In vitro inhibition of multiple cytochrome P450 isoforms by xanthone derivatives from mangosteen extract.
Mangosteen is a xanthone-containing fruit found in Southeast Asia for which health claims include maintaining healthy immune and gastrointestinal systems to slowing the progression of tumor growth and neurodegenerative diseases. Previous studies have identified multiple xanthones in the pericarp of the mangosteen fruit. The aim of the current study was to assess the drug inhibition potential of mangosteen in vitro as well as the cytochrome P450 (P450) enzymes responsible for the metabolism of its individual components. The various xanthone derivatives were found to be both substrates and inhibitors for multiple P450 isoforms. Aqueous extracts of the mangosteen pericarp were analyzed for xanthone content as well as inhibition potency. Finally, in vivo plasma concentrations of alpha-mangostin, the most abundant xanthone derivative found in mangosteen, were predicted using Simcyp and found to be well above their respective in vitro K(i) values for CYP2C8 and CYP2C9.
Foti
Robert S
RS
Amgen, Inc., Pharmacokinetics and Drug Metabolism, 1201 Amgen Court West, Mail Stop AW2/D2751, Seattle, WA 98119, USA. rfoti@amgen.com
Pearson
Josh T
JT
Rock
Dan A
DA
Wahlstrom
Jan L
JL
Wienkers
Larry C
LC
D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D029762:Garcinia mangostana / Q000737:chemistry*; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009249:NADP / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010641:Phenotype; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D044004:Xanthones / Q000737:chemistry / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D010936:Plant Extracts; D044004:Xanthones; D009249:NADP