Rutaecarpine effects on expression of hepatic phase-1, phase-2 metabolism and transporter genes as a basis of herb–drug interactions

Rutaecarpine is an alkaloid of Evodia rutaecarpa which is traditionally used to treat human diseases. Rutaecarpine has been used in combination with other drugs in the treatment of disorders and found to produce herb-drug interactions. The basis of these herb-drug interactions is not completely understood.To examine the effects of rutaecarpine on the expression of drug processing genes, including Phase-1 (P450 enzyme genes), Phase-2 (glucuronidation and sulfation genes) and Phase-3 (drug transporters) in liver of mice.Mice were orally administered rutaecarpine at the doses of 10, 20, and 30 mg/kg for consecutive 7 days. Twenty-four hours after the last dose, blood and liver were collected. Total RNA was isolated, purified, and subjected to real-time RT-PCR analysis of genes of interest.Rutaecarpine administration induced Cyp1a2, 2b10 and 2e1 as previously reported. Cyp3a11 and Cyp4a10 were also induced. For phase-2 enzyme genes, rutaecarpine increased glucuronyltransferases (Ugt1a1 and Ugt1a6), but had no effects on sulfotransferase (Sult1a1 and Sult1b1). Most interestingly, rutaecarpine increased hepatic uptake of organic anion transporting peptides (Oatp1a1, Oayp1a4, Oatp1b2, and Oatp2b1) and induced efflux transporter such as multidrug resistance-associated proteins (Mrp1, Mrp2, Mrp3, and Mrp4), especially at the doses of 20mg/kg and above.The interactions of rutaecarpine with drugs involve not only the induction of cytochrome P450 enzyme genes, but also the induction of hepatic transporters and phase-2 enzyme genes. The effects of rutaecarpine on these drug processing genes could play integrated roles in producing herb-drug interactions.