Calcitonin and Parathyroid Hormone

Pento, Glick and Kagan, Endocrinology (1973),1406 studied the effect of intravenous PHT on calcitonin secretion in the pig. Normal basal levels of calcitonin secretion were not significantly changed by PHT. When calcitonin secretion was stimulated by means of glucagon or calcium administration, PHT tended to reduce the level of elevation in plasma calcitonin produced by these two stimuli. The authors state that these findings are in accord with other demonstrations that PHT does not alter normal basal secretion of pituitary-adrenal hormones; but when unusual stimuli are present, PHT exerts a regulatory influence.

1406. Pento, J. T., Glick, S. M., and Kagan, A., Diphenylhydantoin inhibition of calcitonin secretion in the pig. Endocrinology, 92: 330-333, 1973.

Harris, Jenkins and Wills, British Journal of Pharmacology (1974),1131 reported that PHT (15 µg/ml) significantly inhibited parathyroid hormone-induced calcium release from mouse brain calvaria in culture. Phenobarbital (5-25 Vg/ml) had no effect.

1131. Harris, M., Jenkins, M. V. and Wills, M. R. Phenytoin inhibition of parathyroid hormone induced bone resorption in vitro. Brit. J. Pharmac., 50: 405-408, 1974.

Pento, Hormone and Metabolic Research (1976),2017 observed that PHT slows the onset and prolongs the duration of pentagastrin-stimulated calcitonin secretion in the pig.

2017. Pento, J. T., Diphenylhydantoin inhibitions of penta gastrin-stimulated calcitonin secretion in the pig, Hom. Metab. Res., 8: 399-401, 1976.

Hahn, Scharp, Richardson, Halstead, Kahn and Teitelbaum, Journal of Clinical Investigation (1978),1878 reported that PHT inhibited basal and hormonally-stimulated bone resorption as measured by calcium and [3H]-hydroxyproline release in cultures of rat forelimb rudiments. PHT's effect was independent of cAMP and synergistic with that of human calcitonin.

1878. Hahn, T. J., Scharp, C. R., Richardson, C. A., Halstead, L. R., Kahn, A. J. and Teitelbaum, S. L., Interaction of diphenylhydantoin (phenytoin) and phenobarbital with hormonal mediation of fetal rat bone resorption in vitro, J. Clin. Invest., 62: 406-14,1978.

Lerner and Hanstrom, Acta Pharmacology and Toxicology (1980),2708 found that PHT (50 µg/ml) inhibited both bone resorption and release of lysosomal enzymes (ß-glucuronidase and ß-galactosidase) in mouse calvarial bone in organ culture. The authors suggest that inhibition of lysosomal enzyme release may be one important mechanism by which PHT inhibits bone resorption.

2708. Lemer, U., Hanstrom, L., Influence of diphenylhydantoin on lysosomal enzyme release during bone resorption in vitro, Acta Pharmacol. Toxicol., 47: 144-50, 1980.

Ivic and Klisic, Stereologi Iugoslavica (1981),2613 found that PHT (400 µM) inhibited sodium-potassium-ATPase in thyroid parafollicular cells, while slightly stimulating the same activity in parathyroid cells. The authors suggest that this may be a mechanism by which PHT inhibits calcitonin release.

2613. Ivic, M., Klisic, L., Influence of diphenylhydantoin on the sodium, potassium ATPase activity in thyroid parafollicular cells and on the sodium, potassium-ATPase activity in parathyroid glands, Stereol. lugosl., 3(l): 593-8, 1981.

Yi, Seitz and Cooper, Federation Proceedings (1987),3095 using a radioimmunoassay, found that PHT (100 µM) inhibited the release of calcitonin induced by high extra-cellular calcium (2.5 mM) in rat thyroparathyroid complexes in vitro. Release of calcitonin in normal calcium (1 mM) was unaffected. The calcium channel blocker, nitrendipine, also inhibited calcium-stimulated calcitonin release. A calcium channel activator (BAY-K-8644) reversed the inhibitory effects of both PHT and nitrendipine. The authors suggest that PHT inhibits stimulated calcitonin secretion by interacting with calcium channels in thyroid parafollicular cells.

Cooper, Yi and Seitz, Journal of Bone and Mineral Research (1988),3523 incubated baby rat thyroid glands and cultured rat medullary carcinoma C cells with phenytoin (38-100 æM) and measured by immunoassay the calcitonin (CT) secreted into the serum-free medium. Phenytoin did not alter CT release from glands or C cells incubated in 1mM Ca, but, when Ca was raised to 1.75 or 2.5 mM, a marked inhibitory effect of phenytoin was apparent. The inhibitory effect could be negated by including 10 æM BAY-K-8644 (a calcium channel activator) in the medium. Inhibitory effects on CT release also were obtained with 100 æM trifluoperazine or 100 æM nitrendipine, and these inhibitory effects also were counteracted by 10 æM BAY-K-8644. The authors' results show that clinically relevant amounts of phenytoin can inhibit CT release, perhaps by interfering with C-cell Ca channels or by inhibiting calmodulin-dependent processes.

3523. Cooper, C.W., Yi, S.J., and Seitz, P.K., Inhibition by phenytoin of in vitro secretion of calcitonin from rat thyroid glands and cultured rat c-cells, J. Bone Mineral Res., 3(2): 219-23, 1988.

Seitz and Cooper, Journal of Bone and Mineral Research (1989),3524 exposed cultured rat medullary thyroid carcinoma cells for 2 hours to high calcium in the medium. This provoked an increased release of both calcitonin and calcitonin gene-related peptide. The inclusion of 100 æM phenytoin in the medium almost completely countered the ability of high Ca (2.5 mM) to stimulate the secretion of calcitonin and calcitonin gene-related peptide. The authors also examined several other agents with a potential for affecting Ca dependent secretion.

3524. Seitz, P.K. and Cooper, C.W., Cosecretion of calcitonin and calcitonin gene-related peptide from cultured rat medullary thyroid c cells, J. Bone Mineral. Res., 4(1): 129-134, 1989.

See also Refs. 343, 1104, 1485, 1840, 2088, 2281, 2571, 2574, 2623, 2671, 2672, 2707, 2854, 2855.

3095. Yi, S. J., Seitz, P. K., Cooper, C. W., Inhibition of in vitro secretion of rat calcitonin by phenytoin, Fed. Proc, 46(3): 393,1987.
343. Sklans, S., Taylor, R. G., and Shklar, G., Effect of diphenylhydantoin sodium on healing of experimentally produced fractures  in rabbit mandibles, J. Oral Surg., 25: 310-319, 1967.
1104. Gudmundson, C. and Lidgren, L., Does diphenylbydantoin accelerate healing of fractures in mice, Acta Orthop. Scand., 44: 640-649, 1973.
1485. Rovin, S., Sabes, W. R., Eversole, L. R., and Gordon, H. A., Dilantin as a caries retarder, J. Dent. Res., 52: 267, 1973.
1840. Frymoyer, J. W., Fracture healing in rats treated with diphenylhydantoin (Dilantin), J. Trauma, 16(5): 368-70, 1976.
2088. Somerman, M. J., Au, W. Y. W. and Rifkin, B. R., Phenytoin inhibition of bone resorption in organ culture, J. Dent. Res., 56 (Special Issue B) Abstr. 579, 1977.
2281. Ali, N. N., Harvey, W., Harris, M., Bone matrix turnover and anticonvulsant drugs, J. Dent. Res., 61: 548, 1982.
2571. Hanstrorn, L., The effect of diphenylhydantoin on the metabolism of connective tissue macromolecules in oral mucosa and bone in vitro, University of UMEA, Dissertation, 1981.
2574. Harris, M., Goldhaber, P., Root abnormalities in epileptics and the inhibition of parathyroid hormone induced bone resorption by diphenylhydantoin in tissue culture, Archs. Oral Biol., 19; 981-84, 1974.
2623. Jenkins, M. V., Harris, M., Wills, M. R., The effect of phenytoin on parathyroid extract and 25-hydroxycholecalciferol-induced bone resorption: adenosine 3’, 5’ cyclic rnonophosphate production, Calcif. Tissue Res., 16: 163-7, 1974.
2671. Kruse, K., Kracht, U., Inhibition of calcitonin secretion/synthesis by anticonvulsant drugs, Acta Endocrinol., 96: 38-9,1981.
2672. Kruse, K., Kracht, U., Gopfert, G., Response of kidney and bone to parathyroid hormone in children receiving anticonvulsant drugs, Neuropediatrics, 13(l): 3-9, 1982.
2707. Lerner, U., Fredholm, B. B., Hanstrom, L., Diphenylhydantoin inhibits parathyroid hormone and prostaglandin E2-stimulated bone resorption in mouse calvaria without affecting cyclic AMP formation, J. Oral. Pathol., 14: 644-53, 1985.
2854. Pedersen, J. C., An evaluation of the changes in bone turnover in an in vitro system: the direct effect on bone turnover of diphenylhydantoin, Acta Orthop. Scand., 53 (4): 703, 1981.
2855. Pedersen, J. G., Lund, B. J., Reimann, I., Influence of diphenylhydantoin on isotope release and bone enzymes in vitro, Acta Orthop. Scand., 53: 885-88, 1982.