RT Journal Article
SR Electronic
T1 Effects of Bergamottin on Human and Monkey Drug-Metabolizing Enzymes in Primary Cultured Hepatocytes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 977
OP 984
DO 10.1124/dmd.30.9.977
VO 30
IS 9
A1 Yuan Hua Wen
A1 Jasminder Sahi
A1 Ellen Urda
A1 Shaila Kulkarni
A1 Kelly Rose
A1 Xianxian Zheng
A1 Jacqueline F. Sinclair
A1 Hongbo Cai
A1 Stephen C. Strom
A1 Vsevolod E. Kostrubsky
YR 2002
UL http://dmd.aspetjournals.org/content/30/9/977.abstract
AB We investigated the effect of bergamottin, a major furanocoumarin in grapefruit juice, on phase I and phase II drug-metabolizing enzymes using cultured human and monkey hepatocytes. Both cultured systems were compared and evaluated for the direct effects of bergamottin as well as control treatments on liver enzymes. Treatment of hepatocytes with 0.1, 1, 5, and 10 μM bergamottin resulted in a concentration-dependent reduction in CYP3A4 activity (40–100%) in both human and monkey cells, as measured by testosterone 6β-hydroxylase activity. Bergamottin was potent at eliciting these inhibitory effects at both basal and induced states of CYP3A. Bergamottin (5 μM) completely inhibited α-naphthoflavone-induced ethoxyresorufinO-dealkylase (EROD) and methoxyresorufinO-dealkylase (MROD) activities in human hepatocytes and caused a 100% decrease in EROD activity in monkey hepatocytes. A 48-h exposure of cultured human hepatocytes to bergamottin resulted in increased levels of immunoreactive CYP3A4, CYP1A1, and CYP1A2 proteins, and CYP3A4, CYP1A1, CYP1A2, CYP2B6, and UDP-glucuronosyl transferase mRNAs. There was only a 20 to 30% reduction in glucuronidation and sulfation of 4-methylumbelliferone in human hepatocytes by 10 μM bergamottin and no effect on conjugation in the monkey hepatocytes. These results suggest that bergamottin causes both inhibition of CYP3A and CYP1A1/2 enzymatic activities and induction of correspondent proteins and mRNAs. U.S. Government