Inhibitory effects of the medicinal herb, Thonningia san gunea, on liver drug metabolizing enzymes of rats

Abstract

In this study we examined the effect of the aqueous extract of Thonningia sanguinea (T.S.) on 7-ethoxyresorufin 0- deethylase (EROD, CYPlAl), 7-pentoxyresorufin-dealkylase (PROD, CYP2B1/2), 7-methoxyresorufin 0- demethylase (MROD, CYP1A2), aniline hydroxylase (aniline, CYP2E1), p-nitrophenol hydroxylase (PNPH, CYP2E1) and erythromycin N-demethylase (ERDM, CYP3A1) in rat liver in vitro and in vivo. Although T.S. extract increased ERDM activity in induced rat liver microsomes, it showed a dose-dependent inhibitory effectin vitro on other P450 monooxygenase activities particularly EROD and PROD, which are mediated primarily by CYPlAl and CYP2B1/2, respectively. PROD, EROD and MROD activities were also decreased by 18%, 19% and 40%, respectively, in hepatic microsomes prepared from rats treated with T.S. extract for 3 days. Kinetic analysis of CYP activity of 3-methylchloranthrene-induced microsomes demonstrated that T.S. inhibited EROD and MROD activities by a noncompetitive and competitive mechanism, respectively. The analysis of alterations produced by T.S. on PROD kinetic parameters in phenobarbital-induced microsomes suggested that the inhibition is noncompetitive. Pretreatment of rats with T.S. prolonged pentobarbital and phenobarbital sleeping time; however, plasma phenobarbital concentration determined on awakening showed no significant difference between control and T.S.-treated rats. T.S. was also found to be a potent inhibitor of the liver cytosolic glutathione S-transferase. These data suggest that selective modulation of CYP isoenzymes by T.S. might con-tribute to protection of the liver from xenobiotic-induced intoxication or to alteration of the action of drug (s) conco-mitantly administered besides its antioxidative properties.