Effect of valproyl morpholine on rat hepatic cytochrome P450

Abstract

Effect of valproyl morpholine (VPM) on rat hepatic cytochrome P450 (CYP) was investigated. Median effective anticonvulsant dose of VPM in mice (100 mg/kg/day) as well as of valproic acid (VPA, the prototype of VPM) (250 mg/kg/day) were given intraperitoneally to male Wistar rats for 7 days. VPM at a dose of 200 mg/kg/day was also given to another group of animals in the same manner. On the day after, the animals were sacrificed and hepatic microsomal subfractions were prepared. Microsomal total CYP contents and CYP activities were determined. In addition, an inhibition effect of VPM on CYP was also studied. The results showed that there were neither induction effects of VPM nor VPA on total CYP contents as well as on the activities of CYP1A1 CYP1A2 and CYP2E1. The exception was observed with VPM at a dosage of 200 mg/kg/day that showed significant induction effect on CYP1A1 activity. Both dosage of VPM administered to the animals in this study inducedCYP2B1 and CYP2B2 of which the activities were more enhanced by 200 mg/kg/day of VPM than by the dosage regimen of 100 mg/kg/day. No inhibition effect of VPM at any concentrations used in the study (0, 0.1, 1, 10, 100, and 1000 muM) on CYP2E1 in an in vitro study was noted. VPM demonstrated no inhibition effect on CYP1A1 CYP1A2 CYP2B1 and CYP2B2 at the lower concentrations but exhibited significant inhibition effect on these isoforms of CYP at the higher concentrations as following: CYP1A1 and CYP1A2 were inhibited by VPM at 1000 muM whereas CYP2B1 and CYP2B2 were inhibited at 100 and 1000 muM in the dose-related manner. Effect of VPM on other isoforms of CYP involving human drug metabolism, should be further explored. Further study to clarify the mechanism of induction or inhibition of VPM on the corresponding affected isoforms of CYP should also be proceeded.