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      In vitro inhibitory effects of bergenin on human liver cytochrome P450 enzymes

      research-article
      Author(s): , ,
      Publication date (Electronic):
      Journal: Pharmaceutical Biology
      Publisher: Taylor & Francis
      Keywords: CYP3A4, CYP2E1, CYP2C9, herb–drug interaction

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          Abstract

          Context: Bergenin, isolated from the herb of Bergenia purpurascens (Hook. f. et Thoms.) Engl., has anti-inflammatory, antitussive, and wound healing activities. However, whether bergenin affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear.

          Materials and methods: In this study, the inhibitory effects of bergenin (100 μM) on the eight human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19 and 2C8) were investigated, enzyme kinetics and time-dependent inhibition studies were also performed in vitro using human liver microsomes (HLMs).

          Results : The results showed that bergenin inhibited the activity of CYP3A4, 2E1 and 2C9, with IC 50 values of 14.39, 22.83 and 15.11 μM, respectively, but other CYP isoforms were not affected. Enzyme kinetic studies showed that bergenin was not only a non-competitive inhibitor of CYP3A4, but also a competitive inhibitor of CYP2E1 and 2C9, with K i values of 7.71, 11.39 and 8.89 μM, respectively. In addition, bergenin is a time-dependent inhibitor for CYP3A4 with K inact/ K I value of 0.025/3.50 μM −1 min −1.

          Discussion and conclusions: The in vitro studies of bergenin with CYP isoforms indicate that bergenin has the potential to cause pharmacokinetic drug interactions with other co-administered drugs metabolized by CYP3A4, 2E1 and 2C9. Further clinical studies are needed to evaluate the significance of this interaction.

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          Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4.

          Feng Zhou (2008)
          Human cytochrome P450 (CYP) 3A4 is the most abundant hepatic and intestinal phase I enzyme that metabolizes approximately 50% marketed drugs. The crystal structure of bound and unbound CYP3A4 has been recently constructed, and a small active site and a peripheral binding site are identified. A recent study indicates that CYP3A4 undergoes dramatic conformational changes upon binding to ketoconazole or erythromycin with a differential but substantial (>80%) increase in the active site volume, providing a structural basis for ligand promiscuity of CYP3A4. A number of important drugs have been identified as substrates, inducers and/or inhibitors of CYP3A4. The ability of drugs to act as inducers, inhibitors, or substrates for CYP3A is predictive of whether concurrent administration of these compounds with a known CYP3A substrate might lead to altered drug disposition, efficacy or toxicity. The substrates of CYP3A4 considerably overlap with those of P-glycoprotein (P-gp). To date, the identified clinically important CYP3A4 inhibitors mainly include macrolide antibiotics (e.g., clarithromycin, and erythromycin), anti-HIV agents (e.g., ritonavir and delavirdine), antidepressants (e.g. fluoxetine and fluvoxamine), calcium channel blockers (e.g. verapamil and diltiazem), steroids and their modulators (e.g., gestodene and mifepristone), and several herbal and dietary components. Many of these drugs are also mechanism-based inhibitors of CYP3A4, which involves formation of reactive metabolites, binding to CYP3A4 and irreversible enzyme inactivation. A small number of drugs such as rifampin, phenytoin and ritonavir are identified as inducers of CYP3A4. The orphan nuclear receptor, pregnane X receptor (PXR), have been found to play a critical role in the induction of CYP3A4. The inhibition or induction of CYP3A4 by drugs often causes unfavorable and long-lasting drug-drug interactions and probably fatal toxicity, depending on many factors associated with the enzyme, drugs and the patients. The study of interactions of newly synthesized compounds with CYP3A4 has been incorporated into drug development and detection of possible CYP3A4 inhibitors and inducers during the early stages of drug development is critical in preventing potential drug-drug interactions and side effects. Clinicians are encouraged to have a sound knowledge on drugs that behave as substrates, inhibitors or inducers of CYP3A4, and take proper cautions and close monitoring for potential drug interactions when using drugs that are CYP3A4 inhibitors or inducers.
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            Screening for human ADME/Tox drug properties in drug discovery.

            Albert P Li (2001)
            There is no doubt that ADME/Tox drug properties, absorption, distribution, metabolism, elimination and toxicity, are properties crucial to the final clinical success of a drug candidate. It has been estimated that nearly 50% of drugs fail because of unacceptable efficacy, which includes poor bioavailability as a result of ineffective intestinal absorption and undesirable metabolic stability(1). It has also been estimated that up to 40% of drug candidates have failed in the past because of safety issues(2). In this review, the methodologies that are available for use in drug development as in vitro human-based screens for ADME/Tox drug properties are discussed.
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              The human hepatic cytochromes P450 involved in drug metabolism.

              S A Wrighton, Servi Stevens (1991)
              The cytochromes P450 are a superfamily of hemoproteins that catalyze the metabolism of a large number of xenobiotics and endobiotics. The type and amount (i.e., the animal's phenotype) of the P450s expressed by the animal, primarily in the liver, thus determine the metabolic response of the animal to a chemical challenge. A majority of the characterized P450s involved in hepatic drug metabolism have been identified in experimental animals. However, recently at least 12 human drug-metabolizing P450s have been characterized at the molecular and/or enzyme level. The characterization of these P450s has made it possible to "phenotype" microsomal samples with respect to their relative levels of the various P450s and their metabolic capabilities. The purpose of this review is to compare and contrast the human P450s involved in drug metabolism with their related forms in the rat and other experimental species.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Pharm Biol
                Journal ID (iso-abbrev): Pharm Biol
                Journal ID (publisher-id): IPHB
                Journal ID (publisher-id): iphb20
                Title: Pharmaceutical Biology
                Publisher: Taylor & Francis
                ISSN (Print): 1388-0209
                ISSN (Electronic): 1744-5116
                Publication date Collection: 2018
                Publication date (Electronic): 04 December 2018
                Volume: 56
                Issue: 1
                Pages: 620-625
                Affiliations
                Department of Pharmacy, Yidu Central Hospital of Weifang , Shandong, China
                Author notes
                [*]

                These authors contributed equally to this work.

                CONTACT Xiaoli Song ti48shanyi@ 123456163.com Department of Pharmacy, Yidu Central Hospital of Weifang , No. 4138, South Linglongshan Road, Weifang262500, Shandong, China
                Article
                Publisher ID: 1525413
                DOI: 10.1080/13880209.2018.1525413
                PMC ID: 6282425
                PubMed ID: 31070542
                SO-VID: af40d9b5-8b88-44dc-be3b-2584cf368408
                Copyright © © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 15 July 2018
                Date revision received : 23 August 2018
                Date accepted : 10 September 2018
                Page count
                Figures: 7, Tables: 1, Pages: 10, Words: 3985
                Categories
                Subject: Research Article

                Keywords: cyp3a4,cyp2e1,cyp2c9,herb–drug interaction
                Data availability:
                Keywords: cyp3a4, cyp2e1, cyp2c9, herb–drug interaction

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