Review

Green tea extract and the risk of drug-induced liver injury Rolf Teschke†, Li Zhang, Lena Melzer, Johannes Schulze & Axel Eickhoff †

1.

Introduction

2.

Literature search methodology

3.

Green tea (Camellia sinensis)

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and its extracts 4.

Study group

5.

Genetic variability

6.

Drug toxicity

7.

Hepatoprotective properties

8.

Expert opinion

Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Germany

Introduction: Catechins of green tea extract (GTE) have been associated with the rare risk of hepatotoxicity in a few individuals. As GTE were coadministered with synthetic drugs in some hepatotoxicity cases, uncertainty emerged whether GTE are a risk factor of drug-induced liver injury (DILI). Areas covered: Case reports of liver injury by GTE and related review articles to assess the drugs that were coadministered with GTE were reviewed. The analysis included the question whether a formal causality of liver injury had confidently been attributed to GTE, the comedicated drug(s) or both. To elucidate possible metabolic interactions, GTE and their catechins were analyzed regarding their affinity to various CYP isoforms. Expert opinion: The authors conclude that the published hepatotoxicity case reports in connection with the use of GTE provide no clinical evidence that GTE may increase the risk of DILI by drugs that had been comedicated in only few cases. Although partial inhibition of human hepatic and intestinal microsomal CYP2C8, CYP2B6, CYP3A4, CYP2D6 and CYP2C19 by GTE catechins was observed in vitro, a clinical study of drug bioavailability attributed a small risk of increased plasma drug levels only for substrates metabolized by CYP3A4, lacking clinical relevance. Keywords: Camellia sinensis, catechins, drug-induced liver injury, green tea, green tea extract, green tea extract-induced liver injury, liver injury Expert Opin. Drug Metab. Toxicol. [Early Online]

1.

Introduction

Green tea (GT) is a popular beverage prepared from the leaves of the plant Camellia sinensis, which has been cultivated in China and other Southeast Asian countries since thousands of years [1]. With its export to other countries such as Japan and especially Western countries, tea derived from Camellia sinensis likely is now the second most consumed beverage worldwide next to water, although actual and robust data on a worldwide basis are difficult to obtain. Potential positive health effects of GT and its polyphenolic catechins as main constituents have been thoroughly studied and discussed [2-5]. Since C. sinensis leaves have been used in traditional Chinese medicine (TCM) to treat various ailments, products derived from this plant are considered as a part of TCM. Possible positive features of GT have been postulated for various indications from TCM and Western medicine and include prevention of cancer and cardiovascular diseases, anti-inflammatory, antiarthritic, antibacterial, antiviral, antioxidative, antiangiogenic, neuroprotective and cholesterol-lowering effects [3]. However, the clinical efficacy of prophylactic and therapeutic measures largely remains unproven due to the lack of appropriate evidence-based clinical trials. Therefore, further research should conform to international standards to monitor clinical effects of GT and elucidate their mechanisms of action. Under discussion are various in vitro biological studies, but it is premature to transfer these preliminary results to a clinical situation. Although few side effects due to GT have been observed, 10.1517/17425255.2014.971011 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted

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R. Teschke et al.

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Uncertainty emerged whether green tea extracts (GTE) are a risk factor of drug-induced liver injury (DILI) by coadministered synthetic drugs in some hepatotoxicity cases. Using human liver microsomes in vitro, one study showed that GTE inhibits with decreasing power the CYP isoforms CYP2C8 > CYP2B6 > CYP3A > CYP2D6 > CYP2C19, whereas another report found inhibition of CYP2C9, CYP2D6 and CYP3A4. For human liver microsomal CYP2B6 and CYP2C8, the GTE catechin epigallocatechin-3-gallate (EGCG) appears to be the most relevant inhibitory component of GTE, while EGCG seemed a poor inhibitor for CYP2D6 and CYP2C19. With pooled human intestinal microsomes, GTE and EGCG inhibited CYP3A4 activity in vitro. In a clinical study of drug bioavailability with healthy volunteers who consumed a decaffeinated GTE for 4 weeks with 50 -- 75% EGCG, activities of CYP1A2, CYP2C9 and CYP2D6 remained unchanged, as analyzed by the AUC after oral intake of the appropriate metabolic probes caffeine, dextromethorphan and losartan. However, with buspirone as the metabolic probe drug for CYP3A4, the buspirone AUC was increased by 20%, suggesting a reduction of CYP3A4 activity by GTE and a small risk of increased plasma drug levels for drugs metabolized by CYP3A4 without clinical relevance due to the known major interindividual differences of drug metabolizing enzyme activities. Since GTE catechins do not influence drug disposition and bioavailability especially for CYP1A2, CYP2C9 and CYP2D6 substrates, this obvious lack of metabolic interference in vivo prevents both toxic drug accumulation and likely clinically relevant interactions with the disposition of drugs metabolized by these CYP isoforms. The authors conclude that published hepatotoxicity case reports in connection with the use of GTE provide no clinical evidence that GTE may increase the risk of DILI by drugs that overall had rarely been comedicated.

ancillary causes of liver injury in patients who used GTE has not yet sufficiently been addressed [2,5]. There is also uncertainty whether, in reverse, the use of GTE is a risk factor for comedicated drugs with hepatotoxic potency, also facilitating the development of DILI. On theoretical grounds, both catechins from GTE could have triggered liver injury by drugs, or drugs may have facilitated the development of liver injury by GTE catechins. In this analysis, we identified case reports and case series of liver injury by GT and GTE and related review articles. We assessed the causality contribution of GT/GTE and drugs coadministered with GT and GTE. The evaluation included the question whether any formal causality attribution of the observed liver injury to GTE, the comedicated drug(s), or both had been performed reliably. To elucidate possible metabolic interactions at the CYP level, chemical ingredients of GTE such as catechins were evaluated for their affinity to various CYP isoforms. 2.

Literature search methodology

To collect possible cases of liver injury by GT and GTE derived from C. sinensis, a selective literature search in PubMed was performed. We used the search items ‘green tea’, ‘GT’, ‘Camellia sinensis’ , ‘green tea extract’ and ‘GTE’, alone and combined with the terms ‘hepatotoxicity’, ‘liver injury’, ‘herbal hepatotoxicity’ or ‘herb-induced liver injury’. The search was focused primarily on English language case reports, case series and clinical reviews, published from 1999 to 15 July 2014. From each search, the first 25 publications being the most relevant publications were analyzed for subject matter, data quality and overall suitability. All citations in these publications were searched for other yet unidentified case reports, and 32 single case reports and case series of hepatotoxicity in temporal association with the use of GT, GTE and/or comedication were identified (Table 1) [11-42].

Green tea (Camellia sinensis) and its extracts

3.

the consumption of tea derived from C. sinensis has been considered relatively safe for most individuals when used in normal amounts [2,4]. In addition to its use as a common beverage, GT is marketed as a concentrate labeled as green tea extract (GTE) to aid for instance body weight control [2]. GTE are found as constituents in many herbal dietary supplements (HDS) or other dietary supplements (DS), but their use is associated with the rare risk of hepatotoxicity in a few individuals. The safety and tolerability of long-term GTE use therefore has not been well defined [2], with some uncertainty of the underlying mechanism(s) and possible risk factors [2,5]. It is well documented that individuals taking a DS or HDS often use additional herbal products or even synthetic drugs [6-9]. In general, comedication with two or more drugs increases the risk of drug-induced liver injury (DILI) sixfold [10]. At present, the key question of comedicated drugs as possible 2

Tea The leaves of Camilla sinensis are the raw materials for several commercial kinds of tea including GT, Black tea and Oolong tea [37]. The chemical composition of GTE and other GT products varies from batch to batch [41] and depends on plant variety, climate, season, horticultural practices, age of the plant and specific manufacture processes [1,37]. To obtain GT, fresh leaves are stabilized by dry heating or steaming to inactivate enzymes, then rolled, rapidly dried and -- more or less -- roasted [37]. To obtain Black tea, leaves are allowed to wilt for about 20 h, rolled, fermented in a humid atmosphere and then dried with hot air; Oolong is only partially fermented [37]. Fermentation changes the chemical composition; in addition to developing the aroma following the formation of volatile products, polyphenols undergo oxidation [37]. 3.1

Expert Opin. Drug Metab. Toxicol. (2014) 10(12)

Expert Opin. Drug Metab. Toxicol. (2014) 10(12)

1 1

2

Mathieu et al. (2005) [25]

Porcel et al. (2005) [26]

Stevens et al. (2005) [27]

EGCG: Epigallocatechin-3-gallate; GT: Green tea; GTE: Green tea extract; NR: Not reported.

1

1

1

1

Gloro et al. (2005) [24]

[23]

Peyrin-Biroulet et al. (2004) [22] Abu el Wafa et al. (2005)

1

Duenas Sadomil et al. (2004) [19] Garcia-Moran et al. (2004) [20] Lau et al. (2004) [21] 1

1

Vial et al. (2003) [18]

GTE (EGCG 25%), caffeine 19% (Exolise, Arkopharma) GTE (EGCG 25%), caffeine 19% (Exolise, Arkopharma) GT leaves micronized, caffeine > 2% (Camilina, Arkocapsulas) GT leaves Gynostemma pentaphyllum, Aloe sp. juice, Rhaphanus sativus, Crataegus sp. fruit, N-nitroso-fenfluramine (Slim 10) GT hydroalcoholic extract containing also Cassia sp. (Mincifit, Arkopharma) GTE (EGCG 25%), caffeine 19% (Exolise, Arkopharma) GTE (EGCG 25%), caffeine 19% (Exolise, Arkopharma) GT, C. aurantium, C. paradisi, Cynara scolymus, Petrosileum sativum extracts (x-elles) GT leaves, Ananas sativus maltodex-trine, magnesium stearate, silicium dioxide, citric acid (fitofruits grasas acumuladas) Both: GTE with multiple other ingredients (Hydroxycut)

4

Pedros et al. (2003) [17]

1 1

Bajaj et al. (2003) [14] Kanda et al. (2003) [15]

1

GTE (AR25 EGCG 25%), caffeine 19% (Exolise) GT (7%), Oolong tea, C. angustifolia (Oolong tea fine tonic) GTE and multiple other ingredients (Hydroxycut) GT, Gynostemma pentaphyllum, Nelumbo sp., Chrysanthemum sp., Lycium barbarum, Crataegus monogyna, Citrus aurantium, C. mimosoides, Rhaphanus sativus, beer yeast, B1c Golden tang, raifukushi (Be-petite) GT leaves, Gynostemmma pentaphyllum, barbaloin, polyphenol, total saponin (Ohnshidou-genbikounou) All: GTE (EGCG 25%), caffeine 19% (Exolise Arkopharma)

1 1

Seddik et al. (2001) [12] Thiolet et al. (2002) [13]

Kanda et al. (2003) [16]

GT-powdered leaves (Arkocapsulas)

1

Gavilan et al. (1999) [11]

GTE product, composition (brand name)

Newly reported cases (n)

Authors, publication year

Table 1. Compilation of reported cases with suspected hepatotoxicity by GT, GTE and comedication.

None

NR

None

Bronze Age, paracetamol

None

NR

NR

Orthosiphon

NR

1. NR 2. Moxifloxacin 3, 4 NR Thyroxine, Benfluorex, Chromocarb, diethylamine

NR

Fluticasone, albuterol NR

Various herbal teas: Cassia angustifolia, Fucus vesiculosus, Mentha piperita, Equisetum arvense Thicolchicoside, tetrazepam Levonorgestrel, ethinylestradiol

Comedication (prescription or over-the-counter)

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Green tea extract and the risk of drug-induced liver injury

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4 GTE (Tegreen 97: polyphenols 97%, catechins 64%), Magnolia officinalis, Epimedium koreanum, Lagerstroemia speciosa, calcium, chromium, LTheanine, b-sistosterol, vanadium (The Right Approach Complex, Pharmanex) GT (75%), Menta piperita (25%) infusion (T e verde Hacendado) GTE, vitamin E, wheat germ oil, soy oil, beeswax, glycerolesters of fatty esters (NR) GT infusion (NR) GTE as 82% ethanolic dry extract of Camellia sinensis, Betula alba, Ilex paraguariensis (Cuur Scandinavian Clinical Nutrition)

1

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1. GT dry aqueous extract with 90% EGCG (Epinerve Sifi) 2. GT dry aqueous extract with 90% EGCG (NR) GTE with multiple other ingredients (Hydroxycut) GTE with multiple other ingredients (Hydroxycut) GT, 4 -- 6 cups/d (NR) Multiple GTEs with multiple other ingredients GTE (Applied Nutrition Green Tea Fat Burner) or EGCG

GTE with multiple other ingredients (Hydroxycut)

1 2

C. sinensis (NR)

2

5

EGCG: Epigallocatechin-3-gallate; GT: Green tea; GTE: Green tea extract; NR: Not reported.

Sharma et al. (2010) [38] Chen et al. (2010) [39] Rohde et al. (2011) [40] Navarro et al. (2013) [41] Patel et al. (2013) [42]

[37]

Mazzanti et al. (2009)

[36]

Garcı´a-Cort es et al. (2008) [35] Shim and Saab (2009)

Federico et al. (2007) [33] €rnsson and Olsson Bjo (2007) [34]

1

1

GT infusion (NR)

1

Martinez-Sierra et al. (2006) [31] Molinari et al. (2006) [32]

GT infusion (NR)

1

Jimenez-Saenz et al. (2006) [28] Javaid and Bon-kovsky (2006) [29] Bonkovsky (2006) [30]

GTE product, composition (brand name)

Newly reported cases (n)

Authors, publication year

1. Simvastatin, butizide, potassium canrenoate, travoprost 2. Luteinofta NR None Levothyroxine, Ca, vitamin D NR Whey protein, creatine supplements, GNC Mega Men Sport (Vitamin A, chromium)

Acetaminophen, aspirin, caffeine

Estrogen, progestogen 1. Enalapril 2. Diclofenac 3. Omeprazol 4. Simvastatin, metoprolol, losartan 5. None NR

Progestogen

NR

NR

NR

None

Comedication (prescription or over-the-counter)

Table 1. Compilation of reported cases with suspected hepatotoxicity by GT, GTE and comedication (continued).

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R. Teschke et al.

Green tea extract and the risk of drug-induced liver injury

Green tea extract GTE are products manufactured as water, hydroalcoholic or ethanolic extracts, but the solvent used and its exact composition are rarely described (Table 1) [11-42] and often remain unclear, as reported in a recent careful analysis [41]. There is often uncertainty whether manufacturing standards were met. GTE may or may not contain C. sinensis [41], but they certainly commonly have abundant other ingredients unrelated to the primary plant leaves (Table 1) [11-42], as specified in detail elsewhere [41]. Unrelated ingredients include the weight aid N-nitroso-fenfluramine [37], other chemicals and many herbs considered potentially hepatotoxic (Table 1) [11-43]. These unrelated ingredients are adulterants, may be added to increase GTE efficacy and confound benefit and risk analysis.

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3.2

Product identification Many HDS commonly contain GTE and catechins as their components [2,41], although their presence may not be listed on the product label [41]. Actually, among HDS not labeling GT as ingredient, nearly 40% contained catechins; vice versa, some products labeled GTE or its component catechins actually had no detectable catechins [41]. However, ingredient mislabeling is a well-recognized issue for many HDS [43-48] and not limited to GTE and catechins [41]. These uncertainties of incorrect product labeling create uncertainty and impair a valid causality attribution of any adverse reaction [43], unless the ingredients of a suspected HDS have been analyzed, as done in a recent study [41]. 3.3

Ingredients The main chemical components of unfermented tea are polyphenols, with ~ 20% of the dry weight [37]. Most of the polyphenols are catechins, mainly as epigallocatechin-3-gallate (EGCG, 5 -- 12%) epicatechin-3-gallate (ECG, 1 -5%) [37], epicatechin (EC), epigallocatechin (EGC) and epigallocatechin-3-catechins (EGCG) [37,41]. Tea also contains some amounts of methylxanthines, primarily caffeine (2 -- 5%), with smaller quantities of theobromine and theophylline [37]. In a recent analysis of HDS, catechins have been analyzed as EC, ECG, EGC, EGCG, GC and GCG [41]. If possible, these compounds should be reported in future studies related to GT or GTE. 3.4

Plant varieties Camellia sinensis from the genus Camellia in the family Theaceae is the plant species whose leaves and leaf buds are used to produce Chinese tea and GTE [49]. There are two major varieties, C. sinensis var. sinensis, used for Chinese tea, and C. sinensis var. assamica, used for Assam tea. The list of cultivars is long and includes Benifuuki, Fushun, Kanayamidori, Meiryoku, Saemidori, Okumidori and Yabukita. However, in most clinical and experimental studies, the plant variety and cultivar used are not mentioned, a particular shortcoming evident also for other herbs such as kava [50,51]. 3.5

Herbal product quality Apart from the problem that products labeled as GTE may not contain GT but other undefined and potentially toxic ingredients [41], specific issues relate to herbal misidentification, contamination and adulteration [43-48]. For herbal products, fewer quality standards apply than for chemical drugs worldwide [43,44,51,52], in analogy to herbal TCM products manufactured and used worldwide [53-57]. However, in China itself, strict regulations exist for China FDA-approved herbal TCM products, ameliorating this problem [58]. 3.6

GTE catechin metabolism GTE catechins are metabolized in multiple steps in a multicompartment system [59,60] and undergo Phase II methylation, glucuronidation and sulfation; drug transporters such as P-glycoprotein and multi-drug resistance proteins like MRP1 and 2 may modulate GTE catechins and drug absorption, effects and excretion [59]. Reviewing the multiple studies of GTE effects on transport proteins does not allow a valid and firm quantitative conclusion, whether and which of the various transport proteins may potentially enhance or hinder liver injury in humans, because major discrepancies are evident between the results from human studies, cultured cells and animal models [61-65]. For healthy humans, seven studies on single-dose plasma pharmacokinetics were identified for liquid GT catechins [60]. After consumption of an ‘average’ cup of GT containing 112 mg of EGCG, 51 mg of EGC and 15 mg of EC in 200 ml, the predicted plasma Cmax values for total catechins (free and sulfate/glucuronide conjugates) are 125 nM for EGCG, 181 nM for EGC, 76 nM for EC, 94 nM for methyl-EGC and 51 nM for methyl-EC [60]. Standard deviation was low with 20% after elimination of outlying values, likely due to individual enzyme polymorphism [60]. The oral bioavailability of GT catechins is variable. Consumed with a meal, systemic catechin levels in humans are much lower than the effective concentrations determined in in vitro systems; they are enhanced substantially by > 3.5-fold when GT is consumed after an overnight fast [66]. Therefore, the fasting/fed status is an additional confounding variable to be considered in bioavailability evaluation studies of catechins. The great scientific interest in GT, GTE and their catechins led to numerous studies and critical reviews of hepatic and intestinal drug metabolism, microbial metabolism, excretion, absorption, distribution, bioavailability and pharmacokinetics [59-64]. Currently, there is no evidence that CYP is involved in catechin metabolism via a Phase I reaction [60], but catechins may modulate their own Phase II degradation and possibly influence bioavailability and metabolism of other drugs [59-64]. However, the contribution of catechin bioavailability and metabolism to liver injury by drugs largely remains speculative and poorly understood; CYP interactions are better understood [5,37,59,65-67]. Published results from human studies and 3.7

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R. Teschke et al.

in vitro studies like cell cultures are often contradictory; animal and in vitro studies are poorly transferable to humans [59]. 4.

Study group

Hepatotoxicity cases Overall, 32 single case reports and case series identified 88 individual cases (Table 1) [11-42]. Case data quality was mixed regarding details of the used GT products including GTE and comedication, clinical and laboratory exclusion of alternative causes, and validity of causality assessment. Herbal product identification associated with causality assessment was done in one single study, using the DILIN method [41]. The commonly preferred liver-specific CIOMS (Council for International Organizations of Medical Sciences) scale, also called RUCAM (Roussel Uclaf Causality Assessment Method) [68,69] was applied in some other cases to evaluate causality [34,37,46-48]. In a few cases, a positive reexposure test was reported [46] and subsequently reevaluated using specific test criteria [46-48], providing clear evidence that the use of some GT and GTE products was associated with hepatotoxicity [70]. However, confounding variables have to be considered, if results of product authentication for herbal or other ingredients have not been reported. Various GTE such as Exolise had been withdrawn from the market [2]. On a quantitative basis, human clinical studies have demonstrated that single doses of up to 1.6 g of GTE are well tolerated [2]. The maximum-tolerated dose in humans is reported to be 9.9 g/day, a dose equivalent to 24 cups of GT. The safety and tolerability of long-term use of GTE has not been well defined [2]. Considering the results of the hepatotoxicity cases [2,11,42], duration of GT or GTE use commonly ranged from 4 to 260 weeks [37]. However, data of cumulative doses of catechins are not available which would allow calculating respective threshold values. As one of the authors (LZ) is employee of the China FDA in Beijing with access to the regulatory database, a search revealed no safety data regarding GT. Although widely used in China, GT actually is not marketed as herbal medicine. A further search in the Chinese literature again revealed no data relevant to GT safety. However, GT catechin infusions in Western countries is associated with rare hepatotoxicity (Table 1) and may be well tolerated in China, supported by a recent study using EGGC capsules [66].

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4.1

Comedication In 63/88 cases (71.6%), no comedication was reported (Table 1). The comedication rate may be underestimated because a large case series focused on GTE product analysis rather than clinical and comedication details [41]. In 7/88 cases (7.9%), comedication was declared as none. In 18 other cases (20.5%), comedication was individually listed and consisted of both prescribed drugs and over-the-counter medications (Tables 1 and 2). Of note, individuals who consumed HDS were exposed not only to GT, GTE and their multiple 4.2

6

chemical constituents (Table 2) but also to many other ingredients especially in GTE (Table 1), as reported recently [41]. This coexposure hampers causality assignment to one single comedicated compound. In none of the cases, the CIOMS scale has been applied to comedicated drugs to assess causality (Table 2) [11-42]. Clearly, some of them may be potentially hepatotoxic (Table 1), but no valid clinical criteria are reported in these cases allowing the conclusion that GT or GTE have triggered the evolution of DILI by the comedication. GTE catechins and CYP interactions The metabolism of various GTE catechins is complex. Present evidence suggests interactions of catechins as the chemical constituents of GT and GTE with other drugs at the CYP level in vitro (Table 3) [5,37,65-67,71]. Isoenzyme-specific probes -- bupropion, amodiaquine, (S)-mephenytoin, dextromethorphan, midazolam, tolbutamide, bufuralol and testosterone -- were used to quantify inhibition and/or induction of the CYP isoforms CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A, respectively [65,72]. 4.3

Human liver microsomal CYP Using pooled human liver microsomes in vitro, studies have shown that GTE inhibit with decreasing power the CYP isoforms CYP2C8 > CYP2B6 > CYP3A > CYP2D6 > CYP2C19, as shown by corresponding C50 values (Table 3) [65]. CYP2C8 and CYP2B6 are most sensitive to inhibition by GT catechins with IC50 values of ~5 µmol/l [65]. In another study with human liver microsomes, inhibition of CYP2C9, CYP2D6 and CYP3A4 by GTE was observed (Table 3) [71]. For CYP2B6 and CYP2C8, the catechin EGCG appears to be the most relevant inhibitory component of GTE, whereas EGCG seemed a poor inhibitor for CYP2D6 and CYP2C19 [65]. Although GTE contained 43.4% EGCG, only some IC50 values of GTE were close to EGCG, indicating that other catechins or components in GTE may also contribute to CYP inhibition by GTE [65]. Therefore, a mixture of catechins as contained in GT or GTE has a higher inhibitory potency towards CYP enzyme isoforms compared to EGCG alone. EGCG inhibition of CYP isoforms does not follow identical mechanisms. Whereas CYP2B6 and CYP2C8 in human liver microsomes are inhibited competitively, a noncompetitive inhibition was established for CYP2C19 and CYP3A, and uncompetitive inhibition for CYP2D6 [65]. The inhibitory mechanism of CYP3A in human liver microsomes by EGCG [65] is in line with inhibition of CYP3A expressed bacterial membranes by EGCG [67]. Especially for CYP2B6 and CYP2C8, the low IC50 value indicates that clinically relevant inhibition may be attained by regular GTE amounts. This inhibitory effect could become critical if GT or GTE are consumed by fasting individuals, whereby oral bioavailability of GT/GTE catechins and plasma catechin levels substantially increase [66], with the risk of a more pronounced inhibition of CYP in all organs including the liver and intestine. 4.3.1

Expert Opin. Drug Metab. Toxicol. (2014) 10(12)

Expert Opin. Drug Metab. Toxicol. (2014) 10(12)

NR for: GTE, caffeine (Exolise) NR for: GT, Oolong tea, C. angustifolia (Oolong tea fine tonic) NR for: GTE and multiple other ingredients (Hydroxycut) NR for: GT, Gynostemma pentaphyllum, Nelumbo sp. and multilple other herbs (Be-petite) NR for: GT leaves, Gynostemmma pentaphyllum, barbaloin, polyphenol, saponin (Ohnshidou-genbikounou) NR for 4 cases: GTE (AR25), caffeine (Exolis) NR for: GTE, caffeine (Exolise) NR for: GTE, caffeine (Exolise) NR for: GT leaves, caffeine (Camilina, Arkocapsulas) NR for: GT leaves, Aloe sp., Gynostemma pentaphyllum, Crataegussp.,Rhaphanus sativus, Nnitroso-fenfluramine (Slim 10) Highly probable causality with positive reexposure test result for [22,46-48]: GT hydroalcoholic extract, Cassia sp (Mincifit, Arkopharma) NR for: GTE (AR25), caffeine (Exolise) NR for: GTE, caffeine (Exolise) NR for: GT, C. aurantium, C. paradisi, Cynara scolymus, Petrosileum sativum (x-elles) NR for: GT leaves, Ananas sativus maltodextrine, magnesium stearate, silicium dioxide, citric acid (fitofruits grasas acumuladas) NR for both cases: GTE with multiple other ingredients (Hydroxycut) Probable causality with positive reexposure test result for [28,46-48]: GT infusion

1 1 1 1 1

4 1 1 1 1

1

1 1 1 1

2 1

Seddik et al. (2001) [12] Thiolet et al. (2002) [13]

Bajaj et al. (2003) [14]

Kanda et al. (2003) [15]

Kanda et al. (2003) [16]

Pedros et al. (2003) [17]

Vial et al. (2003) [18]

Duenas Sadoril et al. (2004) [19] Garcia-Moran et al. (2004) [20] Lau et al. (2004) [21]

Peyrin-Biroulet et al. (2004) [22]

Abu el Wafa et al. (2005) [23] Gloro et al. (2005) [24] Mathieu et al. (2005) [25]

Porcel et al. (2014) [26]

Stevens et al. (2005) [27]

Jimenez-Saenz et al. (2006) [28]

No comedication reported

No comedication reported

No comedication reported

No comedication reported NR for: bronze age, paracetamol No comedication reported

No comedication reported

2. NR for moxifloxacin 1, 3 and 4: No comedication reported NR for: thyroxine, benfluorex, chromocarb, diethylamine No comedication reported NR for: orthosiphon No comedication reported

No comedication reported

No comedication reported

NR for: fluticasone, albuterol

NR for: Cassia angustifolia Fucus vesiculosus, Mentha piperita, Equisetum arvense NR for: Thicolchicoside, tetrazepam NR for: levonorgestrel, ethinylestradiol

Causality assessment for comedication

If indicated as reported, causality assessment commonly was performed in the case(s) of the referenced reports with the Council for International Organizations of Medical Sciences scale [68,69], with the exception of one single report which used the DILIN method [41]. EGCG: Epigallocatechin-3-gallate; GT: Green tea; GTE: Green tea extract; NR: Not reported (indicating that for this particular GT, GTE or comedication a causality assessment method was not applied and/or results were not reported).

NR for: GT-powdered leaves (Arkocapsulas)

1

Gavilan et al. (1999) [11]

Causality assessment for GT/GTE product

Cases (n)

First author (year)

Table 2. Causality assessment for GT, GTE and comedication of reported cases with suspected hepatotoxicity.

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Green tea extract and the risk of drug-induced liver injury

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Shim et al. (2009) [36]

Mazzanti et al. (2009) [37]

Sharma et al. (2010) [38]

Chen et al. (2010) [39]

Rohde et al. (2011) [40] Navarro et al. (2013) [41]

Patel et al. (2013) [42]

NR for: GTE with multiple other ingredients (Hydroxycut) Possible causality for: case 1. GT dry aqueous extract with 90% EGCG (Epinerve Sifi) Possible causality for: case 2. Product not specified NR for: GTE with multiple other ingredients (Hydroxycut) NR for: GTE with multiple other ingredients (Hydroxycut) NR for: GT infusion Confirmed causality for 38 cases: multiple GTEs with multiple other ingredients NR for: GTE (Applied Nutrition Green Tea Fat Burner) or EGCG

[35,46-48]

Highly probable or probable causality for: C. sinensis

NR for: Whey protein, creatine supplements, GNC Mega Men Sport (Vitamin A, chromium)

NR for: levothyroxine, Ca, vitamin D No comedication reported

No comedication reported

NR for:1. Simvastatin, butizide, potassium canrenoate, travoprost; NR for: 2. Luteinofta No comedication reported

NR for: acetaminophen, aspirin, caffeine

NR for: Estrogen, progestogen NR for comedications: 1. Enalapril 2. Diclofenac 3. Omeprazol 4. Simvastatin, metoprolol, losartan 5. None No comedication reported

NR for: Progestogen

No comedication reported

No comedication reported No comedication reported

Causality assessment for comedication

If indicated as reported, causality assessment commonly was performed in the case(s) of the referenced reports with the Council for International Organizations of Medical Sciences scale [68,69], with the exception of one single report which used the DILIN method [41]. EGCG: Epigallocatechin-3-gallate; GT: Green tea; GTE: Green tea extract; NR: Not reported (indicating that for this particular GT, GTE or comedication a causality assessment method was not applied and/or results were not reported).

2

1

Molinari et al. (2006) [32]

Garcı´a-Cort es et al. (2008) [35]

1

Martinez-Sierra et al. (2006) [31]

1 5

NR for: GT infusion Probable causality and positive reexposure test result for [30,46-48]: GTE (Tegreen 97), Magnolia officinalis, Epimedium koreanum, Lagerstroemia speciosa, calcium, chromium, L-Theanine, b-sistosterol, vanadium (The Right Approach Complex, Pharmanex) NR for: GT (75%), Menta piperita (25%) infusion (T e verde Hacendado) NR for: GTE, vitamin E, wheat germ oil, soy oil, beeswax, glycerolesters of fatty esters NR for: GT infusion Highly probable or probable causality [34,46-48] for cases 1 -- 5: GTE as ethanolic dry extract 82% of C. sinensis, Betula alba, Ilex paraguariensis (Cuur Scandinavian Clinical Nutrition)

1 1

Javaid et al. (2006) [29] Bonkovsky et al. (2006) [30]

Federico et al. (2007) [33] €rnsson et al. (2007) [34] Bjo

Causality assessment for GT/GTE product

Cases (n)

First author (year)

Table 2. Causality assessment for GT, GTE and comedication of reported cases with suspected hepatotoxicity (continued).

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R. Teschke et al.

Green tea extract and the risk of drug-induced liver injury

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Table 3. Modification of human CYP isoforms by GT, GTE and their major catechin constituents. GT/GTE/catechins

Clinical/experimental conditions

Parameter

GT Decaffeinated green tea (dGT)

NR Clinical study: oral intake of capsules for 4 weeks

GTE

Clinical study: oral use of capsules for 2 weeks

GTE

In vitro study: human hepatic microsomes

GTE

In vitro study: human intestinal microsomes

Epigallocatechin-3-gallate (EGCG)

In vitro study: human hepatic microsomes

Epigallocatechin-3-gallate (EGCG)

In vitro study: human intestinal microsomes

Epigallocatechin-3-gallate (EGCG)

In vitro study: membrane fraction of human CYP isoforms expressed in Salmonella typhimurium TA 1538 cells

Epicatechin (EC)

In vitro study: membrane fraction of human CYP isoforms expressed in S. typhimurium TA 1538 cells

Epicatechin-3-gallate (EC)

In vitro study: membrane fraction of human CYP isoforms expressed in S. typhimurium TA 1538 cells

Epigallocatechin (EGC)

In vitro study: membrane fraction of human CYP isoforms expressed in S. typhimurium TA 1538 cells

NR Human CYP activity: CYP1A2 ! [66] CYP2C9 ! [66] CYP2D6 ! [66] CYP3A4 (#) [66] Human CYP activity: CYP2D6 ! [73] CYP3A4 ! [73] Human CYP activity: CYP2C8 # [65] CYP2B6 # [65] CYP2C9 # [71] CYP2C19 # [65] CYP2D6 # [65,71] CYP3A4/5 # [65] CYP3A4 # [71] Human CYP activity: CYP3A4 # [65] Human CYP activity: CYP2B6 # [65] CYP2C8 # [65] CYP2C19 (#) [65] CYP2D6 (#) [65] CYP3A # [65] Human CYP activity: CYP3A4 # [65] Human CYP activity: CYP1A1 # [67] CYP1A2 # [67] CYP2A6 # [67] CYP2C19# [67] CYP2E1# [67] CYP3A4 # [67] Human CYP activity: CYP1A1 # [67] CYP1A2 # [67] CYP3A4 # [67] Human CYP activity: CYP1A1 # [67] CYP1A2 # [67] CYP3A4 # [67] Human CYP activity: CYP1A1 # [67] CYP1A2 # [67] CYP3A4 # [67]

GT: Green tea; GTE: Green tea extract; NR: Not reported.

Increasing the concentrations of GTE or ECGC had a more pronounced inhibitory effect on hepatic CYP isoforms [65].

drugs comedicated with GTE in the hepatotoxicity cases of the present study (Tables 1 and 2).

Human intestinal microsomal CYP In pooled human intestinal microsomes, GTE and EGCG inhibited CYP3A4 in vitro (Table 3) noncompetitively and dose dependently with an intermediate IC50 value [65]. CYP3A4, the most abundant CYP isoform in the human liver and intestinal epithelium, is responsible for the metabolism of almost half of the currently available drugs [72], also of some

4.3.3

4.3.2

Human microsomal CYP reductase The effect of EGCG was also examined on human NADPHCYP reductase expressed in the membrane fraction of Salmonella typhimurium [67]. EGCG inhibited NADPH-CYP reductase activity with a K(i) value of 2.5 µM. These results suggest that the inhibition of the CYP enzyme activity may be accounted for partially by the inhibition of the reductase.

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4.3.4

Plasma drug concentrations

In 42 volunteers who consumed a decaffeinated GT extract for 4 weeks with 50 -- 75% EGCG, activities of CYP1A2, CYP2C9 and CYP2D6 remained unchanged, as analyzed by the AUC after oral intake of the appropriate metabolic probes caffeine, dextromethorphan and losartan (Table 3) [66]. With buspirone as the metabolic probe drug for CYP3A4, the AUC was increased by 20% [66], indicating a small reduction in CYP3A4 enzyme activity, which appears clinically irrelevant [72-75]. It is well known that the interindividual difference of CYP3A4 activity is considerable and commonly much > 20%, with figures of 5- to 20-fold [76] and 31-fold [77]. Based on their results, the authors concluded that repeated GT catechin administration is unlikely to result in clinically relevant effects on the disposition of drugs metabolized by CYP1A2, CYP2C9 and CYP2D6 [66]; however, this may not necessarily extend to drugs metabolized by CYP3A4, because some inhibition of CYP3A4 enzyme activity had been reported, when GT catechin products were taken on an empty stomach after an overnight fast to optimize the oral bioavailability of EGCG [66]. In a similar designed study of 11 healthy subjects who also consumed decaffeinated GT, both CYP2D6 and CYP3A4 enzyme activities remained unchanged, as calculated on the basis of a similar AUC following the administration of the respective metabolic probe drugs after an overnight fast (Table 3) [73]. Overall, it appears that GT and GTE with their various catechins have no major impact on the bioavailability of drug metabolism by various CYP isoforms in the human body, when drug pharmacokinetic parameters (AUC, Cmax, Vmax, KM) are compared after the administration of the appropriate metabolic probe drug [66,73]. Some uncertainty remains related to drugs metabolized by CYP3A4. One recent clinical study provided evidence that catechins inhibit the CYP3A4 isoform in vivo in 42 volunteers, increasing the buspirone AUC by 20% [66], as opposed to the results of an earlier similar clinical study reporting the lack of such a metabolic impairment in 11 individuals using alprazolam as the metabolic probe drug with 7.5% increase in the alprazolam AUC [73]. Actually, this is a clinical issue, because most prescribed drugs are metabolized by this particular CYP isoform. Both studies show large interindividual variability; the study reporting the lack of CYP3A4 inhibition [73] has been criticized since a sample size of 11 individuals may not detect smaller changes in CYP enzyme activities [66]. The differing effects on CYP3A4 activity might also be explained by the different probe drugs used to calculate enzyme activities in vivo, because the same CYP3A4 inhibitor EGCG led to greater changes in buspirone AUC than midazolam AUC [66]. In addition, no relevant inhibition was observed with 504 mg EGCG daily for 2 weeks in the earlier study [73], whereas 800 mg EGCG daily was used for 4 weeks in the subsequent study [66]. Lack of inhibition of CYP3A4 might be ascribed to the lower daily dose of EGCG, the shorter 10

duration of EGCG treatment, and the resulting lower cumulative EGCG dose [73]. In the past, an enzyme induction of CYP1A1 and CYP1A2 was consistently observed in studies with experimental animals after treatment with GT; this induction was ascribed to caffeine, an ingredient of GT and a potent inducer of these CYP isoforms. Since the GT extract used in the clinical studies [66,73] contained only small amounts of caffeine, CYP1A2 enzyme activity had not been modulated by GT extracts and catechins [66]. 5.

Genetic variability

Genetic variability has been evaluated in one of the clinical GT studies of drug bioavailability [66], but it was not explicitly considered in the cohort of the analyzed hepatotoxicity cases (Table 1) [11-42]. The influence of a possible genetic variability was addressed in a recent case report of an autoimmune hepatitis, possibly of genuine, drug or GTE etiology [78]. Due to these and other uncertainties, this particular report was not included in our present analysis (Table 1), but it is worth mentioning due to some interesting discussion points, because it addresses the possible interplay between toxic and immunologic reactions in the liver [78]. 6.

Drug toxicity

Catechins, GT and GTE are unlikely to cause clinically relevant interactions with the disposition of drugs metabolized by CYP1A2, CYP2C9 and CYP2D6 [66]. Consequently, there is no evidence that the use of this particular group of drugs may be associated with high and/or toxic plasma drug levels when administered together with GT or GTE. A limited risk for toxic accumulation remains for drugs metabolized by CYP3A4, including the majority of commonly used drugs since CYP3A4 is the most important CYP isoform catalyzing drug metabolism. For other herbs, clinically based evidence of drug--herb interactions has been presented in a systematic review [79]. 7.

Hepatoprotective properties

Apart from being harmful for the liver (Table 1) [11-42], GT and GTE may also exert hepatoprotective properties, both in experimental animals [80-82] and in humans [83]. In human liver diseases, additional clinical evidence-based studies are required to verify efficacy of GT and GTE. 8.

Expert opinion

Hepatotoxicity cases in connection with the use of GTE are well documented in the literature but occur only in a few individuals; causality attribution for GTE is strong as assessed by the CIOMS scale, the DILIN method and/or a positive unintentional reexposure test result. In hepatotoxicity patients who

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Green tea extract and the risk of drug-induced liver injury

used GTE alone without any comedication, GTE were likely the cause for the toxic event, provided other liver diseases had been excluded. Some uncertainty remains regarding the GTE product quality, because authenticity for GT itself and ingredients in other GTE products rarely was verified. In other patients who experienced clinical hepatotoxicity, GTEs were coadministered with one or several synthetic drugs, herbal drugs or herbal dietary supplements. Clinical features, laboratory tests or even liver histology do not differentiate between causing agents, GTE or comedication, as histological appearance and clinical features are identical or similar regardless of the causative agent. GTE hepatotoxicity is dose-dependent and thereby differs from most DILI forms caused by chemical drugs preferentially at low doses, which are idiosyncratic and unpredictable. Despite these differences, toxic features are not diagnostic in this particular clinical setting. In the analyzed cases, comedication was rare, and in none of these patients, causality of hepatotoxicity for comedication could be proven by the CIOMS scale or the DILIN method. The authors, therefore, conclude that the published case reports of hepatotoxicity provide no clinical evidence for an increased risk of DILI by the rarely comedicated drugs promoted by GTE intake. Clinical evidence is also lacking for a reverse causation, that is, comedication could have triggered the hepatotoxicity of GTE. The proposed lack of clinical interference between GTE ingredients and drugs in the hepatotoxicity patients was unexpected because catechins, the main ingredients of GT and GTE, have a high affinity to various CYP isoforms, which are involved in drug metabolism. In vitro studies showed that GTE and catechins partially inhibited various CYP isoforms in the human liver and intestinal microsomal fraction, including CYP2C8, CYP2B6, CYP3A, CYP2D6 and CYP2C19. Obviously, these in vitro results from human microsomes cannot be transferred to the in vivo situation. Still, it seemed plausible that catechin inhibition of CYP isoforms may lead to increased plasma drug levels and could enhance the risk for DILI caused by comedication. Although DILI is commonly caused by drugs at a low daily dose, there is increasing evidence that for selected drugs higher daily doses or high cumulative doses in prolonged treatment are risk factors for DILI. These conditions could also apply to the hepatotoxicity from GTE and concomitant drug use. In clinical studies with extended GTE intake by volunteers, the bioavailability of various drugs was tested. There was no change in CYP1A2, CYP2C9 and CYP2D6 activities, as

assessed by plasma drug concentration-time profiles after oral intake of the appropriate metabolic probes caffeine, dextromethorphan and losartan, respectively. These data also show that the in vitro inhibition of GTE catechins on human liver and intestinal microsomal CYP isoforms is not corroborated in vivo in humans. Catechins thus do not influence drug disposition, especially for CYP1A2, CYP2C9 and CYP2D6 substrates. Consequently, this obvious lack of metabolic interference in vivo prevents both accumulation and toxic effects from these compounds. Concern remains for drugs metabolized by CYP3A4, since the in vivo metabolism of this particular group of drugs may be impaired as seen by a 20% increase in buspirone AUC by GTE catechins (800 mg/day) taken for a period of 4 weeks, yielding a high cumulative catechin dose. The resulting increased plasma drug levels pose a risk and could imply organ toxicity including the liver. The extent of the risk associated with this condition remains unclear and can only be assessed on a case basis, considering. Actually, plasma drug levels were determined only in healthy subjects but not in hepatotoxicity patients, so factors affecting overall drug bioavailability remain speculative. For the case patients, no details are available for a possible genetic variability, such as genetic variants of Phase I and II drug metabolism as well as membrane drug transporter systems. These data would allow a more precise case analysis. The authors conclude that GTE catechins do not increase the risk of DILI by coadministered drugs, as judged by clinical criteria. Although GTE catechins inhibit the enzyme activity of various CYP isoforms in vitro, they impair the in vivo metabolism only selectively and mainly for substrates of CYP3A4. Whether the increased plasma drug levels represent a hepatotoxicity risk, must be decided on a case basis, since major interindividual differences of enzyme activities metabolizing drugs are well established and have to be considered. As a precaution, individuals consuming GTE should carefully use drugs that are substrates for CYP3A4.

Declaration of interest The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Affiliation

Rolf Teschke†1,2, Li Zhang3, Lena Melzer4, Johannes Schulze4 & Axel Eickhoff1,2 † Author for correspondence 1 Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Germany E-mail: [email protected] 2 Teaching Hospital of the Medical Faculty of the Goethe University Frankfurt/Main, Frankfurt/Main, Germany 3 Center for Drug Reevaluation, China Food and Drug Administration, Beijing, China 4 Institute of Industrial, Medical Faculty of the Goethe University Frankfurt/Main, Environmental and Social Medicine, Frankfurt/Main, Germany