In Vitro and in Silico Identification and Characterization of Thiabendazole as a Mechanism-Based Inhibitor of CYP1A2 and Simulation of Possible Pharmacokinetic Drug-Drug Interactions

Thelingwani, Roslyn; Zvada, Simbarashe; Dolgos, Hugues; Ungell, Anna‐Lena; Masimirembwa, Collen

doi:10.1124/dmd.108.024604

Cited by 28 publications

(9 citation statements)

References 34 publications

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“…ciceri. The main mechanism of action of benzimidazole compounds including carbendazim is primarily binding to the β-tubulin and then disturbing the microtubule dynamic (Thelingwani et al, 2009 andJamieson et al, 2011). This binding effect of carbendazim may be the reason for inhibition of growth of the pathogen.…”

Section: Resultsmentioning

confidence: 99%

Evaluation of Efficacy of Fungicides Against Fusarium oxysporum f. sp. lentis in Vitro at Lamjung, Nepal

Dahal¹,

Shrestha²

2018

J. Inst. Agric. Anim. Sci.

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Fusarium is a soil borne pathogen which is common in almost all types of soil causing heavy losses in the crop production. Long term survival of pathogen in the soil as chlamydospores has increased its threat making it a highly devastating disease. High accessibility and simple application process of chemical control method has made it an effective and highly adopted approach of eliminating disease causing organisms. The present study was conducted in IAAS, Lamjung Campus to test the efficacy of fungicides in-vitro by poisoned food technique in PDA medium against Fusarium oxysporum f. sp. lentis. The fungicides tested were Carbendazim (50% WP), Chlorothalonil (75% WP) and Dithane M-45 (75% WP) at three different concentrations (100 ppm, 150 ppm and 200 ppm). The treatments were arranged in complete randomized design and replicated five times. The measurement of diameter of the fungal mycelium was taken 8 times at 48 hours interval until the fungus nearly covered the plate in control treatment and inhibition percent of the chemicals were calculated. All the fungicides inhibited the fungal growth significantly, among which carbendazim was highly effective in all the concentrations reducing 100% of mycelial growth followed by chlorothalonil. Dithane M-45 showed least inhibition i.e. 26.62% in 200 ppm (day 13). The chemicals exhibited increased tendency of inhibition with increased concentration.

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Section: Resultsmentioning

confidence: 99%

Evaluation of Efficacy of Fungicides Against Fusarium oxysporum f. sp. lentis in Vitro at Lamjung, Nepal

Dahal¹,

Shrestha²

2018

J. Inst. Agric. Anim. Sci.

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“…In addition, desethylamiodarone also inactivated CYP1A2 but amiodarone inactivated CYP3A4 only (33). The metabolite of thiabendazole, 5-hydroxythiabendazole, is also a mechanism-based inhibitor of CYP1A2 (34). Antofloxacin, an 8-NH 2 derivative of levofloxacin, was found to be a mechanism-based inhibitor of rat CYP1A2 (35).…”

Section: Inhibition Of Cyp1a2 and Clinical Relevancementioning

confidence: 97%

Insights into the Substrate Specificity, Inhibitors, Regulation, and Polymorphisms and the Clinical Impact of Human Cytochrome P450 1A2

Zhou

Yang

Zhou

et al. 2009

AAPS J

197

156

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Human CYP1A2 is one of the major CYPs in human liver and metabolizes a variety of clinically important drugs (e.g., clozapine, tacrine, tizanidine, and theophylline), a number of procarcinogens (e.g. benzo[a]pyrene and aflatoxin B(1)), and several important endogenous compounds (e.g. steroids and arachidonic acids). Like many of other CYPs, CYP1A2 is subject to induction and inhibition by a number of compounds, which may provide an explanation for some drug interactions observed in clinical practice. A large interindividual variability in the expression and activity of CYP1A2 and elimination of drugs that are mainly metabolized by CYP1A2 has been observed, which is largely caused by genetic (e.g., SNPs) and epigenetic (e.g., DNA methylation) and environmental factors (e.g., smoking and comedication). CYP1A2 is primarily regulated by the aromatic hydrocarbon receptor (AhR) and CYP1A2 is induced through AhR-mediated transactivation following ligand binding and nuclear translocation. To date, more than 15 variant alleles and a series of subvariants of the CYP1A2 gene have been identified and some of they have been associated with altered drug clearance and response to drug therapy. For example, lack of response to clozapine therapy due to low plasma drug levels has been reported in smokers harboring the -163A/A genotype; there is an association between CYP1A2*1F (-163C>A) allele and the risk for leflunomide-induced host toxicity. The *1F allele is associated with increased enzyme inducibility whereas *1C causes reduced inducibility. Further studies are warranted to explore the clinical and toxicological significance of altered CYP1A2 expression and activity caused by genetic, epigenetic, and environmental factors.

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“…[27] with minor modifications as described by Bapiro et al [28] and Thelingwani et al . [29]. A two stage evaluation procedure was followed, the first one being a two concentration of herbal extract inhibition screen of all 9 herbal medicines against each of the 5 CYPs.…”

Section: Fluorometric Assaysmentioning

confidence: 99%

“…TDI screening was conducted using a protocol described by Yamamoto et al [30] and Thalingwani et al [29] with slight modification. In brief, a two- step incubation consisting of an inactivation and activity assay were performed.…”

Section: Fluorometric Assaysmentioning

confidence: 99%

Inhibition of Major Drug Metabolizing CYPs by Common Herbal Medicines used by HIV/AIDS Patients in Africa– Implications for Herb- Drug Interactions

Awortwe¹,

Bouic²,

Masimirembwa³

et al. 2014

DML

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The purpose of this study was to evaluate the potential risk of common herbal medicines used by HIV-infected patients in Africa for herb-drug interactions (HDI). High throughput screening assays consisting of recombinant Cytochrome P450 enzymes (CYPs) and fluorescent probes, and parallel artificial membrane permeability assays (PAMPA) were used. The potential of herbal medicines to cause HDI was ranked according to FDA guidelines for reversible inhibition and categorization of time dependent inhibition was based on the normalized ratio. CYPs 1A2 and 3A4 were most inhibited by the herbal extracts. H. hemerocallidea (IC50 = 0.63 μg/mL and 58 μg/mL) and E. purpurea (IC50 = 20 μg/mL and 12 μg/mL) were the potent inhibitors of CYPs 1A2 and 3A4 respectively. L. frutescens and H. hemerocallidea showed clear time dependent inhibition on CYP3A4. Furthermore, the inhibitory effect of both H. hemerocallidea and L. frutescens before and after PAMPA were identical. The results indicate potential HDI of H. hemerocallidea, L. frutescens and E. purpurea with substrates of the affected enzymes if maximum in vivo concentration is achieved.

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In Vitro and in Silico Identification and Characterization of Thiabendazole as a Mechanism-Based Inhibitor of CYP1A2 and Simulation of Possible Pharmacokinetic Drug-Drug Interactions

Abstract: ABSTRACT:Thiabendazole (TBZ) and its major metabolite 5-hydroxythiabendazole (5OH-TBZ) were screened for potential time-dependent inhibition (TDI) against CYP1A2. Screen assays were carried out in the absence and presence of NADPH.

Cited by 28 publications

References 34 publications

Evaluation of Efficacy of Fungicides Against Fusarium oxysporum f. sp. lentis in Vitro at Lamjung, Nepal

Evaluation of Efficacy of Fungicides Against Fusarium oxysporum f. sp. lentis in Vitro at Lamjung, Nepal

Insights into the Substrate Specificity, Inhibitors, Regulation, and Polymorphisms and the Clinical Impact of Human Cytochrome P450 1A2

Inhibition of Major Drug Metabolizing CYPs by Common Herbal Medicines used by HIV/AIDS Patients in Africa– Implications for Herb- Drug Interactions

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