Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1979 Oct;64(4):1112–1117. doi: 10.1172/JCI109550

Phenobarbital-induced Alterations in the Metabolism of [3H]Vitamin D3 by the Perfused Rachitic Rat Liver In Vitro

Daniel T Baran 1, Aurora C Fausto 1, Marilyn L Roberts 1, Irene Karl 1, Louis V Avioli 1
PMCID: PMC372223  PMID: 225352

Abstract

Anticonvulsant therapy of seizure disorders in man is associated with the development of complications involving bone and mineral metabolism including hypocalcemia, elevated serum immunoreactive parathyroid hormone levels, and increased amounts of unmineralized bone or osteoid. The latter has been attributed to a reduction in serum-25-hydroxycholecalciferol levels resulting from increased hepatic metabolism of vitamin D. Using an in vitro recycling hepatic perfusion system, we have demonstrated that 5 d of phenobarbital treatment increases the hepatic production of [3H]25-hydroxyvitamin D3 (4.3±0.3 vs. 3.3±0.2%/h, P <0.025) without affecting the biliary excretion of radioactivity. Furthermore, rachitic livers perfused with blood obtained from animals treated with phenobarbital for 5 d also manifested an increase in [3H]25-hydroxyvitamin D3 production (4.6±0.5 vs. 3.3±0.2%/h, P < 0.02). Addition of phenobarbital or its major metabolite, p-hydroxyphenobarbital, directly to the perfusion apparatus had no effect on [3H]25-hydroxyvitamin D3 production. Phenobarbital treatment was also attended by a decrease in the intrahepatic content of [3H]vitamin D3 (11.7±0.4 vs. 17.5±0.7 dpm/mg liver protein, P < 0.001) without alterations in the content of [3H]25-hydroxyvitamin D3. The data collectively suggest that the increased hepatic conversion of [3H]vitamin D3 to [3H]25-hydroxyvitamin D3 attending phenobarbital treatment is secondary to stimulation of the hepatic 25-hydroxylation system(s) by a metabolite of phenobarbital other than p-hydroxyphenobarbital and/or by metabolic alterations resulting from phenobarbital therapy.

Full text

PDF
1117

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Avioli L. V., Lee S. W., McDonald J. E., Lund J., DeLuca H. F. Metabolism of vitamin D3-3H in human subjects: distribution in blood, bile, feces, and urine. J Clin Invest. 1967 Jun;46(6):983–992. doi: 10.1172/JCI105605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. BRAUER R. W., PESSOTTI R. L., PIZZOLATO P. Isolated rat liver preparation; bile production and other basic properties. Proc Soc Exp Biol Med. 1951 Oct;78(1):174–181. doi: 10.3181/00379727-78-19012. [DOI] [PubMed] [Google Scholar]
  3. Bhattacharyya M. H., DeLuca H. F. Subcellular location of rat liver calciferol-25-hydroxylase. Arch Biochem Biophys. 1974 Jan;160(1):58–62. doi: 10.1016/s0003-9861(74)80008-1. [DOI] [PubMed] [Google Scholar]
  4. Björkhem I., Holmberg I. Assay and properties of a mitochondrial 25-hydroxylase active on vitamine D3. J Biol Chem. 1978 Feb 10;253(3):842–849. [PubMed] [Google Scholar]
  5. Bouillon R., Reynaert J., Claes J. H., Lissens W., De Moor P. The effect of anticonvulsant therapy on serum levels of 25-hydroxy-vitamin D, calcium, and parathyroid hormone. J Clin Endocrinol Metab. 1975 Dec;41(06):1130–1135. doi: 10.1210/jcem-41-6-1130. [DOI] [PubMed] [Google Scholar]
  6. DeLuca H. F., Schnoes H. K. Metabolism and mechanism of action of vitamin D. Annu Rev Biochem. 1976;45:631–666. doi: 10.1146/annurev.bi.45.070176.003215. [DOI] [PubMed] [Google Scholar]
  7. Habener J. F., Mahaffey J. E. Osteomalacia and disorders of vitamin D metabolism. Annu Rev Med. 1978;29:327–342. doi: 10.1146/annurev.me.29.020178.001551. [DOI] [PubMed] [Google Scholar]
  8. Haddad J. G., Chyu K. J. Competitive protein-binding radioassay for 25-hydroxycholecalciferol. J Clin Endocrinol Metab. 1971 Dec;33(6):992–995. doi: 10.1210/jcem-33-6-992. [DOI] [PubMed] [Google Scholar]
  9. Hahn T. J., Birge S. J., Scharp C. R., Avioli L. V. Phenobarbital-induced alterations in vitamin D metabolism. J Clin Invest. 1972 Apr;51(4):741–748. doi: 10.1172/JCI106868. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hahn T. J. Bone complications of anticonvulsants. Drugs. 1976;12(3):201–211. doi: 10.2165/00003495-197612030-00003. [DOI] [PubMed] [Google Scholar]
  11. Hahn T. J., Hendin B. A., Scharp C. R., Haddad J. G., Jr Effect of chronic anticonvulsant therapy on serum 25-hydroxycalciferol levels in adults. N Engl J Med. 1972 Nov 2;287(18):900–904. doi: 10.1056/NEJM197211022871803. [DOI] [PubMed] [Google Scholar]
  12. Hahn T. J., Scharp C. R., Avioli L. V. Effect of phenobarbital administration on the subcellular distribution of vitamin D3-3H in rat liver. Endocrinology. 1974 Jun;94(6):1489–1495. doi: 10.1210/endo-94-6-1489. [DOI] [PubMed] [Google Scholar]
  13. Hahn T. J., Scharp C. R., Richardson C. A., Halstead L. R., Kahn A. J., Teitelbaum S. L. Interaction of diphenylhydantoin (phenytoin) and phenobarbital with hormonal mediation of fetal rat bone resorption in vitro. J Clin Invest. 1978 Aug;62(2):406–414. doi: 10.1172/JCI109142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Herz R., Cueni B., Bircher J., Paumgartner G. The excretory capacity of the isolated rat liver. An in vitor--in vivo comparison. Naunyn Schmiedebergs Arch Pharmacol. 1973;277(3):297–304. doi: 10.1007/BF00505668. [DOI] [PubMed] [Google Scholar]
  15. Holick M. F., DeLuca H. F. A new chromatographic system for vitamin D3 and its metabolites: resoluation of a new vitamin D3 metabolite. J Lipid Res. 1971 Jul;12(4):460–465. [PubMed] [Google Scholar]
  16. Jubiz W., Haussler M. R., McCain T. A., Tolman K. G. Plasma 1,25-dihydroxyvitamin D levels in patients receiving anticonvulsant drugs. J Clin Endocrinol Metab. 1977 Apr;44(4):617–621. doi: 10.1210/jcem-44-4-617. [DOI] [PubMed] [Google Scholar]
  17. Kuntzman R. Drugs and enzyme induction. Annu Rev Pharmacol. 1969;9:21–36. doi: 10.1146/annurev.pa.09.040169.000321. [DOI] [PubMed] [Google Scholar]
  18. Levison J. C., Kent G. N., Worth G. K., Retallack R. W. Anticonvulsant induced increase in 25-hydroxy-vitamin D3-1alpha-hydroxylase. Endocrinology. 1977 Dec;101(6):1898–1901. doi: 10.1210/endo-101-6-1898. [DOI] [PubMed] [Google Scholar]
  19. Lund J., DeLuca H. F. Biologically active metabolite of vitamin D3 from bone, liver, and blood serum. J Lipid Res. 1966 Nov;7(6):739–744. [PubMed] [Google Scholar]
  20. MILLER L. L., BLY C. G., WATSON M. L., BALE W. F. The dominant role of the liver in plasma protein synthesis; a direct study of the isolated perfused rat liver with the aid of lysine-epsilon-C14. J Exp Med. 1951 Nov;94(5):431–453. doi: 10.1084/jem.94.5.431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Mosekilde L., Christensen M. S., Lund B., Sorensen O. H., Melsen F. The interrelationships between serum 25-hydroxycholecalciferol, serum parathyroid hormone and bone changes in anticonvulsant osteomalacia. Acta Endocrinol (Copenh) 1977 Mar;84(3):559–565. doi: 10.1530/acta.0.0840559. [DOI] [PubMed] [Google Scholar]
  22. Norman A. W., Bayless J. D., Tsai H. C. Biologic effects of short-term phenobarbital treatment on the response to vitamin D and its metabolites in the chick. Biochem Pharmacol. 1976 Jan 15;25(2):163–168. doi: 10.1016/0006-2952(76)90285-9. [DOI] [PubMed] [Google Scholar]
  23. Reynolds E. H. Chronic antiepileptic toxicity: a review. Epilepsia. 1975 Jun;16(2):319–352. doi: 10.1111/j.1528-1157.1975.tb06062.x. [DOI] [PubMed] [Google Scholar]
  24. Richens A., Rowe D. J. Disturbance of calcium metabolism by anticonvulsant drugs. Br Med J. 1970 Oct 10;4(5727):73–76. doi: 10.1136/bmj.4.5727.73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Silver J., Neale G., Thompson G. R. Effect of phenobarbitone treatment on vitamin D metabolism in mammals. Clin Sci Mol Med. 1974 Apr;46(4):433–448. doi: 10.1042/cs0460433. [DOI] [PubMed] [Google Scholar]
  26. Stamp T. C., Round J. M., Rowe D. J., Haddad J. G. Plasma levels and therapeutic effect of 25-hydroxycholecalciferol in epileptic patients taking anticonvulsant drugs. Br Med J. 1972 Oct 7;4(5831):9–12. doi: 10.1136/bmj.4.5831.9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Whyte M. P., Dekaban A. S. Metabolic fate of phenobarbital. A quantitative study of p-hydroxyphenobarbital elimination in man. Drug Metab Dispos. 1977 Jan-Feb;5(1):63–70. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES