Induction of cytochrome P450s by rutaecarpine and metabolism of rutaecarpine by cytochrome P450s.
Rutaecarpine is an alkaloid originally isolated from the unripe fruit of Evodia rutaecarpa. Recently, rutaecarpine has been characterized to have an anti-inflammatory activity through cyclooxygenase-2 inhibition. In the present studies, the effects of rutaecarpine on liver cytochrome P450 s (P450s) and P450 s involved in the metabolism of rutaecarpine were studied in vivo and in vitro, respectively, because the data are crucial in the early development of rutaecarpine as a new drug candidate. Oral administration to male ICR mice of rutaecarpine for 3 consecutive days induced liver P450 1A-, 2B- and 2E1-selective monooxygenase activities. The induction of P450 1A and 2B by rutaecarpine was confirmed by Western immunoblotting. When rutaecarpine was incubated with rat liver microsomes in the presence of an NADPH-generating system, five metabolites were detected by UV and mass spectral analyses. The 3-methylcholanthrene- and phenobarbital-induced microsomes greatly increased the formation of metabolites. Our present results suggest that rutaecarpine might induce P450 1A and 2B in mice, and that P450 1A and 2B might predominantly metabolize rutaecarpine in rat liver microsomes.
College of Pharmacy, Yeungnam University, Kyungsan, Korea.
Sang Kyu
SK
Lee
Nam Hee
NH
Kim
Jaeick
J
Lee
Dong Hyun
DH
Kim
Eung Seok
ES
Lee
Han-Gon
HG
Choi
Hyeun Wook
HW
Chang
Yurngdong
Y
Jahng
Tae Cheon
TC
Jeong
D000470:Alkaloids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D032086:Evodia; D005638:Fruit; D015151:Immunoblotting; D026121:Indole Alkaloids; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines; D051381:Rats; D017207:Rats, Sprague-Dawley; D052999:Quinazolinones
D000470:Alkaloids; D003577:Cytochrome P-450 Enzyme System; D026121:Indole Alkaloids; D010936:Plant Extracts; D011799:Quinazolines; C028632:rutecarpine; D052999:Quinazolinones