title: Dissociation of phosphaturia and 25(OH)D-1 alpha-hydroxylase trophism using a novel analogue of parathyroid hormone.
abstract: Certain parathyroid hormone (PTH) analogues have been shown to selectively impair some but not all physiological actions of PTH. In this study, transaminated rat (r) PTH [TA-rPTH-(1-34)], a PTH analogue that differs from the rPTH-(1-34) fragment in that the NH2-terminal alanine is converted to pyruvate, was infused into mice to determine its properties in vivo and specifically to determine whether stimulation of 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-hydroxylase) activity was more dependent on concomitant renal handling of phosphate or on generation of adenosine 3',5'-cyclic monophosphate (cAMP). High-performance liquid chromatography-purified TA-rPTH-(1-34) was infused into C57BL mice at 10 or 30 pmol/h for 24 h. At 30 pmol/h, TA-rPTH-(1-34) was comparable with rPTH-(1-34) in its hypophosphatemic and phosphaturic effects but was less potent than rPTH-(1-34) in raising serum calcium. TA-rPTH-(1-34) was markedly less effective in stimulating renal 1 alpha-hydroxylase than rPTH-(1-34). Stimulation of urinary cAMP excretion occurred after infusion with TA-rPTH-(1-34), but this effect was significantly less than that seen with rPTH-(1-34). These findings indicate that PTH-induced hypophosphatemia and phosphaturia can be uncoupled from PTH stimulation of 1 alpha-hydroxylase. Furthermore, cAMP-related signal transduction appears to be more significant in regulation of 1 alpha-hydroxylase than mechanisms that mediate PTH-sensitive phosphate transport, independent of cAMP.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06510.
authors.forename: T O
authors.initials: TO
authors.lastname: Carpenter
authors.forename: M D
authors.initials: MD
authors.lastname: McPhee
authors.forename: R
authors.initials: R
authors.lastname: Bort
authors.forename: M A
authors.initials: MA
authors.lastname: Mitnick
authors.forename: D L
authors.initials: DL
authors.lastname: Carnes
mesh_terms: D000818:Animals; D002118:Calcium / Q000097:blood / Q000652:urine; D053493:Cholestanetriol 26-Monooxygenase; D000242:Cyclic AMP / Q000652:urine; D051379:Mice; D008810:Mice, Inbred C57BL; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010710:Phosphates / Q000652:urine*; D010758:Phosphorus / Q000097:blood / Q000652:urine; D013250:Steroid Hydroxylases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D010281:Parathyroid Hormone; D010710:Phosphates; D010758:Phosphorus; D000242:Cyclic AMP; D013250:Steroid Hydroxylases; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse; D002118:Calcium