Biomedical subjects
Publications and source records attributed to I MacIntyre.
The chemistry and physiology of calcitonin are reviewed with particular emphasis on the evolution of the hormone and its modern role in humans. It seems likely that the relative deficiency of calcitonin in women may be important in postmenopausal bone loss. A major therapeutic application of calcitonin is in the treatment of Paget's disease of bone, and current recommendations for therapy are presented.
A 2-wk course of rifampicin orally (600 mg/day) in 8 male subjects resulted in a consistent fall in plasma 25-hydroxycholecalciferol (25-OHD) levels of around 70%, accompanied by increased oxidation of antipyrine and 6 beta-hydroxycortisol (indicative of hepatic enzyme induction). Plasma levels of 1,25-dihydroxycholecalciferol, parathyroid hormone, and calcitonin were not altered. The fall in 25-OHD may represent the earliest lesion of drug-induced osteomalacia.
A molecule very closely resembling human calcitonin immunologically and chromatographically was extracted from the nervous systems of several protochordates and a cyclostome, Myxine. The presence of human calcitonin-like molecules in the nervous systems of primitive chordates suggests that they have some function in the nervous system of these species and that the bone-regulating function of the calcitonins may have arisen much later in the vertebrates.
Five human breast cancer cell lines (MCF 7, T 47D, BT 20, MDA 157, and MDA 231) and a human breast epithelial cell line (HBL 100) have been found to contain specific high-affinity receptors for 1,25-dihydroxyvitamin D3, Kd values ranged from 0.6 to 2.0 X 10(-11) M and receptor concentration from 31 to 150 fmol/mg cytosol protein. Two of the breast cancer lines (MCF 7 and T 47D) contain specific high-affinity receptors for calcitonin and a calcitonin-responsive adenylate cyclase, which have been characterized with the aid of salmon, eel, and human calcitonins and in several substituted analogues of human calcitonin. The 1,25-dihydroxyvitamin D3 receptor may reflect a normal property of the breast cell. Breast cancer cell lines provide a useful source of 1,25-dihydroxyvitamin D3 receptors. Their coexistence with a calcitonin receptor and biological response in some breast cancers offers the opportunity to investigate new aspects of breast cancer endocrinology.
We have demonstrated that a variety of cultured breast cancer cell lines, human breast cancers, non-malignant breast tumours and normal rabbit breast tissue contain specific, high-affinity, low-capacity receptors for 1,25-(OH)2D3. Considered with the ability of normal breast tissue to transport calcium from blood into breast milk, which has recently been shown to be stimulated by 1,25-(OH)2D3, the presence of this receptor could explain the high incidence of hypercalcaemia in this common disease and has important implications for the management of metastatic breast cancer. Finally these findings suggest that breast is a normal target organ for 1,25-(OH)2D3 action.
Plasma-calcitonin levels, measured with an established and reliable extraction radioimmunoassay technique, were significantly higher throughout normal pregnancy and lactation than in normal non-pregnant women, and were not immediately influenced by the acute stimulation of breast-feeding. Thus, more calcitonin circulates at times of physiologically increased calcium need. It is suggested that an important function of calcitonin is the protection of the healthy maternal skeleton from excessive resorption by opposing the resorptive action of 1,25-dihydroxycholecalciferol on bone.
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The kidney should be regarded as an organ of central importance in the regulation of calcium metabolism. Its secretion product, 1 alpha,25(OH)2D3, is regulated by several factors, including the calcium and phosphorus content of the diet, parathyroid hormone and the level of 1 alpha,25(OH)2D3 itself. The main occasions in health where 1 alpha,25(OH)2D3 secretion is enhanced are during growth and reproduction. In these situations the secretion of this new renal hormone is under at least partial control of growth hormone and prolactin.
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Primary cultures of chick kidney cells convert 25-hydroxycholecalciferol into more-polar metabolites. Cells from vitamin D-deficient chicks have high 25-hydroxycholecalciferol 1 alpha-hydroxylase (1 alpha-hydroxylase) activity, but no 25-hydroxycholecalciferol 24-hydroxylase (24-hydroxylase) activity. Physiological concentrations of 1,25-dihydroxycholeclaciferol suppress 1 alpha-hydroxylase and induce 24-hydroxylase activity. The inhibition of 1 alpha-hydroxylase preceded the induction of 24-hydroxylase. In contrast, oestradiol-17 beta had no effect on the activity of either hydroxylase under a variety of experimental conditions. These results clearly demonstrate that 1,25-dihydroxycholecalciferol, but not oestrogen, acts directly on the kidney cells to regulate the metabolism of 25-hydroxycholecalciferol.
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A new radioimmunoassay technique was used to measure plasma-calcitonin in normal subjects. Plasma-calcitonin concentrations in women were less than 25% of those in men, and were often undetectable. However, during pregnancy or administration of the oestrogen-progestagen contraceptive pill, plasma-calcitonin equalled or exceeded male concentrations. These findings are consistent with an effect on calcitonin production of normal male testosterone concentrations and concentrations of the sex steroids during pregnancy. Calcitonin may protect the skeleton during calcium stress. Further, although it is unknown whether a deficiency of the hormone plays a role in postmenopausal osteoporosis, this is now a definite possibility which requires urgent investigation.
(1) Vitamin D is the precursor of an extremely potent calcium regulating hormone, 1,25(OH)2D3, which is secreted by the kidney. (2) The secretion of 1,25(OH)2D3 by the kidney is influenced by the calcium and phosphorus content of the diet, parathyroid hormone, and 1,25(OH)2D3 itself. (3)Prolactin and growth hormone are importnat regulators of vitamin D metabolism during pregnancy and growth.
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