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Hepatotoxicity of Herbal Supplements Mediated by Modulation of Cytochrome P450

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Hepatotoxicity of Herbal Supplements Mediated by Modulation of Cytochrome P450 International Journal of Molecular Sciences Review Hepatotoxicity of Herbal Supplements Mediated by Modulation of Cytochrome P450 Christopher Trent Brewer 1,2 ID and Taosheng Chen 1,2,* 1 Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; [email protected] 2 Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN 38163, USA * Correspondence: [email protected]; Tel.: +1-901-595-5937 Received: 26 September 2017; Accepted: 3 November 2017; Published: 8 November 2017 Abstract: Herbal supplements are a significant source of drug-drug interactions (DDIs), herb-drug interactions, and hepatotoxicity. Cytochrome P450 (CYP450) enzymes metabolize a large number of FDA-approved pharmaceuticals and herbal supplements. This metabolism of pharmaceuticals and supplements can be augmented by concomitant use of either pharmaceuticals or supplements. The xenobiotic receptors constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) can respond to xenobiotics by increasing the expression of a large number of genes that are involved in the metabolism of xenobiotics, including CYP450s. Conversely, but not exclusively, many xenobiotics can inhibit the activity of CYP450s. Induction of the expression or inhibition of the activity of CYP450s can result in DDIs and toxicity. Currently, the United States (US) Food and Drug Administration does not require the investigation of the interactions of herbal supplements and CYP450s. This review provides a summary of herbal supplements that inhibit CYP450s, induce the expression of CYP450s, and/or whose toxicity is mediated by CYP450s. Keywords: cytochrome P450; pregnane X receptor; constitutive androstane receptor; herbal supplement; drug-induced liver injury; herb-induced liver injury; drug-drug interactions; drug-herb interactions; herb-herb interactions; xenobiotic metabolism 1. Introduction The aim of this review is to highlight the effects of herbal supplement use on xenobiotic metabolism and the development of hepatotoxicity or modulation of therapeutic efficacy, either alone or with concurrent use of other herbal supplements and Food and Drug Administration (FDA)-approved pharmaceuticals. Cytochrome P450 (CYP450) enzymes metabolize a large number of xenobiotics, which may lead to the formation of hepatotoxic compounds. Fortunately, pharmaceuticals are evaluated for the potential to inhibit or induce CYP450 enzymes before being marketed in the United States (US) [1]. However, regulations for herbal supplements in the United States do not require surveillance or the reporting of adverse events by the manufacturer to the FDA [2]. Thus, the data concerning the hepatotoxicity of herbal supplements are derived from case reports and series, retrospective databases, and progressive registries, such as the US Drug-Induced Liver Injury (DILI) Network and the Spanish DILI Registry [3,4]. Therefore, herbal supplements that inhibit CYP450 enzymes are problematic, because in addition to affecting the therapeutic efficacy of drugs that require bioactivation for effect, these interactions may inhibit the metabolism of toxic parent compounds to less toxic daughter compounds (Figure1)[5]. Int. J. Mol. Sci. 2017, 18, 2353; doi:10.3390/ijms18112353 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2017, 18, 2353 2 of 28 Int. J. Mol. Sci. 2017, 18, 2353 2 of 27 Int. J. Mol. Sci. 2017, 18, 2353 2 of 27 FigureFigure 1. The 1. effectThe effect of P450 of P450 inhibitors inhibitors on on drug drug toxicity. toxicity. The parent parent compound compound can can be bethe theherbal herbal supplementsupplement itself itself or aor co-administereda co-administered Food an andd Drug Drug Administration Administration (FDA)-approved (FDA)-approved drug. (A drug.) (A) SchematicSchematic of of the the general general mechanism; (B (B) a) specific a specific example example discussed discussed in the in text the [5]. text [5]. Figure 1. The effect of P450 inhibitors on drug toxicity. The parent compound can be the herbal The supplementexpression itself of CYP450 or a co-administered enzymes is Food induced and Drug by nuclearAdministration receptors (FDA)-approved that respond drug. to (A xenobiotics.) TheMany expression CYP450Schematic enzymes of of CYP450 the general are enzymes mechanism;transcriptionally is(B) induced a specific regula example byted nuclear discussed by the receptors inxenobiotic the text [5]. that receptors respond pregnane to xenobiotics. X Manyreceptor CYP450 (PXR, enzymes also are known transcriptionally as NR1I2, SXR, regulated or PAR) by and the constitutive xenobiotic receptorsandrostane pregnane receptor X(CAR; receptor (PXR,NR1I3) also known [6–9].The expression We as NR1I2,will discuss of CYP450 SXR, the or enzymes involvement PAR) andis induced constitutive of PXR by nuclear and CAR androstane receptors in herbal that receptorrespondsupplement to (CAR;xenobiotics. hepatotoxicity NR1I3) [6 –9]. later Manyin this CYP450 review. enzymes Many herbalare transcriptionally supplements regulacan activateted by thethese xenobiotic receptors receptors leading pregnane to an increased X We will discussreceptor the (PXR, involvement also known as of NR1I2, PXR and SXR, CAR or PAR) in herbaland constitutive supplement androstane hepatotoxicity receptor (CAR; later in this expression of CYP450 enzymes and can affect the metabolism of other xenobiotics. In many instances review. ManyNR1I3) herbal [6–9]. We supplements will discuss the can involvement activate of these PXR and receptors CAR in herbal leading supplement to an increasedhepatotoxicity expression of this can lead to hepatotoxicity, as well as deactivating active drugs and decreasing the therapeutic of CYP450later enzymes in this review. and can Many affect herbal the supplements metabolism can activate of other these xenobiotics. receptors leading In many to an increased instances of this effect. The induction of CYP450 enzymes may result in hepatotoxicty by increasing the metabolism can lead toexpression hepatotoxicity, of CYP450 as enzymes well as and deactivating can affect the meta activebolism drugs of other and xenobiotics. decreasing In many the therapeuticinstances effect. of lessof toxicthis can parent lead to compounds hepatotoxicity, to muchas well more as dea toxicctivating daughter active drugs compounds and decreasing (Figure the 2) therapeutic[10–14]. The inductioneffect. of The CYP450 induction enzymes of CYP450 may enzymes result may in result hepatotoxicty in hepatotoxicty by by increasing increasing thethe metabolism metabolism of less toxic parentof less compounds toxic parent to compounds much more to much toxic more daughter toxic daughter compounds compounds (Figure (Figure2)[ 2)10 [10–14].–14]. Figure 2. TheFigure effect 2. The of effect P450 of inducersP450 inducers on on toxicity. toxicity.The The parent compound compound can be can the beherbal the supplement herbal supplement Figureitself 2. Theor a effectco-administered of P450 inducers FDA-approved on toxicity. drug. The (A )parent Schematic compound of the general can be mechanism;the herbal supplement(B,C) itself or a co-administered FDA-approved drug. (A) Schematic of the general mechanism; (B,C) specific itselfspecific or a co-administered examples discussed FDA-approved in the text [10–14]. drug. (A) Schematic of the general mechanism; (B,C) examples discussed in the text [10–14]. specific examples discussed in the text [10–14]. Concurrent use of pharmaceuticals with herbal supplements, as well as the use of multiple herbal supplements, presents additional problems. Many patients do not report herbal supplement use to Int. J. Mol. Sci. 2017, 18, 2353 3 of 28 Int. J. Mol. Sci. 2017, 18, 2353 3 of 27 their physiciansConcurrent [15–18], withuse of onepharmaceuticals study showing with herbal that supplements, approximately as well one-third as the use of of patients multiple do not disclose the useherbal of supplements, herbal supplements presents additi to theironal problems. physicians Many [19 patients]. Complicating do not report matters herbal supplement further, a Spanish study showsuse that to their 20% physicians of patients [15–18], use with herbal one supplementsstudy showing that concurrently approximately with one-third prescription of patientsdrugs do [20], not disclose the use of herbal supplements to their physicians [19]. Complicating matters further, with another study showing that 20% of patients reported the use of one or more herbal supplements, a Spanish study shows that 20% of patients use herbal supplements concurrently with prescription and 30% of patientsdrugs [20], reported with another taking study an showing herbal that supplement 20% of patients to treatreported the the same use of condition one or more that herbal they were concomitantlysupplements, taking prescription and 30% of patients medication reported taking to treat an herbal [21]. supplement Combining to treat herbal the same supplements condition with prescriptionthat drugs they without were concomitantly the knowledge taking ofprescription primary medication care providers to treat is [21]. especially Combining troubling herbal when supplements with prescription drugs without the knowledge of primary care providers is especially considering that the hepatotoxicity of herbal supplements can also arise from herb-drug interactions troubling when considering that the hepatotoxicity of herbal supplements can also arise from herb- (Figure3)[22drug–24]. interactions
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