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Vol. 30, Issue 9, 977-984, September 2002

Effects of Bergamottin on Human and Monkey Drug-Metabolizing Enzymes in Primary Cultured Hepatocytes

Yuan Hua Wen, Jasminder Sahi, Ellen Urda, Shaila Kulkarni, Kelly Rose, Xianxian Zheng, Jacqueline F. Sinclair, Hongbo Cai, Stephen C. Strom, and Vsevolod E. Kostrubsky

Departments of Drug Safety Evaluation (Y.H.W., E.U., S.K., V.E.K.), Pharmacokinetics, Dynamics, and Metabolism (J.S., K.R), and Molecular Sciences (X.Z.), Pfizer Global Research and Development, Ann Arbor, Michigan; Veterans Administration Medical Center, White River Junction, Vermont (J.F.S.); Departments of Biochemistry and Pharmacology/Toxicology, Dartmouth Medical School, Hanover, New Hampshire (J.F.S.); and University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania (H.C., S.C.S.)

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 6beta -hydroxylase activity. Bergamottin was potent at eliciting these inhibitory effects at both basal and induced states of CYP3A. Bergamottin (5 µM) completely inhibited alpha -naphthoflavone-induced ethoxyresorufin O-dealkylase (EROD) and methoxyresorufin O-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.

Copyright © 2002 by U.S. Government


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