title: Inhibitory effects of cytochrome P450 enzymes CYP2C8, CYP2C9, CYP2C19 and CYP3A4 by Labisia pumila extracts.
abstract: BACKGROUND
  Labisa pumila (LP), popularly known with its local name, Kacip Fatimah, is a well known herb grown in Indochina and Southeast Asia and is traditionally used to regain energy after giving birth in women. The propensity of LP to cause drug-herb interaction via cytochrome P450 (CYP) enzyme system has not been investigated.
  
  
  OBJECTIVE
  To evaluate the in vitro inhibitory effects of various LP extracts (aqueous, ethanol, dichloromethane (DCM) and hexane) on cytochrome P450 2C8 (CYP2C8), CYP2C9, CYP2C19 and CYP3A4 activities.
  
  
  METHODS
  Probe substrate-based high performance liquid chromatography (HPLC) methods were established for CYP2C9, CYP2C19 and CYP3A4 whereas a fluorescence-based enzyme assay was established for CYP2C8. The metabolite formations were examined after incubation of probe substrate with respective CYP isoform in the present or absent of LP extracts. The inhibitory effect of LP was characterized with kinetic parameters IC(50) and K(i) values.
  
  
  RESULTS
  LP extracts showed differential effect of CYP activities with the order of inhibitory potency as follows: dichloromethane>hexane>ethanol>aqueous. This differential effect was only observed in CYP2C isoforms but not CYP3A4. Both the hexane and DCM extracts exhibited moderate to potent inhibition towards CYP2C activities in different modes including non-competitive, competive and mixed-type. The DCM effect was notably strong for CYP2C8 and CYP2C9 showing K(i) values of below 1 μg/ml. The selectivity of LP for CYP2C isoforms rather than CYP3A4 may be attributed to the presence of relatively small, lipophilic yet slightly polar compounds within the LP extracts.
  
  
  CONCLUSIONS
  The results of our study revealed that phytoconstituents contained in LP, particularly in hexane and dichloromethane extracts, were able to selectively inhibit CYP2C isoforms. The inactivation was characterized by low K(i) values, in particular, in CYP2C8 and CYP2C9. These in vitro data indicate that LB preparations contain constituents that can potently inhibit CYP2C activities and suggest that this herb should be examined for potential pharmacokinetic drug interactions in vivo.
authors.affiliation: School of Pharmacy and Health Sciences, International Medical University, 126, Jalan 19/155B, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
authors.forename: Yan
authors.initials: Y
authors.lastname: Pan
authors.forename: Kai Hung
authors.initials: KH
authors.lastname: Tiong
authors.forename: Badrul Amini
authors.initials: BA
authors.lastname: Abd-Rashid
authors.forename: Zakiah
authors.initials: Z
authors.lastname: Ismail
authors.forename: Rusli
authors.initials: R
authors.lastname: Ismail
authors.forename: Joon Wah
authors.initials: JW
authors.lastname: Mak
authors.forename: Chin Eng
authors.initials: CE
authors.lastname: Ong
mesh_terms: D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000431:Ethanol / Q000737:chemistry; D006586:Hexanes / Q000737:chemistry; D008752:Methylene Chloride / Q000737:chemistry; D010936:Plant Extracts / Q000494:pharmacology*; D029623:Primulaceae; D012997:Solvents / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006586:Hexanes; D010936:Plant Extracts; D012997:Solvents; D014867:Water; C026385:n-hexane; D000431:Ethanol; D008752:Methylene Chloride; D003577:Cytochrome P-450 Enzyme System