PT - JOURNAL ARTICLE AU - Bernard J. Komoroski AU - Shimin Zhang AU - Hongbo Cai AU - J. Matthew Hutzler AU - Reginald Frye AU - Timothy S. Tracy AU - Stephen C. Strom AU - Thomas Lehmann AU - Catharina Y. W. Ang AU - Yan Yan Cui AU - Raman Venkataramanan TI - INDUCTION AND INHIBITION OF CYTOCHROMES P450 BY THE ST. JOHN'S WORT CONSTITUENT HYPERFORIN IN HUMAN HEPATOCYTE CULTURES AID - 10.1124/dmd.32.5.512 DP - 2004 May 01 TA - Drug Metabolism and Disposition PG - 512--518 VI - 32 IP - 5 4099 - http://dmd.aspetjournals.org/content/32/5/512.short 4100 - http://dmd.aspetjournals.org/content/32/5/512.full SO - Drug Metab Dispos2004 May 01; 32 AB - St. John's wort extract (SJW) (Hypericum perforatum L.) is among the most commonly used herbal medications in the United States. The predominance of clinical reports indicates that SJW increases the activity of cytochrome P450 3A4 (CYP3A4) enzyme and reduces plasma concentrations of certain drugs. Although the inductive effect of SJW on CYP3A4 is clear, other reports indicate that SJW constituents may have, to a small degree, some enzyme inhibitory effects. Therefore, we sought to study the induction and inhibition effects of the constituents of SJW on CYP3A4 in the human hepatocyte model. Moreover, most research has focused on the induction of CYP3A4 by SJW with little attention paid to other prominent drug-metabolizing enzymes such as CYP1A2, CYP2C9, and CYP2D6. To examine the effects of SJW on CYP1A2, CYP2C9, CYP2D6, as well as CYP3A4, hepatocytes were exposed to hyperforin and hypericin, the primary constituents of SJW extract. Hepatocytes treated with hypericin or hyperforin were exposed to probe substrates to determine enzyme activity and protein and RNA harvested. Hyperforin treatment resulted in significant increases in mRNA, protein, and activity of CYP3A4 and CYP2C9, but had no effect on CYP1A2 or CYP2D6. Acute administration of hyperforin at 5 and 10 μM 1 h before and along with probe substrate inhibited CYP3A4 activity. Hypericin had no effect on any of the enzymes tested. These results demonstrate that with chronic exposure, the inductive effect of SJW on drug-metabolizing enzymes predominates, and human hepatocyte cultures are a versatile in vitro tool for screening the effect of herbal products on cytochrome P450 enzymes. The American Society for Pharmacology and Experimental Therapeutics