Bioactivation of herbal constituents: simple alerts in the complex system

Fang, Zhong‐Ze; Zhang, Yan Yan; Wang, Xiuli; Cao, Yun‐Feng; Huo, Hong; Yang, Ling

doi:10.1517/17425255.2011.586335

Cited by 34 publications

(22 citation statements)

References 115 publications

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“…may influence in vivo predictions. 32) Finally, individual differences in pharmacokinetics may change in vivo doses of HET or NGR and this may alter susceptibility to adverse effects with HET or NGR co-administration.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effect of Hesperetin and Naringenin on Human UDP-Glucuronosyltransferase Enzymes: Implications for Herb–Drug Interactions

Liú

Xie

et al. 2016

Biological & Pharmaceutical Bulletin

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Hesperetin (HET) and naringenin (NGR) are flavanones found in citrus (oranges and grapefruit) andAurantii Fructus Immaturus. The present study aims to investigate the inhibition potential of HET and NGR derivatives towards one of the most important phase II drug-metabolizing enzymes-uridine diphosphate (UDP)-glucuronosyltransferases (UGTs). We used trifluoperazine as a probe substrate to test UGT1A4 activity, and recombinant UGT-catalyzed 4-methylumbelliferone glucuronidation was used as a probe reaction for other UGT isoforms. Data show that HET and NGR displayed broad-spectrum inhibition against human UGTs. Besides, HET exhibited strong inhibitory effects on UGT1A1, 1A3 and 1A9 (both IC 50 and K i values lower than 10 µM), and the inhibitory effects of NGR against three major UGTs, including UGT1A1, 1A3 and 2B7. In a combination of inhibition parameters (K i ) and in vivo concentration of HET and NGR, the potential in vivo inhibition magnitude was predicted. Based on the reported maximum plasma concentration of HET and NGR in vivo, these findings indicate the potential herb-drug interactions (HDI) between HET or NGR and the drugs mainly undergoing UGT1A3 or UGT2B7 catalyzed metabolic elimination. Considering the variety of citrus that contains HET and NGR, so caution should be applied when taking drugs that utilize UGTs for metabolism and clearance with citrus fruits. Key words herb-drug interaction; hesperetin; naringenin; uridine diphosphate (UDP)-glucuronosyltransferaseHesperetin (HET; 4′-methoxy-3′,5,7-trihydroxyflavanone) and naringenin (NGR; 4,5,7-trihydroxyflavanone), aglycones of the flavanone glycoside hesperidin (chiefly in oranges) and naringin (grapefruits) are also used as dietary flavonoids. 1)Moreover, flavanones are bioactive components of Aurantii Fructus Immaturus, which is reported to be used in traditional Chinese medicine.2) Several animal studies have been performed to document pharmacokinetics of HET and NGR. 3,4) The role of HET and NGR in the treatment of disease has received considerable attention, and it is reported to have antioxidant, anti-inflammatory, anti-hypertensive, anti-atherogenic, anti-diabetic, antiviral, and neuroprotective activities. 5-8)Thus, HET and NGR have multiple uses and pharmacokinetic studies of both compounds may elucidate information about efficacy and safety. Chemical structures of HET and NGR appear in Fig. 1.Herb-drug interaction (HDI) strongly limits the clinical application of herbs and drugs, and the inhibition of herbal components towards important drug-metabolizing enzymes (DMEs) has been regarded as one of the most important reasons.9) CYP450 and uridine diphosphate (UDP)-glucuronosyltransferase (UGT) are two enzymes responsible for oxidative phase I and conjugative phase II reactions, respectively. 10) In the past decades, the CYP450 inhibition by HET and NGR has been widely studied, the effects of HET and NGR on UGTs activity have not been fully characterized. Moreover, a large number of different UGTs that exhibit a wide range of substrates are...

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Section: Discussionmentioning

confidence: 99%

Inhibitory Effect of Hesperetin and Naringenin on Human UDP-Glucuronosyltransferase Enzymes: Implications for Herb–Drug Interactions

Liú

Xie

et al. 2016

Biological & Pharmaceutical Bulletin

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“…Their presence in compounds or a molecular structure alerts the investigator to their potential toxicity (Jacobson-Kram and Contrera, 2007). A few well-characterized compounds include (i) 1-2 unsaturated pyrrolizidine alkaloids esters from many Boraginaceae, Asteraceae and Fabaceae (Prakash et al, 1999b;Fang et al, 2011) that exhibit a large variety of genotoxicities, including DNA binding, DNA cross-linking, DNA-protein cross-linking, sister chromatid exchange, and chromosomal aberrations (Roeder, 2000;Fu et al, 2001Fu et al, , 2002aFu et al, , 2004; (ii) aristolochic acids (AA), nitro-polyaromatic compounds responsible for terminal nephropathies observed after intoxication by many Aristolochia species (Fang et al, 2011); a series of studies confirmed that they are genotoxic in both bacterial and mammalian cells, yielding highly persistent and non-repaired DNA adducts; (iii) allylalkoxybenzenes (e.g. eugenol, methyleugenol, estragole), safrole (4-allyl-1,2-methylenedioxybenzene) and ␤-asarone, potentially genotoxic components from some essential oils (Liu et al, 2004;Munerato et al, 2005;Zhang et al, 2005;Smith et al, 2010).…”

Section: Conventional Methodsmentioning

confidence: 99%

“…In this section, we will focus on applicable methods in assessing drug renal toxicity and discuss advantages and disadvantages of each method. In silico methods have also been applied to nephrotoxicity studies (Wolfgang and Johnson, 2002;Ursem et al, 2009) and some structural alerts are known such as aristolochic acids (Fang et al, 2011), ochratoxin A (Sieber et al, 2009) or the diterpen triptolide (Xia et al, 2009 …”

Section: Part C: Methods For Nephrotoxicity Assessmentmentioning

confidence: 99%

Review of current and “omics” methods for assessing the toxicity (genotoxicity, teratogenicity and nephrotoxicity) of herbal medicines and mushrooms

Ouédraogo

Baudoux

Stévigny

et al. 2012

Journal of Ethnopharmacology

122

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“…Among all the classes, benzodioxole group constitutes the highest number of phytochemicals (31) and they are shown to be clustered together. It is the widely dispersed class of compounds among natural as well as synthetic drugs (Fang et al, 2011).…”

Section: Compounds Classification and Clusteringmentioning

confidence: 99%

Piper longum: A review of its phytochemicals and their network pharmacological evaluation

Choudhary¹,

Singh²

2017

Preprint

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Absorption Distribution Metabolism Excretion Toxicity ADMETModule and GO analysis AbstractPiper longum L. (P. longum, also called as long pepper) is one of the common culinary herb and has been extensively used as an important constituent of various indigenous medicines, specifically in traditional Indian medicinal system known as Ayurveda. Towards obtaining a global regulatory framework of P. longum's constituents, in this work we first reviewed phytochemicals present in this herb and then studied their pharmacological and medicinal features using network pharmacology approach. We developed high-confidence level tripartite networks consisting of phytochemicals -protein targets -disease association and explain the role of its phytochemicals to various chronic diseases. 7 drug-like phytochemicals in this herb were found as the potential regulators of 5 FDA approved drug targets; and 28 novel drug targets were also reported. 105 phytochemicals were linked with immunomodulatory potency by pathway level mapping in human metabolic network. A sub-network of human PPI regulated by its phytochemicals was derived and various modules in this sub-network were successfully associated with specific diseases.

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Bioactivation of herbal constituents: simple alerts in the complex system

Cited by 34 publications

References 115 publications

Inhibitory Effect of Hesperetin and Naringenin on Human UDP-Glucuronosyltransferase Enzymes: Implications for Herb–Drug Interactions

Inhibitory Effect of Hesperetin and Naringenin on Human UDP-Glucuronosyltransferase Enzymes: Implications for Herb–Drug Interactions

Review of current and “omics” methods for assessing the toxicity (genotoxicity, teratogenicity and nephrotoxicity) of herbal medicines and mushrooms

Piper longum: A review of its phytochemicals and their network pharmacological evaluation

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