Mechanism of Action of Tetrandrine, a Natural Inhibitor of <i>Candida albicans</i> Drug Efflux Pumps

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  • ZHANG Hong
    Department of Dermatology, The First Affiliated Hospital, Jinan University
  • GAO Aili
    Department of Dermatology, The First Affiliated Hospital, Jinan University
  • LI Fengxia
    Department of Dermatology, The First Affiliated Hospital, Guangdong College of Pharmacy
  • ZHANG Gehua
    The Third Affiliated Hospital, Sun Yat-sen University
  • HO Hon In
    Department of Dermatology, The First Affiliated Hospital, Jinan University
  • LIAO Wanqing
    Department of Dermatology, Shanghai Changzheng Hospital, National Laboratory of Medical Mycology, Second Military Medical University

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  • Mechanism of action of tetrandrine, a natural inhibitor of Candida albicans drug efflux pumps

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Abstract

  Synergistic effects have previously been observed for a natural compound, tetrandrine (TET), with fluconazole (FLC) in vitro and in the treatment of Candida albicans-infected mice. To investigate the mechanisms of these synergistic effects, 16 strains of C. albicans from the same parent but with different FLC sensitivities were examined using flow cytometry and fluorescent spectrophotometry. Rhodamine 123 (Rh123)-positive cells and intracellular Rh123 fluorescence intensity were determined in accumulation/efflux experiments involving no or a noncytotoxic dose of TET. Total RNA extracted from each strain was used to compare the expressions of drug efflux pump genes in FLC-susceptible, -susceptible dose-dependent, and -resistant strains before and 24 h after TET administration. Accumulation experiments determined that mean percentages of Rh123-positive cells were 26.65% (TET-free) and 70.99% (TET 30 μg/ml), and mean respective intracellular Rh123 fluorescence intensities were 11.34 and 18.00. Efflux experiments showed that percentages of Rh123-positive cells were 1.79% (TET free) and 42.57% (TET 30 μg/ml), respectively, and respective mean intracellular Rh123 fluorescence intensities were 0.74 and 2.19. Differences in MDR1, FLU1, CDR1, and CDR2 expression levels in the absence of TET were statistically significant (p<0.05) between FLC-susceptible, -susceptible dose-dependent, and -resistant strains. Compared with TET-free conditions, 24 h TET-treated strains showed statistically different (p<0.05) expression of MDR1 (FLC-resistant strain), FLU1 (FLC-susceptible dose-dependent and -resistant strains), and CDR1 and CDR2 (FLC-susceptible, -susceptible dose-dependent, and -resistant strains). Thus TET can inhibit the C. albicans drug efflux system and reduce drug efflux. Its mechanism of action is related to the inhibition of expression of the drug efflux pump genes MDR1, FLU1, CDR1, and CDR2.<br>

Journal

  • YAKUGAKU ZASSHI

    YAKUGAKU ZASSHI 129 (5), 623-630, 2009-05-01

    The Pharmaceutical Society of Japan

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