Phenobarbital-induced alterations in the metabolism of [3H]vitamin D3 by the perfused rachitic rat liver in vitro.
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 [(3)H]25-hydroxyvitamin D(3) (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 [(3)H]25-hydroxyvitamin D(3) 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 [(3)H]25-hydroxyvitamin D(3) production. Phenobarbital treatment was also attended by a decrease in the intrahepatic content of [(3)H]vitamin D(3) (11.7+/-0.4 vs. 17.5+/-0.7 dpm/mg liver protein, P < 0.001) without alterations in the content of [(3)H]25-hydroxyvitamin D(3). The data collectively suggest that the increased hepatic conversion of [(3)H]vitamin D(3) to [(3)H]25-hydroxyvitamin D(3) 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.
D000818:Animals; D002762:Cholecalciferol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D010477:Perfusion; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D012279:Rickets / Q000378:metabolism*
D002762:Cholecalciferol; D010634:Phenobarbital