Effect of (N-Hydroxymethyl)-2-propylpentamide on rat hepatic cytochrome P450

Abstract

The effect of (N-hydroxymethyl)-2-propylpentamide (HPP), one of valproic acid (VPA) derivative possessing anticonvulsant activity, on rat hepatic cytochrome P450 (CYP) was studied in ex vivo and in vitro systems. In ex vivo study, to study the short-term effect of HPP, HPP at a dosage of 100, 200 mg/kg/day or VPA 250 mg/kg/day were given intraperitoneally to male wistar rats once daily for 7 days. On the day after, rat liver microsomes were prepared and total CYP contents as well as CYP activities were determined using ethoxyresorufin o-dealkylase for CYP1A1, methoxyresorufin 0-dealkylase for CYP1A2, benzyloxy- & pentoxyresorufin o-dealkylase for CYP2B1/2B2 and aniline 4-hydroxylase for CYP2E1. In in vitro study, inhibitory effects of HPP at final concentrations of 0.1, 1, 10, 100 and 1000 micro m. on beta-napthoflavone-induced CYP1A1/1A2, phenobarbital-induced CYP2B1/2B2 and ethanol-induced CYP2E1 activities were studied. The results showed that VPAat the dose studied did not have any effect on total CYP contents and all CYP activities. However, HPP 100 and 200 mg/kg/day significantly induced CYP1A1 and CYP2B1/2B2 activities. Stronger induction effect was seen on CYP2B1/2B2 than on CYP1A1. In addition, HPP at 100 and 1000 micro m. significantly inhibited CYP2B1/2B2 activities in vitro with IC50 of about 752 micro m. These results suggested that the inhibitory effect of HPP on CYP2B1/2B2 activities may be, in part, responsible for prolongation of barbiturate sleeping time after single dose administration of HPP. The induction effect of HPP, but not VPA, on CYP1A1 and CYP2B1/2B2 activities after being administered for 7 days may be resulted from direct effect of HPP or its metabolites. Since CYP2B1/2B2 which were found to be strongly induced in rats are not expressed in himan, further studies are needed to clarify the metabolic pathways of HPP and the CYPs involved as well as the effect of HPP on human CYPs. Furthermore, in vivo studies to verify the potential of drug interaction and carcinogenic risk are also needed