Perilla frutescens modulates CYP1A1/2 and HO-1 and activates Nrf2 in oxidative stress-induced hepatotoxicity

Abstract

We speculated that lipid peroxidation induced by tert-butyl hydroperoxide (t-BHP) in liver is closely linked with the metabolism mediated by CYPs. In this study, we have examined the effect of Perilla leaf extract (PLE) on CYPs using 7-ethoxyresorufin-O-deethylase (EROD, indicator of CYP1A1), 7-methoxyresorufin-O-demethylase (MROD, indicator of CYP1A2), erythromycin N-demethylase (ERDM, indicator of CYP3A), and p-nitrophenol hydroxylase (PNPH, indicator of CYP2E1) in rat liver. Rats orally pretreated with PLE (250, 500, and 1,000 mg/kg b.w.) for 5 days were administered with a single i.p. dose of t-BHP (0.5 mmol/kg). Kinetic analysis of CYP1A1/2 activities in t-BHP-treated liver demonstrated that PLE inhibits the enzyme activities by competitive and noncompetitive inhibitions. The pretreatment with PLE decreased the expression of CYP1A1/2 mRNA and protein compared with t-BHP treatment alone. A Phase II enzyme, heme oxygenase-1 (HO-1), is involved in hepatoprotection against oxidative damage, and we confirmed that PLE increases the levels of HO-1 mRNA and protein, as well as its activity in t-BHP-induced liver damage. PLE administration resulted in enhanced nuclear translocation and ARE binding of NF-E2-related factor 2. These findings suggest that PLE protects against t-BHP-induced hepatotoxicity through modulated activity and expression of selective CYPs, and ARE-driven induction of HO-1 expression and its activity.