Potentiating effects of non-active/active vitamin D analogues and ketoconazole in parathyroid cells
2007 (English)In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 66, no 3, 399-404 p.Article in journal (Refereed) Published
Background and objective: 1,25-dihydroxyvitamin D3 [1α,25(OH)2D3, calcitriol], and its less calcaemic synthetic analogues have therapeutic potential in several diseases, including hyperparathyroidism (HPT). We have suggested that non-1α-hydroxylated (nonactive) vitamin D analogues may present an alternative in tumour cells expressing 25-hydroxyvitamin D3 1α-hydroxylase (1α-hydroxylase). The aim of this study was to investigate biological effects of a non-1α-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-1α-hydroxylated precursor of the vitamin D analogue EB1089, suppressed PTH secretion and PTH mRNA level as well as increased expression of 25-hydroxyvitamin D3-24-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-1α-hydroxylated vitamin D analogue may elicit vitamin D receptor (VDR) effects in 1α-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.
Place, publisher, year, edition, pages
2007. Vol. 66, no 3, 399-404 p.
Imidazole derivatives, Endocrinology, Ketoconazole, Parathyroid glands, Analog, Vitamin D
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-11155DOI: 10.1111/j.1365-2265.2006.02746.xISI: 000244110100014PubMedID: 17302875OAI: oai:DiVA.org:uu-11155DiVA: diva2:38923