Document Detail

Inhibition of CYP3A4 by 6',7'-dihydroxybergamottin in human CYP3A4 over-expressed hepG2 cells.
MedLine Citation:
PMID:  23146034     Owner:  NLM     Status:  Publisher    
Objectives  We previously established HepG2-GS-3A4, a cell line from hepatoblastoma with overexpression of human CYP3A4 and glutamine synthetase (GS). We further reported that these cells can be applied for screening inhibitors of CYP3A4 in vitro. The purpose of this study was to determine whether our CYP3A4-overexpresed cell could be applied to evaluate mechanisms of CYP3A4 inhibition by 6',7'-dihydroxybergamottin (DHB), which is one of the major furanocoumarins in grapefruit juice, by using these cells. Methods  Nifedipine oxidation, activity and protein expression of NADPH-cytochrome reductase (POR) of HepG2-GS-3A4 cell were measured. CO-binding spectrumassay in microsomal fraction of the cells was also evaluated. Key findings  DHB and ketoconazole, a well-known inhibitor of CYP3A4, inhibited nifedipine oxidation in a concentration-dependent manner. DHB at a concentration of 3.0 µm, sufficient to inhibit the nifedipine oxidation, decreased POR activity; however, ketoconazole at a concentration of 0.9 µm, sufficient to inhibit the oxidation, did not affect the activity. The expression of POR protein in HepG2-GS-3A4 cells was not changed by either DHB or ketoconazole. The expression of CYP3A4 mRNA and protein was not changed by the addition of DHB or ketoconazole. DHB also reduced the absorption rate at 450 nm in a CO-binding spectrum assay without alteration of the wavelength of maximum absorption. The mean absorption value at 450 nm slightly decreased with ketoconazole; however, the difference was not significant. Conclusions  We concluded that inhibition of CYP3A4 activity by DHB includes the inhibition of POR activity. HepG2-GS-3A4 might be a good tool to evaluate the mechanisms.
Nobutaka Araki; Shuichi Tsuruoka; Gohki Hasegawa; Hayato Yanagihara; Takeshi Omasa; Shin Enosawa; Yasushi Yamazoe; Akio Fujimura
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-8-2
Journal Detail:
Title:  The Journal of pharmacy and pharmacology     Volume:  64     ISSN:  2042-7158     ISO Abbreviation:  J. Pharm. Pharmacol.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-13     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0376363     Medline TA:  J Pharm Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  1715-1721     Citation Subset:  -    
Copyright Information:
© 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.
Department of Clinical Pharmacology, Jichi Medical University, Tochigi Department of Nephrology, Faculty of Medicine, University of Tsukuba, Ibaraki Department of Biotechnology, Graduate School of Engineering, Osaka University, Osaka Department of Innovative Surgery, National Research Institute for Child Health and Development, Tokyo Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
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