The effects of anticonvulsant drugs on vitamin D3-activating cytochrome P-450-linked monooxygenase systems.
The effects of two anticonvulsant drugs, phenytoin and sodium valproate, on the bioactivation of vitamin D3 have been studied with respect to the microsomal and mitochondrial cytochrome P-450-linked monooxygenase systems that contribute to 25-hydroxylation of vitamin D3 in rabbit liver, and the mitochondrial cytochrome P-450-linked monooxygenase system that catalyzes 1 alpha-hydroxylation of 25-hydroxyvitamin D3 in rabbit kidney. These anticonvulsant drugs were found to inhibit the 25-hydroxylase activity on vitamin D3 in liver microsomes and mitochondria, respectively, but not to inhibit the 1 alpha-hydroxylation of 25-hydroxyvitamin D3, even over a wide concentration range. Moreover, the activities of the components of the cytochrome P-450-linked monooxygenase systems: NADPH-cytochrome P-450 reductase, NADPH-ferredoxin reductase and ferredoxin, were never inhibited by these drugs. It is possible that the inhibition of bioactivation of vitamin D3 by these anticonvulsant drugs causes rickets and osteomalacia, and the site of inhibition is expected to be the cytochrome P-450 mediated reactions in liver mitochondria.
Tomita
S
S
Department of Biochemistry, University Hospital, Faculty of Medicine, Kagawa Medical School, Japan.
Ohnishi
J
J
Nakano
M
M
Ichikawa
Y
Y
D000818:Animals; D001711:Biotransformation; D002762:Cholecalciferol / Q000378:metabolism*; D053493:Cholestanetriol 26-Monooxygenase; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005287:Ferredoxin-NADP Reductase / Q000378:metabolism; D005288:Ferredoxins / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010672:Phenytoin / Q000494:pharmacology*; D011817:Rabbits; D013250:Steroid Hydroxylases / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology*
D005288:Ferredoxins; D007527:Isoenzymes; D002762:Cholecalciferol; D014635:Valproic Acid; D010672:Phenytoin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D053493:Cholestanetriol 26-Monooxygenase; D005287:Ferredoxin-NADP Reductase; D009251:NADPH-Ferrihemoprotein Reductase