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  • Title: Participation of a rat liver cytochrome P-450 induced by pregnenolone 16 alpha-carbonitrile and other compounds in the 4-hydroxylation of mephenytoin.
    Author: Shimada T, Guengerich FP.
    Journal: Mol Pharmacol; 1985 Aug; 28(2):215-9. PubMed ID: 4022003.
    Abstract:
    Mephenytoin 4-hydroxylation, which has been found to be one of the reactions showing genetic polymorphism in humans, has been studied using rat liver microsomes. Pregnenolone 16 alpha-carbonitrile, dexamethasone, troleandomycin, and phenobarbital (but not beta-naphthoflavone) induced the hydroxylation activity to various extents. Mephenytoin itself also increased 4-hydroxylation considerably. Liver microsomes prepared from male rats contained higher mephenytoin hydroxylase activity than preparations isolated from females. These results suggest that a cytochrome P-450 which is inducible by pregnenolone 16 alpha-carbonitrile is involved in the 4-hydroxylation of mephenytoin. We purified cytochrome P-450PCN-E from pregnenolone 16 alpha-carbonitrile-treated rats using modifications of previous methods and compared its 4-hydroxylase activity with other purified rat cytochromes P-450. P-450PCN-E had the highest activity among the 10 purified rat cytochromes P-450 tested and antibodies raised to P-450PCN-E completely inhibited mephenytoin 4-hydroxylase in rat liver microsomes, suggesting the involvement of P-450PCN-E in this reaction. The microsomal concentration of P-450PCN-E, estimated by immunoelectrophoretic blotting analysis, correlated well with the hydroxylase activity in rat liver microsomes (r = 0.906). Mephenytoin induced P-450PCN-E as well as other phenobarbital-inducible cytochromes P-450.
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