effects of a non-1alpha-hydroxylated vitamin D analogue in normal and tumour parathyroid cells.

PATIENTS AND METHODS:

Effects of vitamin D analogues and ketoconazole on parathyroid hormone (PTH) secretion (radioimmunoassay) and PTH mRNA expression (reverse transcription-polymerase chain reaction) were studied in primary bovine parathyroid cells. Proliferation of tumour cells isolated from HPT patients was determined by thymidine incorporation.

RESULTS:

EB1285, non-1alpha-hydroxylated precursor of the vitamin D analogue EB1089, suppressed PTH secretion and PTH mRNA level as well as increased expression of 25-hydroxyvitamin D(3)-24-hydroxylase (24-hydroxylase) in bovine parathyroid cells. EB1285 also inhibited cell proliferation of parathyroid tumour cells from primary (pHPT) and secondary HPT (sHPT) patients. Combined treatment with the cytochrome P450-dependent enzyme inhibitor ketoconazole and EB1285 or with active vitamin D compounds potentiated the suppressive effect on PTH secretion from bovine parathyroid cells. Ketaconazole alone displayed PTH suppression and increased 24-hydroxylase expression.

CONCLUSION:

The results support the idea that a non-1alpha-hydroxylated vitamin D analogue may elicit vitamin D receptor (VDR) effects in 1alpha-hydroxylase expressing parathyroid tumour cells. Further studies are warranted to elucidate whether precursor vitamin D analogues as well as inhibitors of 24-hydroxylase present therapeutic alternatives in patients suffering from HPT.

• Authors: Ulrika Segersten, Peyman Björklund, Per Hellman, Göran Akerström, Gunnar Westin
• Journal: Clinical endocrinology (Clin Endocrinol (Oxf)) Vol. 66 Issue 3 Pg. 399-404 (Mar 2007) ISSN: 0300-0664 [Print] England
• PMID: 17302875 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Parathyroid Hormone
• Prodrugs
• RNA, Messenger
• Receptors, Calcitriol
• Vitamin D
• Steroid Hydroxylases
• Vitamin D3 24-Hydroxylase
• 25-Hydroxyvitamin D3 1-alpha-Hydroxylase
• Ketoconazole

Topics

• 25-Hydroxyvitamin D3 1-alpha-Hydroxylase (antagonists & inhibitors)
• Animals
• Cattle
• Cell Proliferation (drug effects)
• Cells, Cultured
• Depression, Chemical
• Drug Synergism
• Enzyme Inhibitors (pharmacology)
• Humans
• Immunohistochemistry
• Ketoconazole (pharmacology)
• Parathyroid Glands (metabolism)
• Parathyroid Hormone (genetics, metabolism)
• Parathyroid Neoplasms (metabolism)
• Prodrugs (pharmacology)
• RNA, Messenger (analysis)
• Receptors, Calcitriol (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Steroid Hydroxylases (analysis, metabolism)
• Tumor Cells, Cultured
• Vitamin D (analogs & derivatives, pharmacology)
• Vitamin D3 24-Hydroxylase