Interactions between folate metabolism, phenytoin metabolism, and liver microsomal cytochrome P450.
The majority of epileptic patients treated with phenytoin (DPH) develop a drug-related decrease in serum folate levels. In the present study the hypothesis was investigated that increased folate utilization for DPH metabolism or for enzyme induction may contribute to the mechanism by which DPH induces folate deficiency. In addition, the effect of folate deficiency on microsomal enzyme induction was determined. Sprague-Dawley rats were fed AIN-76 diet which contained either no folate or 2 mg/kg folic acid. The DPH metabolism as well as the folate-dependent oxidation of formate and histidine and the metabolism of model substrates of microsomal cytochrome P450 (ethoxycourmarin and p-nitroanisole) were measured in hepatocytes isolated from these rats. Hepatocyte concentrations of cytochrome P450 were also determined. Cells from rats fed folate-deficient diet had reduced concentrations of folate, but the cytochrome P450 concentrations were unchanged. Phenobarbital increased cytochrome P450 concentration to an equal extent in both diet groups, but it had no effect on liver folate levels. Phenytoin, at the dose given, did not induce cytochrome P450, but a small increase in the metabolism of DPH, p-nitroanisole, and ethoxycoumarin was observed. The metabolism of formate and histidine to CO2 was decreased in folate-deficient cells but not altered by phenobarbital pretreatment. Ethoxycoumarin and p-nitroanisole metabolism were the same in control and folate-deficient hepatocytes, and the rates were increased in both diet groups by phenobarbital pretreatment. The rate of DPH metabolism was unaltered by folate deficiency and the rate was increased by phenobarbital pretreatment in both folate-deficient and control cells. The results of these experiments show that hepatic DPH metabolism is not dependent upon the cellular concentration of folates. Furthermore, folate deficiency does not alter the activity of the liver microsomal cytochrome P450 system or its inducibility. The results suggest that the folate deficiency induced by DPH is not due to utilization of folates in DPH metabolism.
D000818:Animals; D004032:Diet; D005492:Folic Acid / Q000378:metabolism* / Q000494:pharmacology; D005494:Folic Acid Deficiency / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D010672:Phenytoin / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D010672:Phenytoin; D005492:Folic Acid; D010634:Phenobarbital