Inhibition of cytochrome P450 activities by oleanolic acid and ursolic acid in human liver microsomes.
Oleanolic acid (OA) and ursolic acid (UA), triterpene acids having numerous pharmacological activities including anti-inflammatory, anti-cancer, and hepato-protective effects, were tested for their ability to modulate the activities of several cytochrome P450 (CYP) enzymes using human liver microsomes. OA competitively inhibited CYP1A2-catalyzed phenacetin O-deethylation and CYP3A4-catalyzed midazolam 1-hydroxylation, the major human drug metabolizing CYPs, with IC50 (Ki) values of 143.5 (74.2) microM and 78.9 (41.0) microM, respectively. UA competitively inhibited CYP2C19-catalyzed S-mephenytoin 4'-hydroxylation with an IC50 (Ki) value of 119.7 (80.3) microM. However, other CYPs tested showed no or weak inhibition by both OA and UA. The present study demonstrates that OA and UA have inhibitory effects on CYP isoforms using human liver microsomes. It is thus likely that consumption of herbal medicines containing OA or UA, or administration of OA or UA, can cause drug interactions in humans when used concomitantly with drugs that are metabolized primarily by CYP isoforms. In addition, it appears that the inhibitory effect of OA on CYP1A2 is, in part, related to its anti-inflammatory and anticancer activities.
Kim
Kyoung-Ah
KA
Research Group of Pain and Neuroscience, East-West Medical Research Institute, Kyung Hee University, 1 Hoegidong, Dongdaemoongu, Seoul, 130-701, South Korea.
Lee
Ji-Suk
JS
Park
Hi-Joon
HJ
Kim
Jin-Woo
JW
Kim
Chang-Ju
CJ
Shim
In-Sop
IS
Kim
Nam-Jae
NJ
Han
Seung-Moo
SM
Lim
Sabina
S
D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D028321:Plant Preparations / Q000737:chemistry / Q000378:metabolism; D014315:Triterpenes / Q000032:analysis / Q000494:pharmacology*; D000097245:Ursolic Acid
D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D028321:Plant Preparations; D014315:Triterpenes; D000097245:Ursolic Acid; C450739:oleanonic acid