title: Vitamin D3 polyunsaturated side-chain analogues (EB1089, GS1590) and the 20-epi-vitamin D3 analogue CB1393 suppress parathyroid hormone secretion and mRNA level in bovine parathyroid cells.
abstract: Several vitamin D analogues, with reduced hypercalcemic and hyperphosphatemic toxicity at therapeutic dosages, are in clinical use for prevention and treatment of secondary hyperparathyroidism (HPT) in chronic renal failure. We have performed a first in vitro evaluation of five vitamin D analogues displaying less calcemic activity in normal rats, considerably more antiproliferative ability and higher transcription activation potential than 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), with the future prospects in mind to identify even more effective and less calcemic vitamin D analogues for treatment of HPT. The vitamin D analogues EB1089 and GS1590 have polyunsaturated side-chains, whereas HEP187, MC1598 and CB1393 display altered stereochemistry at carbon 20. In primary cultures of bovine parathyroid cells EB1089, GS1590, CB1393 and MC1598 as well as the comparative controls 1,25(OH)(2)D(3), 22-oxacalcitriol (OCT, maxacalcitol), 19-nor-1,25(OH)(2)D(2) (paricalcitol) and 1alpha(OH)D(2) (doxercalciferol) significantly suppressed PTH secretion or reduced PTH mRNA level at 10(-8), 10(-10), and 10(-11)M for all compounds except for MC1598 at the lowest concentration. The analogue HEP187 displayed no PTH suppressive activity. We conclude that the vitamin D analogues EB1089, GS1590 and CB1393 may be suitable for treatment of hyperparathyroidism secondary to uremia and that further evaluation in vivo should be considered.
authors.affiliation: Department of Surgical Sciences, Uppsala University Hospital, Klinisk forskningsavdelning 2, Ingang 70, Plan 3, Lab 9, SE-751 85 Uppsala, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Segersten
authors.forename: Pernille Kaae
authors.initials: PK
authors.lastname: Holm
authors.forename: Lise
authors.initials: L
authors.lastname: Binderup
authors.forename: Göran
authors.initials: G
authors.lastname: Akerström
authors.forename: Per
authors.initials: P
authors.lastname: Hellman
authors.forename: Gunnar
authors.initials: G
authors.lastname: Westin
mesh_terms: D000818:Animals; D001483:Base Sequence; D002417:Cattle; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000031:analogs & derivatives / Q000494:pharmacology*; D017931:DNA Primers; D006801:Humans; D010281:Parathyroid Hormone / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D002762:Cholecalciferol