FCT 7959

No. of Pages 8, Model 5G

14 May 2014 Food and Chemical Toxicology xxx (2014) xxx–xxx 1

Contents lists available at ScienceDirect

Food and Chemical Toxicology journal homepage: www.elsevier.com/locate/foodchemtox 5 6

Effect of commercially available green and black tea beverages on drug-metabolizing enzymes and oxidative stress in Wistar rats

3 4 7 8 9 11 10 12 1 2 4 6 15 16 17 18 19 20 21 22 23 24 25

Q1

Hsien-Tsung Yao a,⇑, Ya-Ru Hsu a, Chong-Kuei Lii a,b, Ai-shen Lin a, Keng-Hao Chang a, Hui-Ting Yang a,⇑ a b

Department of Nutrition, China Medical University, 91, Hsueh-shih Road, Taichung 404, Taiwan Department of Health and Nutrition Biotechnology, Asia University, 500, Lioufeng Road, Wufeng, Taichung 413, Taiwan

a r t i c l e

i n f o

Article history: Received 24 September 2013 Accepted 30 April 2014 Available online xxxx Keywords: Green tea Black tea Drug-metabolizing enzymes Oxidative stress Rats

a b s t r a c t The effect of commercially available green tea (GT) and black tea (BT) drinks on drugmetabolizing enzymes (DME) and oxidative stress in rats was investigated. Male Wistar rats were fed a laboratory chow diet and GT or BT drink for 5 weeks. Control rats received de-ionized water instead of the tea drinks. Rats received the GT and BT drinks treatment for 5 weeks showed a significant increase in hepatic microsomal cytochrome P450 (CYP) 1A1 and CYP1A2, and a significant decrease in CYP2C, CYP2E1 and CYP3A enzyme activities. Results of immunoblot analyses of enzyme protein contents showed the same trend with enzyme activity. Significant increase in UDP-glucuronosyltransferase activity and reduced glutathione content in liver and lungs were observed in rats treated with both tea drinks. A lower lipid peroxide level in lungs was observed in rats treated with GT drink. Electrophoretic mobility shift assay revealed that both tea drinks decreased pregnane X receptor binding to DNA and increased nuclear factorerythroid 2 p45-related factor 2 binding to DNA. These results suggest that feeding of both tea drinks to rats modulated DME activities and reduced oxidative stress in liver and lungs. GT drink is more effective on reducing oxidative stress than BT drink. Ó 2014 Published by Elsevier Ltd.

27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43

44 45

1. Introduction

46

Cytochrome P450 (CYP) enzymes are the most important Phase I drug-metabolizing enzymes (DMEs) and are responsible for catalyzing the oxidative biotransformation of many drugs, xenobiotics, and endogenous compounds. Phase II enzymes catalyze the conjugation of glucuronate, glutathione, sulfate, or glycine to foreign molecules (Rendic, 2002) to facilitate the elimination of electrophiles and reactive oxygen species (ROS) generated by Phase I

47 48 49 50 51 52

Abbreviations: AhR, aryl hydrocarbon receptor; ARE, antioxidant response element; BT, black tea; CYP, cytochrome P450; DME, drug-metabolizing enzymes; DR4, direct repeat with 4 bp spacer; DRE, dioxin response elements; GT, green tea beverage; EC, epicatechin; EGC, epigallocatechin; EGCG, epigallocatechin gallate; GCG, gallocatechin gallate; GA, gallic acid; GT, green tea; GST, glutathioneS-transferase; NQO1, NADPH:quinone oxidoreductase 1; Nrf2, nuclear factor erythroid 2-related factor 2; PXR, pregnane X receptor; UGT, UDP-glucuronosyltransferase; GCLc/m, glutamate cysteine ligase catalytic and modifier subunits; GSH, reduced glutathione; GSSG, oxidized glutathione; MRP2, multidrug resistanceassociated protein 2; OATP1a1, organic anion transporting protein 1a1; ROS, reactive oxygen species; SDS, 1-chloro-2,4-dinitrobenzene, sodium dodecylsulfate. ⇑ Corresponding authors. Tel.: +886 4 22053366x7526; fax: +886 4 22062891 (H.-T. Yao). Tel.: +886 4 22053366x7525; fax: +886 4 22062891 (H.-T. Yang). E-mail addresses: [email protected] (H.-T. Yao), [email protected]. tw (H.-T. Yang).

enzyme reactions, thereby protecting organisms against chemical insult (Krajka-Kuz’ niak, 2007; Kondraganti et al., 2008). Induction of Phase II enzymes, such as glutathione S-transferase (GST), UDPglucuronosyltransferase (UGT), and NADPH:quinone oxidoreductase 1 (NQO1), and reduction of ROS is most pronounced in the prevention of chemical-induced tissue injuries and carcinogenesis (Krajka-Kuz’ niak, 2007). CYP and Phase II enzymes have been shown to be modulated by complex mixtures of phytochemicals in fruits and vegetables (Rodríguez-Fragoso et al., 2011). Induction or inhibition of DMEs may change the pharmacological activities and toxicities of drugs and carcinogens and may also cause drug interactions (Rodríguez-Fragoso et al., 2011). A number of nuclear receptors, including pregnane X receptor (PXR), constitutive androstane receptor, peroxisome proliferatoractivated receptor, retinoid X receptor, and aryl hydrocarbon receptor (AhR), and transcription factors, including nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), have been demonstrated to play important roles in the transcription of Phase I and II enzymes and Phase III transporter genes (Xu et al., 2005). For example, AhR transcriptionally induces the expression of human CYP1A1, CYP1A2, and CYP1B1 (Beischlag et al., 2008). AhR can be induced by chemicals such as 20 ,30 ,70 ,80 -tetrachlorodibenzop-dioxin (TCDD) (Budinsky et al., 2010). Studies have also indicated

http://dx.doi.org/10.1016/j.fct.2014.04.043 0278-6915/Ó 2014 Published by Elsevier Ltd.

Please cite this article in press as: Yao, H.-T., et al. Effect of commercially available green and black tea beverages on drug-metabolizing enzymes and oxidative stress in Wistar rats. Food Chem. Toxicol. (2014), http://dx.doi.org/10.1016/j.fct.2014.04.043

53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75

FCT 7959

No. of Pages 8, Model 5G

14 May 2014 2 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117

H.-T. Yao et al. / Food and Chemical Toxicology xxx (2014) xxx–xxx

that CYP3A as well as CYP2C are regulated by PXR (Pascussi et al., 2000; Rana et al., 2010). Nrf2 is a transcription factor that is activated in response to electrophiles and oxidative stress that is involved in the transcription of some Phase II enzymes, such as GST and UGT (Aleksunes and Manautou, 2007; Saracino and Lampe, 2007) and glutamate cysteine ligase (GCL), the rate-limiting step in the formation of the cellular antioxidant glutathione (GSH) (Huang et al., 2013). Green tea (GT) and black tea (BT) have been reported to act as chemoprevention agents by modulating both Phase I CYP and Phase II conjugating enzymes (Yang and Pan, 2012; Murugan et al., 2008). Previous studies have indicated that the polyphenols in GT and BT induce the activation of Nrf2 (Mann et al., 2007; Patel and Maru, 2008; Han et al., 2012) and inhibit AhR-regulated genes (e.g., CYP1A1) and the binding of toxic chemicals to the AhR (Fukuda et al., 2004, 2005; Han et al., 2012). Rats treated with GT or BT extracts have been reported to have increased hepatic Q2 CYP1A2 and UGT activities (Bu-Abbas et al., 1997; Nikaidou et al., 2005). However, GT was also reported to have no effect on hepatic CYP1A2 and CYP3A activities in rats (Niwattisaiwong et al., 2004). Inhibition of CYP3A and 2E1 in liver by GT catechins has also been reported in mice (Chen et al., 2009). Furthermore, an increase of GST and NQO1 activities in both liver and lungs was observed in mice treated with BT polyphenols (Patel and Maru, 2008). On the other hand, mice that were treated with decaffeinated GT and BT extracts were found to have lower CYP enzyme activities in the lungs than control mice (Shi et al., 1994). These results indicate that the effects of tea or tea extracts on DMEs in tissues differ depending on the experimental conditions. Although the effects of various tea components on the regulation of DMEs are not consistent, these results do indicate that GT and BT consumption may play an important role in modulating DMEs and redox status. Recently, commercially available tea beverages have become more popular worldwide. Sugar is supplemented to various tea beverages to reduce the bitterness of taste and to provide an energy source. To date, little or no data on the effects of sugar-containing tea beverages on DMEs and oxidative stress have been reported. In this study, therefore, the effects of consumption of commercially available GT and BT on DMEs and oxidative stress in rats were investigated. The possible regulation of PXR, AhR, and Nrf2 in liver by the GT and BT was also evaluated.

Table 1 Constituents of green tea (GT) and black tea (BT) beverages.a Amount (lg/ml)

Gallic acid (GA) Epigallocatechin (EGC) Epigallocatechin gallate (EGCG) Epicatechin (EC) Epicatechin gallate (ECG) Gallocatechin gallate (GCG) Total catechinsb Caffeine Ascorbic acid Total phenolicsc (gallic acid Eq/mL) Sucrose (g/L)

GT

BT

3.2 201.9 271.5 29.2 32.6 49 587.4 179.7 21.1 576.6 65.5

24.6 25.0 59.1 2.6 3.7 1.8 116.8 208.3 6.0 323.2 70.2

a Two bottles of tea from the same batch were pooled and the constituents were then determined in triplicate. Values are expressed as the mean of two batches of tea beverages. b Total catechins = EGC + EGC + ECG + EGCG + GCG. c The total phenol content of the tea beverages is expressed as lg of gallic acid equiv/mL of tea.

2.3. Animals and treatments

140

Eighteen male Wistar rats, weighing approximately 150 g (4 weeks old) each, were obtained from BioLASCO, Taiwan (Ilan, Taiwan). During the adaptation period, the rats were fed a pelleted diet for 1 week. Then the animals were randomly divided into three groups with six rats in each group. The animals in the control group were given a standard pelleted diet with tap water. The animals in the other two groups were given the same diet with GT or BT. The tea beverages were the sole source of drinking fluid in the tea groups. All drinking fluid was given to rats in plastic bottles, which were replaced daily with fresh water or tea. Rats were housed in individual plastic cages in a room kept at 23 ± 1 °C and 60 ± 5% relative humidity with a 12-h light and dark cycle. Food and drinking fluid were available ad libitum for 5 weeks. Body weight and food intake were determined every week. This study was approved by the Animal Center Management Committee of China Medical University. The animals were maintained in accordance with the guidelines for the care and use of laboratory animals as issued by the Animal Center of the National Science Council, Taiwan.

141 142 143 144 145 146 147 148 149 150 151 152 153 154 155

2.4. Collection of blood and tissue samples

156

At the end of the 5-week feeding period, animals were fasted overnight (12 h) before being killed by exsanguination via the abdominal aorta while under carbon dioxide (70%/30%, CO2/O2) anesthesia. Heparin was used as the anticoagulant. Plasma was separated from the blood by centrifugation (1750g) at 4 °C for 20 min and stored at 20 °C. Plasma alanine aminotransferase was determined by using a commercial kit (Randox Laboratories, Antrum, UK) within 2 weeks. The liver and lungs from each animal were excised, weighed, and stored at 80 °C.

157 158 159 160 161 162 163

118

2. Materials and methods

2.5. Determination of DME activities

164

119

2.1. Tea beverages

120 121 122 123 124 125 126 127

GT and BT (Manufactured by Uni-President Enterprises Corp, Taiwan) were obtained commercially. The concentrations of ascorbate, caffeine, gallic acid, and catechins in the tea beverages were determined by a high-performance liquid chromatography (HPLC) method reported previously (Wu et al., 2011). The sucrose concentration in the tea beverages was determined with a commercial assay kit (Megazyme, Bray, Ireland). Two consecutive batches of beverages were used for this experiment. The concentrations of the major constituents in the tea beverages are shown in Table 1.

128

2.2. Chemicals

129 130 131 132 133 134 135 136 137 138 139

Epicatechin (EC), epigallocatechin (EGC), epigallocatechin-gallate (EGCG), epicatechin-gallate (ECG), gallocatechin gallate (GCG), gallic acid (GA), caffeine, formic acid, ammonium acetate, testosterone, ethoxyresorufin, methoxyresorufin, pentoxyresorufin, resorufin, p-nitrophenol, 4-nitrocatechol, NADPH, glutathione, glutathione reductase, 1-chloro-2,4-dinitrobenzene, sodium dodecylsulfate (SDS), cytochrome c, heparin, Ponceau S, phenacetin, diclofenac (sodium salt), chlorzoxazone, 1,1,3,3-tetraethoxypropan, thiobarbituric acid, and pyrogallol were obtained from Sigma (St. Louis, MO, USA). 4-Hydroxydiclofenac, 6-hydroxychlorzoxazone, midazolam, 6-b-hydroxytestosterone, and 1-hydroxymidazolam were purchased from Ultrafine Chemicals (Manchester, UK). All other chemicals and reagents were of analytical grade and were obtained commercially.

The frozen livers and lungs were thawed and the same portion of each liver or lung sample was used to prepare microsomes. Each gram of liver or lung was then homogenized with 4 mL of ice-cold 0.1 M phosphate buffer (pH 7.4) containing 1 mM EDTA. The homogenates were centrifuged at 10,000g for 15 min at 4 °C. The supernatant was then re-centrifuged at 105,000g for 1 h at 4 °C. The resulting microsomal pellet was suspended in 0.25 M sucrose solution containing 1 mM EDTA and was stored at 80 °C until use. The microsomal protein concentration was determined by using a BCA protein assay kit (Pierce, Rockford, IL). The contents of total CYP and cytochrome b5 in the microsomes were quantified according to the method of Omura and Sato (1964). NADPH-CYP reductase activity was measured according to the procedure of Phillips and Langdon (1962) by using cytochrome c as the substrate. A number of substrates were used to determine the activity of each specific CYP enzyme as reported previously (Yao et al., 2011). Ethoxyresorufin (2 lM), methoxyresorufin (5 lM), and pentoxyresorufin (5 lM) were respectively used as the probe substrates for ethoxyresorufin O-deethylation (CYP1A1), methoxyresorufin Odemethylation (CYP1A2), and pentoxyresorufin O-depentylation (CYP2B). Diclofenac (4 lM), dextromethorphen (5 lM), p-nitrophenol (50 lM), testosterone (60 lM), midazolam (2.5 lM), and lauric acid (100 lM) were respectively used as the probe substrates for diclofenac 4-hydroxylation (CYP2C), dextromethorphen O-demethylation (CYP2D), p-nitrophenol 6-hydroxylation (CYP2E1), testosterone 6b-hydroxylation (CYP3A), midazolam 1-hydroxylation (CYP3A), and lauric acid 12-hydroxylation (CYP4A). Microsomal proteins (0.2 mg/mL) and the incubation time (15 min) were the same for all metabolic reactions except for the midazolam 1-hydroxylation (CYP3A) reaction, which was incubated for 5 min. The metabolites

165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189

Please cite this article in press as: Yao, H.-T., et al. Effect of commercially available green and black tea beverages on drug-metabolizing enzymes and oxidative stress in Wistar rats. Food Chem. Toxicol. (2014), http://dx.doi.org/10.1016/j.fct.2014.04.043

FCT 7959

No. of Pages 8, Model 5G

14 May 2014 H.-T. Yao et al. / Food and Chemical Toxicology xxx (2014) xxx–xxx 190 191 192 193 194 195

of each CYP enzyme reaction were determined by HPLC/mass spectrometry (MS) methods as reported previously (Yao et al., 2008). Enzyme activities were expressed as picomoles of metabolite formed/min/mg protein. The microsomal UGT activity was determined by using p-nitrophenol as the substrate where the rate of formation of p-nitrophenol glucuronic acid was measured by HPLC (Mennier and Verbeeck, 1999).

196 197

2.6. Determinations of lipid peroxide, reactive oxygen species and glutathione concentrations, and antioxidant enzyme activities

198 199 200 201 202 203 204 205 206 207 208 209 210

Liver and lung homogenates were prepared by homogenizing each gram of tissue with 9 mL of ice-cold 1.15% KCl to obtain a 10% (w/v) homogenate. The homogenate was then centrifuged at 10,000g for 15 min at 4 °C. The resulting supernatant was used to determine the lipid peroxide and GSH contents and GST and NQO1 activities. The lipid peroxide level in tissue homogenates was determined by measuring thiobarbituric acid–reactive substance (TBARS) values according to the method of Uehiyama and Mihara (1978). The contents of reduced (GSH) and oxidized (GSSG) glutathione in the liver and lung homogenates were determined by LC/MS (Guan et al., 2003). GST (Habig and Jakoby, 1981) and NQO1 (Tsvetkov et al., 2005) activities were determined spectrophotometrically. Glutathione peroxidase activity was determined spectrophotometrically according to the method of Mohandas et al. (1984). ROS production was measured according to the method of Ali et al. (1992) by determining fluorescent product of dichlorofluorescein.

211

2.7. Western blot analysis

212 213 214 215 216 217 218 219 220 221 222 223 224 225 226

Proteins in liver microsomes (CYP1A1 and CYP1A2, 12.5 lg; CYP2C11, 3A1, and 3A2, 4 lg; CYP2E1, 10 lg) or liver homogenates (GCL catalytic and modifier subunits [GCLc and GCLm]; 10 lg) were separated by 10% SDS-PAGE and transferred to nitrocellulose membranes. Subsequently, the membranes were blocked with 5% skim milk in PBST buffer (137 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4, 2 mM KH2PO4, and 0.1% Tween-20) for 1 h at room temperature and were then hybridized with primary antibodies against CYP enzymes and GCLc/m (Abcam, Cambridge) with gentle agitation overnight at 4 °C. After two washings with PBST, the membranes were incubated with a horseradish peroxidase-conjugated secondary antibody from Abcam for 1 h at room temperature. Immunoreactive bands were detected by using enhanced chemiluminescence (Western Lightning Chemiluminescence Reagent; Perkin–Elmer, Boston, MA). Densitometric measurements of the bands were made by using a luminescent image analyzer (FUJIFILM LAS4000, Japan) and the bands were quantitated with an ImageGauge (FUJIFILM). Equal loading across the lanes was confirmed by staining the blot with Ponceau S solution.

227

2.8. Determination of caffeine concentrations in plasma and liver

228 229 230 231 232

The 10% (w/v) liver homogenates in 1.15% KCl were prepared as described above. An aliquot (100 lL) of plasma or liver homogenate was mixed with 200 lL of acetonitrile (1:2, v/v), mixed by vortexing, and then centrifuged at 10,000g for 20 min. The supernatant was transferred to a clean tube and then a 10-lL aliquot of the supernatant was injected into the LC/MS system for analysis (Lad, 2010).

233

2.9. Determination of triglyceride and cholesterol contents in liver

234 235 236 237

Lipids were extracted from liver by the method of Folch et al. (1957) and solubilized in Triton X-100 according to the method of Carlson and Goldford (1979). The hepatic total cholesterol and triglyceride contents were assayed enzymatically by using kits purchased from Audit Diagnostics (Cork, Ireland).

238

2.10. Extraction of nuclear proteins and electrophoretic mobility shift assay (EMSA)

239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258

Liver nuclear proteins were extracted according to the method of Tian et al. (2004) with some modifications. Briefly, 50 mg liver was homogenized (1:18, w/v) in an ice-cold hypotonic buffer containing 10 mM HEPES, 10 mM KCl, 1 mM MgCl2, 0.1 mM EDTA, 0.5 mM dithiothreitol, 0.5 mM PMSF, 4 lg/mL leupeptin, and 20 lg/ mL aprotinin, pH 7.9. The homogenate was placed in an ice bath for 15 min and then centrifuged at 600g for 10 min. The supernatant was mixed with 100 lL of 10% (v/v) Nonidet P-40 and kept in the ice bath for another 10 min. The supernatant was then centrifuged at 5000g for 5 min. The crude nuclei pellet was resuspended in 100 lL of a hypertonic buffer containing 10 mM HEPES, 400 mM KCl, 1 mM MgCl2, 0.1 mM EDTA, 0.5 mM dithiothreitol, 0.5 mM PMSF, 4 lg/mL leupeptin, 20 lg/mL aprotinin, and 25% glycerol at 4 °C for 45 min. Nuclear proteins were then collected by centrifugation at 12,000g for 15 min. EMSA was performed with the LightShift Chemiluminescent EMSA kit (Pierce, Rockford, IL) according to the method of Yang et al. (2001). The synthetic biotin-labeled double-stranded oligonucleotides used were as follows: antioxidant response element (ARE), 50 -AACCATGACACAGCATAAAA-30 ; dioxin response elements (DRE), 50 -GATCCGGAGTTGCGTGAGAAGAGCCA-30 ; direct repeat with 4 bp spacer (DR4), 50 -AGCTTCAGGTCACAGGAGGTCAGAGAG-30 . Four micrograms of nuclear protein, poly(dI-dC), and biotin-labeled double-stranded oligonucleotide were mixed with the binding buffer to a final volume of 20 lL and were incubated at room temperature for 30 min. Unlabeled double-stranded ARE, DR4,

3

and DRE oligonucleotide and mutant double-stranded oligonucleotide were used to confirm the binding specificity of nuclear proteins. The nuclear protein-DNA complex was separated by electrophoresis on a 6% Tris-boric acid-EDTA polyacrylamide gel and was then electrotransferred to a Hybond-N+ nylon membrane (GE Healthcare, Buckinghamshire). The membrane was incubated with streptavidin–horseradish peroxidase, and the nuclear protein-DNA bands were developed with an enhanced chemiluminescence kit (Thermo).

259 260 261 262 263 264 265

2.11. Statistical evaluation

266

Statistical differences among groups were calculated by using one-way ANOVA (SAS Institute, Cary, NC, USA) and were considered to be significant at p < 0.05 as determined by Duncan’s new multiple-range test.

Q3

267 268 269

3. Results

270

3.1. Constituents of the GT and BT

271

As shown in Table 1, the GT had higher contents of catechins (EGC, EGCG, EC, ECG, GCG), ascorbic acid, and total phenols than did the BT. On the other hand, the gallic acid content was higher in the BT than in the GT. The contents of caffeine and sucrose were comparable in the two beverages.

272

3.2. Effect on body weight and tissue weight

277

After the 5-week feeding period, consumption of the GT and BT resulted in an increase (p < 0.05) in body weight (control: 340.3 ± 16.1 g; GT: 369.2 ± 13.0 g; BT: 379.5 ± 30.7 g) and relative liver weight (g/100 g body weight; control: 2.9 ± 0.2; GT: 3.1 ± 0.1; BT: 3.5 ± 0.2) compared with the values in the control group. A significant increase (p < 0.05) in fluid consumption was also noted in rats given the GT or BT compared with the water control (control: 22.8 ± 2.5 mL/day/rat; GT: 44.8 ± 7.4 mL/day/rat; BT: 54.0 ± 8.0 mL/day/rat). However, tea consumption did not affect daily food intake (control: 25.0 ± 1.0 g; GT: 25.1 ± 1.2 g; BT: 25.5 ± 1.0 g). Furthermore, consumption of the GT or BT did not cause any change in the plasma alanine aminotransaminase level (data not shown).

278

3.3. Effect on DME activities

291

The total CYP and cytochrome b5 contents and the DME activities in rat liver microsomes after 5 weeks of GT or BT intake are shown in Table 2. A statistically significant decrease in cytochrome b5 content was observed in rats treated with the BT (p < 0.05). Furthermore, diclofenac 4-hydroxylation (CYP2C), testosterone 6b-hydroxylation (CYP3A), midazolam 1-hydroxylation (CYP3A), and nitrophenol 6hydroxylation (CYP2E1) were significantly decreased (p < 0.05) in the liver microsomes of rats treated with both GT and BT. These results indicate that GT and BT consumption may reduce the metabolism of xenobiotics catalyzed by CYP3A, CYP2C, and CYP2E1 in liver. In contrast, an increase of methoxyresorufin O-demethylation (CYP1A2) was found in rats treated with both GT and BT (p < 0.05). An increase of ethoxyresorufin O-deethylation (CYP1A1) activity was observed in rats treated with the GT (p < 0.05) but not with the BT beverage. Neither beverage had a significant effect (p > 0.05) on the activities of pentoxyresorufin O-depentylation (CYP2B), dextromethorphen O-deethylation (CYP2D), and lauric acid 12-hydroxylation (CYP4A). Rats treated with the GT or BT showed an increase in UGT activity (p < 0.05) but showed no significant difference in GST or NQO1 activities compared with that in the rats given water. The GT and BT also had no significant effects on ethoxyresorufin O-deethylation (CYP1A1), methoxyresorufin Odemethylation (CYP1A2), or nitrophenol 6-hydroxylation (CYP2E1) activities in lung tissues (Table 3). However, higher pulmonary UGT activity and lower GST activity were observed (p < 0.05).

292

Please cite this article in press as: Yao, H.-T., et al. Effect of commercially available green and black tea beverages on drug-metabolizing enzymes and oxidative stress in Wistar rats. Food Chem. Toxicol. (2014), http://dx.doi.org/10.1016/j.fct.2014.04.043

273 274 275 276

279 280 281 282 283 284 285 286 287 288 289 290

293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316

FCT 7959

No. of Pages 8, Model 5G

14 May 2014 4

H.-T. Yao et al. / Food and Chemical Toxicology xxx (2014) xxx–xxx

Table 2 The activities of drug-metabolizing enzymes in the liver microsomes.a

a

Groups

Control

Cytochrome P450 (pmol/mg protein) Cytochrome b5 (pmol/mg protein) NADPH-cytochrome P450 reductase (lmol/min/mg protein) Testosterone 6b-hydroxylation (CYP3A) (pmol/min/mg protein) Midazolam 1-hydroxylation (CYP3A) (pmol/min/mg protein) Diclofenac 4-hydroxylation (CYP2C) (pmol/min/mg protein) p-Nitrophenol 6-hydroxylation (CYP2E1) (pmol/min/mg protein) Lauric acid 12-hydroxylation (CYP4A) (pmol/min/mg protein) Detromethorphen O-deethylation (CYP2D) (pmol/min/mg protein) Ethoxyresorufin O-deethylation (CYP1A1) (pmol/min/mg protein) Methoxyresorufin O-demethylation (CYP1A2) (pmol/min/mg protein) Pentoxyresorufin O-depentylase (CYP2B) (pmol/min/mg protein)

665.5 ± 57.8 227.0 ± 73.2a 281.2 ± 39.7 1272.8 ± 508.0a 102.3 ± 25.0a 119.4 ± 31.0a 347.8 ± 67.4a 492.0 ± 116.1 142.5 ± 23.8 69.4 ± 12.4b 32.6 ± 11.8b 14.1 ± 6.0

Phase II enzyme activities Glutathione S-transferase (nmol/min/mg protein) UDP-glucuronosyltransferase (nmol/min/mg protein) NADPH:quinone oxidoreductase 1 (nmol/min/mg protein)

1202.0 ± 73.1 22.2 ± 2.8b 117.6 ± 66.8

GT

BT

608.2 ± 114.2 180.3 ± 67.4ab 298.6 ± 15.0 483.5 ± 141.7b 58.6 ± 6.9b 95.2 ± 11.8b 223.1 ± 36.4b 376.5 ± 123.1 136.9 ± 56.1 92.0 ± 11.6a 88.5 ± 26.5a 15.7 ± 5.3 1272.0 ± 220.3 27.2 ± 2.1a 122.0 ± 47.3

735.2 ± 142.5 137.1 ± 52.3b 318.5 ± 60.5 427.0 ± 101.6b 72.6 ± 20.3b 74.7 ± 14.0b 162.8 ± 25.3c 464.7 ± 167.2 133.6 ± 33.9 74.1 ± 11.7b 72.5 ± 24.3a 16.2 ± 7.3 1398.2 ± 240.0 31.2 ± 4.5a 183.9 ± 63.5

Values are the mean ± SD of n = 6. Values in the same row with different letters differ significantly (p < 0.05).

Table 3 The activities of drug-metabolizing enzymes in the lung microsomes.a

a

317 318 319

Groups

Control

GT

BT

Ethoxyresorufin O-deethylation (CYP1A1) (pmol/min/mg protein) Methoxyresorufin O-demethylation (CYP1A2) (pmol/min/mg protein) p-Nitrophenol 6-hydroxylation (CYP2E1) (pmol/min/mg protein) Glutathione S-transferase (nmol/min/mg protein) UDP-glucuronosyltransferase (nmol/min/mg protein) NADPH:quinone oxidoreductase 1 (nmol/min/mg protein)

3.7 ± 1.4 2.4 ± 0.5 166.7 ± 25.8 112.4 ± 7.8a 2.7 ± 0.5c 102.7 ± 15.8

6.0 ± 2.7 2.3 ± 0.4 179.9 ± 52.6 58.4 ± 4.0b 3.8 ± 0.6b 110.9 ± 17.1

6.2 ± 2.2 2.4 ± 0.3 172.8 ± 18.8 57.9 ± 3.8b 4.9 ± 0.7a 113 ± 21

Values are the mean ± SD of n = 6. Values in the same row with different letters differ significantly (p < 0.05).

Fig. 1 shows the immunoblots of CYP proteins in liver microsomes. Similar to the changes in CYP enzyme activities, BT and GT consumption decreased CYP2C11, 2E1, 3A1, and 3A2 protein

Fig. 1. Effects of tea beverages on CYP protein expression in rat liver microsomes. Protein contents were measured by immunoblotting assay. Values are the mean ± SD of n = 6. The protein band was quantified by densitometry, and the level of the control was set at 1. b-Actin was used as an internal control for Western blot.

expression and increased CYP1A2 protein expression in liver tissues. Only rats fed the GT showed increased CYP1A1 expression in liver.

320

3.4. Effect on GSH and ROS contents, antioxidant enzyme activities, and lipid peroxidation

323

As shown in Table 4, after 5 weeks of treatment, GT and BT increased the GSH level and GSH/GSSG ratio in liver and lungs (p < 0.05) and decreased the GSSG level in liver (Table 4). An increase in hepatic GSH peroxidase activity was observed in rats treated with the GT (p < 0.05) but not the BT. Consumption of both tea beverages reduced GSH reductase activity in lungs (p < 0.05) but not in liver. Neither tea beverage caused a significant change in TBARS contents in liver (p < 0.05). However, a lower TBARS level was found in the lungs of rats treated with the GT (p < 0.05). Both tea beverages resulted in a lower ROS level in liver (p < 0.05). By contrast, in lungs, only the GT resulted in a lower ROS level (p < 0.05).

325

3.5. Effect on hepatic lipids content

337

The GT and BT had no significant effects on hepatic cholesterol or triglyceride levels in rats (data not shown).

338

3.6. Plasma and liver caffeine levels

340

The caffeine levels in plasma of rats treated with the GT and BT were 2.3 ± 2.0 and 3.6 ± 4.1 lg/ml, respectively. The corresponding values in liver were 367 ± 241 and 512 ± 464 lg/g, respectively.

341

3.7. Effect on GCLc and GCLm protein expression

344

As shown in Fig. 2, rats treated with both tea beverages showed increased GCLc and GCLm protein expression in liver. In the lungs,

345

Please cite this article in press as: Yao, H.-T., et al. Effect of commercially available green and black tea beverages on drug-metabolizing enzymes and oxidative stress in Wistar rats. Food Chem. Toxicol. (2014), http://dx.doi.org/10.1016/j.fct.2014.04.043

321 322

324

326 327 328 329 330 331 332 333 334 335 336

339

342 343

346

FCT 7959

No. of Pages 8, Model 5G

14 May 2014 5

H.-T. Yao et al. / Food and Chemical Toxicology xxx (2014) xxx–xxx Table 4 The GSH and GSSG contents and the enzyme activities of antioxidant defense system in rat liver and lungs.a Liver

GSH (nmol/mg protein) GSSG (nmol/mg protein) GSH/GSSG Glutathione peroxidase (nmol/min/mg protein) Glutathione reductase (nmol/min/mg protein) TBARS (nmol/g protein) ROS (nmol/mg protein) a

347 348

Lungs

Control

GT

BT

Control

GT

BT

20.7 ± 2.5b 0.56 ± 0.14a 36.9 ± 14.0b 198.1 ± 25.7b 56.4 ± 4.4 47.9 ± 3.4 1.51 ± 0.38a

43.4 ± 10.6a 0.07 ± 0.02b 620.0 ± 155.7a 280.7 ± 74.0a 67.9 ± 4.5 47.5 ± 7.5 1.03 ± 0.27b

38.3 ± 6.5a 0.06 ± 0.02b 638.3 ± 213.6a 216.4 ± 30.4ab 62.3 ± 5.8 46.8 ± 6.9 1.00 ± 0.28b

2.8 ± 1.8b 0.3 ± 0.2 9.3 ± 3.6b 61.3 ± 5.7 35.1 ± 3.7a 232 ± 22.3a 0.67 ± 0.11a

11.6 ± 1.0a 0.2 ± 0.1 58.0 ± 10.1a 57.3 ± 6.7 16.7 ± 2.7c 193.8 ± 25.0b 0.52 ± 0.06 b

11.5 ± 1.9a 0.2 ± 0.1 57.5 ± 2.8a 59.5 ± 3.1 25.5 ± 3.7b 219.6 ± 27.2ab 0.58 ± 0.18ab

Values are the mean ± SD of n = 6. Values in the same row with different letters differ significantly (p < 0.05).

both tea beverages increased GCLc protein expression but did not significantly affect GCLm protein expression.

349

3.8. Effect on DNA binding activity of nuclear Nrf2, PXR, and AhR

350

357

We also examined the effect of tea consumption on the binding activity of nuclear transcription factors to DNA. As shown in Fig. 3, rats treated with both tea beverages showed increased binding activity of nuclear Nrf2 to the ARE consensus sequences (Fig. 3A). Similarly, rats treated with the GT but not the BT showed increased binding activity of AhR to the DRE consensus sequences (Fig. 3B). Rats treated with both tea beverages showed decreased binding activity of PXR to the DR4 consensus sequences (Fig. 3C).

358

4. Discussion

359

In this study, our results show that consumption of BT and GT by rats changed the activity of DMEs and increased glutathione levels in liver and lungs. Consumption of both tea beverages led to decreased hepatic PXR and increased Nrf2 binding to DNA. In addition, consumption of the GT increased the binding activity of AhR to the DRE. These results suggest that consumption of GT and BT by rats modulates the metabolism of drugs and chemical carcinogens and reduces oxidative stress in liver and lungs. Many phytochemicals have been shown to prevent chemicalinduced tissue damage and carcinogenesis in animals, mainly as a result of the modulation of DMEs after their administration (Kondraganti et al., 2008; Yang and Pan, 2012). In the present study, significantly higher CYP1A2 activity in liver was noted in rats treated with GT and BT. It has been reported that caffeine, but not the polyphenols, in GT or BT extract may contribute to the induction of CYP1A2 activity (Bu-Abbas et al., 1997; Nikaidou et al., 2005). In this study, the caffeine concentration in plasma (GT: 2.3 ± 2.0 lg/mL; BT: 3.6 ± 4.1 lg/mL) was higher than the level (0.2 lg/mL) that was reported to induce hepatic CYP1A2

351 352 353 354 355 356

360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377

(Chen et al., 1996). Therefore, the induction of CYP1A2 activity and protein expression after BT and GT consumption might have been due to the caffeine in the tea beverages. We also observed an increase of UGT activity in the liver and lungs of rats treated with tea beverages in the present study. This result agrees with the observation of Srinivasan et al. (2008) showing that rats treated with tea catechins had higher UGT activity in liver. Because UGT has been implicated as an important detoxifying enzyme that catalyzes the conjugation of the metabolites of major tobacco carcinogens, such as benzo[a]pyrene, to facilitate their excretion (Zheng et al., 2002), the consumption of tea beverages may aid in the detoxification of smoking. GSH, a vital antioxidant in cells, protects tissues against oxidative stress, inflammation, and injury. GSH acts as a radical-scavenging antioxidant and also is the preferred substrate for several enzymes in drug metabolism and antioxidant defense (Lu, 2009). GSH biosynthesis is completed in two steps that are catalyzed by GCL and GSH synthetase. GCL is a heterodimeric holoenzyme composed of the GCLc and GCLm subunits and is the rate-limiting enzyme in GSH biosynthesis (Franklin et al., 2009). In the present study, the GT and BT induced both GCLc and GCLm protein expression in rat liver. Accompanied by the increase in GCLc and GCLm protein expression, a higher GSH level was observed in rats treated with the GT and BT, thus indicating the induction of GSH synthesis. Furthermore, higher GSH/GSSG ratios and UGT activity in liver and lungs were observed after GT and BT treatment. The higher GSH level and Phase II detoxification enzyme activity (e.g., UGT) will, in turn, enhance the protection of liver and lung tissues against chemical insult. Because lower TBARS and ROS levels were observed only in the lungs of rats treated with the GT, our results suggest that the GT was more effective for reducing oxidative stress than the BT in the lungs. Phytochemicals are known to be potent modulators of the transcription of Phase I and II DMEs and the Phase III transporter genes (Xu et al., 2005). For instance, andrographolide induces rat hepatic CYP2C6/11, CYP1A1/2, and CYP3A1/2 protein expression by

Fig. 2. Effects of tea beverages on GCLc and GCLm protein expression in the liver and lungs of rats. Protein contents in liver (A) and lung (B) homogenates were measured by immunoblotting assay. Values are the mean ± SD of n = 6. The protein band was quantified by densitometry, and the level of the control was set at 1. b-Actin was used as an internal control for Western blot.

Please cite this article in press as: Yao, H.-T., et al. Effect of commercially available green and black tea beverages on drug-metabolizing enzymes and oxidative stress in Wistar rats. Food Chem. Toxicol. (2014), http://dx.doi.org/10.1016/j.fct.2014.04.043

378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413

FCT 7959

No. of Pages 8, Model 5G

14 May 2014 6

H.-T. Yao et al. / Food and Chemical Toxicology xxx (2014) xxx–xxx

Fig. 3. Effects of tea beverages on PXR, AhR, and Nrf2 DNA-binding activity. Nuclear extracts of liver homogenate were used to determine Nrf2 (A), AhR (B), and PXR (C) nuclear protein-DNA binding activity. 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442

increasing PXR and AhR binding activity to DNA (Chen et al., 2013). Liquiritigenin stimulates Nrf2 translocation into the nucleus (Kim et al., 2010) and enhances the expression of not only hepatic Phase II enzymes (e.g., UGT and GST) but also the canalicular efflux transporters (e.g., multidrug resistance-associated protein 2, or MRP2) and basolateral uptake transporters (e.g., organic anion transporting protein 1a1, or OATP1a1) (Kim et al., 2009). Our results revealed up-regulated GCLc/m protein expression in the liver of rats treated with the GT and BT, and this was related to the increase of DNA binding activity of Nrf2 (Fig. 3A). Tea polyphenols are known to play a role in the induction of Nrf2 activation, which in turn triggers ARE-driven transcription of GCL (Huang et al., 2013). Therefore, the increased DNA binding activity of Nrf2 after the consumption of both tea beverages might be attributed to the increased GSH level in the liver. In line with previous studies, our results showed induction of CYP1A2 activity by GT and BT in liver of rats (Niwattisaiwong et al., 2004; Jang et al., 2005). Other CYP enzymes such as CYP3A and CYP2E1 were suppressed by the GT (Park et al., 2009; Chen et al., 1996). Regarding the changes in CYP protein expression, the consistent decrease in the expression of CYP3A and CYP2C proteins and the DNA binding activity of PXR by the consumption of BT and GT suggest that both tea beverages may suppress PXR activation (Fig. 3C). The suppressed PXR activation, then, results in lower protein expression and activity of CYP3A and CYP2C. In contrast with the decrease in PXR activation and CYP3A and CYP2C protein expression and activity, GT administration increased the DNA binding activity of AhR (Fig. 3B). Activation of AhR explains, at least in part, the induction of hepatic CYP1A1

and CYP1A2 protein expression and activity by the GT. It is interesting to note that consumption of the BT induced hepatic CYP1A2 protein expression and activity. However, the BT had little or no effect on the DNA binding activity of AhR. Taken together, these results suggest that the modulation of DME activity by tea beverages is likely to work at the transcriptional stage. Moreover, the modulation of DME gene transcription by tea beverages may be CYP isozyme- and beverage-specific. The increased fluid intake (approximately 2–2.5 folds) of the rats in the GT and BT treatment groups, compared with that of the control group in which tap water was given, might have been due to the sweetness of the drinks. Although the sucrose in the tea beverages may increase lipid synthesis in liver (RoncalJimenez et al., 2011), the results of our study showed no increase of liver triglyceride or cholesterol levels in the treated rats compared with the controls. The lipid-lowering effects of tea catechins, particularly EGCG, may have played a role in this result (Koo and Noh, 2007). In summary, the present study showed that consumption of GT and BT by rats reduced CYP2C, 2E1, and 3A activities and protein expression and induced CYP1A1 and/or CYP1A2 activity and protein expression in liver. GT and BT treatment also increased UGT activity and the GSH level in both liver and lungs. Thus, GT and BT may act as chemopreventive agents. Also, the GT was more effective for reducing oxidative stress in lungs than was the BT. The modulation of DMEs by GT and BT is likely to work at the transcriptional stage. Given that tea beverages are becoming more popular worldwide, their possible interactions with drugs or toxic compounds should be taken into account.

Please cite this article in press as: Yao, H.-T., et al. Effect of commercially available green and black tea beverages on drug-metabolizing enzymes and oxidative stress in Wistar rats. Food Chem. Toxicol. (2014), http://dx.doi.org/10.1016/j.fct.2014.04.043

443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471

FCT 7959

No. of Pages 8, Model 5G

14 May 2014 H.-T. Yao et al. / Food and Chemical Toxicology xxx (2014) xxx–xxx 472 473

474 478 477 475 479

Conflict of Interest The authors declare that there are no conflicts of interest. Transparency Document

476

The Transparency document associated with this article can be found in the online version.

480

Acknowledgment

481 482

This study was financially supported by grant aid from China Medical University (CMU99-N1-10), Taiwan.

483

References

484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549

Aleksunes, L.M., Manautou, J.E., 2007. Emerging role of Nrf2 in protecting against hepatic and gastrointestinal disease. Toxicol. Pathol. 35, 459–473. Ali, S.F., LeBel, C.P., Bondy, S.C., 1992. Reactive oxygen species formation as a biomarker of methylmercury and trimethyltin neurotoxicity. Neurotoxicology 13, 637–648. Beischlag, T.V., Luis Morales, J., Hollingshead, B.D., Perdew, G.H., 2008. The aryl hydrocarbon receptor complex and the control of gene expression. Crit. Rev. Eukaryot. Gene Expr. 18, 207–250. Bu-Abbas, A., Copeland, E., Clifford, M.N., Walker, R., Ioannides, Costas, 1997. Fractionation of green tea extracts: correlation of antimutagenic effect with flavanol content. J. Sci. Food Agric. 75, 453–462. Budinsky, R.A., LeCluyse, E.L., Ferguson, S.S., Rowlands, J.C., Simon, T., 2010. Human and rat primary hepatocyte CYP1A1 and 1A2 induction with 2,3,7,8tetrachlorodibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzofuran, and 2,3,4,7,8pentachlorodibenzofuran. Toxicol. Sci. 118, 224–235. Carlson, E., Goldford, S., 1979. A sensitive enzymatic method for determination of free and esterified tissue cholesterol. Clin. Chim. Acta 79, 575–582. Chen, L., Bondoc, F.Y., Lee, M.J., Hussin, A.H., Thomas, P.E., Yang, C.S., 1996. Caffeine induces cytochrome P4501A2: induction of CYP1A2 by tea in rats. Drug Metab. Dispos. 24, 529–533. Chen, X., Sun, C.K., Han, G.Z., Peng, J.Y., Li, Y., Liu, Y.X., Lv, Y.Y., Liu, K.X., Zhou, Q., Sun, H.J., 2009. Protective effect of tea polyphenols against paracetamol-induced hepatotoxicity in mice is significantly correlated with cytochrome P450 suppression. World J. Gastroenterol. 15, 1829–1835. Chen, H.W., Huang, C.S., Liu, P.F., Li, C.C., Chen, C.T., Liu, C.T., Chiang, J.R., Yao, H.T., Lii, C.K., 2013. Andrographis paniculata extract and andrographolide modulate the hepatic drug metabolism system and plasma tolbutamide concentrations in rats. Evid. Based Complement. Alternat. Med., 982689. Folch, J., Lees, M., Sloane-Stanley, G.M., 1957. A purification of total lipid from animal tissue. J. Biol. Chem. 226, 497–509. Franklin, C.C., Backos, D.S., Mohar, I., White, C.C., Forman, H.J., Kavanagh, T.J., 2009. Structure, function, and post-translational regulation of the catalytic and modifier subunits of glutamate cysteine ligase. Mol. Aspects Med. 30, 86–98. Fukuda, I., Sakane, I., Yabushita, Y., Kodoi, R., Nishiumi, S., Kakuda, T., Sawamura, S., Kanazawa, K., Ashida, H., 2004. Pigments in green tea leaves (Camellia sinensis) suppress transformation of the aryl hydrocarbon receptor induced by dioxin. J. Agric. Food Chem. 52, 2499–2506. Fukuda, I., Sakane, I., Yabushita, Y., Sawamura, S., Kanazawa, K., Ashida, H., 2005. Black tea theaflavins suppress dioxin-induced transformation of the aryl hydrocarbon receptor. Biosci. Biotechnol. Biochem. 69, 883–890. Guan, X., Hoffman, B., Dwivedi, C., Matthees, D.P., 2003. A simultaneous liquid chromatography/mass spectrometric assay of glutathione, cysteine, homocysteine and their disulfides in biological samples. J. Pharm. Biomed. Anal. 31, 251–261. Habig, W.H., Jakoby, W.B., 1981. Assays for differentiation of glutathione S-transferases. Methods Enzymol. 77, 398–405. Han, S.G., Han, S.S., Toborek, M., Hennig, B., 2012. EGCG protects endothelial cells against PCB 126-induced inflammation through inhibition of AhR and induction of Nrf2-regulated genes. Toxicol. Appl. Pharmacol. 261, 181–188. Huang, C.S., Lii, C.K., Lin, A.H., Yeh, Y.W., Yao, H.T., Li, C.C., Wang, T.S., Chen, H.W., 2013. Protection by chrysin, apigenin, and luteolin against oxidative stress is mediated by the Nrf2-dependent up-regulation of heme oxygenase 1 and glutamate cysteine ligase in rat primary hepatocytes. Arch. Toxicol. 87, 167–178. Jang, E.H., Choi, J.Y., Park, C.S., et al., 2005. Effects of green tea extract administration on the pharmacokinetics of clozapine in rats. J. Pharm. Pharmacol. 57, 311–316. Kim, Y.W., Kang, H.E., Lee, M.G., Hwang, S.J., Kim, S.C., Lee, C.H., Kim, S.G., 2009. Liquiritigenin, a flavonoid aglycone from licorice, has a choleretic effect and the ability to induce hepatic transporters and phase-II enzymes. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G372–G381. Kim, Y.W., Kim, Y.M., Yang, Y.M., Kay, H.Y., Kim, W.D., Lee, J.W., Hwang, S.J., Kim, S.G., 2010. Inhibition of LXRa-dependent steatosis and oxidative injury by liquiritigenin, a licorice flavonoid, as mediated with Nrf2 activation. Antioxid. Redox Signal. 14, 733–745. Kondraganti, S.R., Jiang, W., Jaiswal, A.K., Moorthy, B., 2008. Persistent induction of hepatic and pulmonary phase II enzymes by 3-methylcholanthrene in rats. Toxicol. Sci. 102, 337–342.

7

Koo, S.I., Noh, S.K., 2007. Green tea as inhibitor of the intestinal absorption of lipids: potential mechanism for its lipid-lowering effect. J. Nutr. Biochem. 18, 179–183. Krajka-Kuz’ niak, V., 2007. Induction of phase II enzymes as a strategy in the chemoprevention of cancer and other degenerative diseases. Postepy Hig. Med. Dosw. 61, 627–638. Lad, R., 2010. Validation of individual quantitative methods for determination of cytochrome P450 probe substrates in human dried blood spots with HPLC-MS/ MS. Bioanalysis 2, 1849–1861. Lu, S.C., 2009. Regulation of glutathione synthesis. Mol. Aspects Med. 30, 42–59. Mann, G.E., Rowlands, D.J., Li, F.Y., de Winter, P., Siow, R.C., 2007. Activation of endothelial nitric oxide synthase by dietary isoflavones: role of NO in Nrf2mediated antioxidant gene expression. Cardiovasc. Res. 75, 261–274. Mennier, C.J., Verbeeck, R.K., 1999. Glucuronidation of R- and S-ketoprofen, acetaminophen, and diflunisal by microsomes of adjuvant induced arthritic rats. Drug Metab. Dispos. 27, 26–31. Mohandas, J., Marshall, J.J., Duggin, G.G., Horvath, J.S., Tiller, D.J., 1984. Low activities of glutathione-related enzymes as factors in the genesis of urinary bladder cancer. Cancer Res. 44, 5086–5091. Murugan, R.S., Uchida, K., Hara, Y., Nagini, S., 2008. Black tea polyphenols modulate xenobiotic-metabolizing enzymes, oxidative stress and adduct formation in a rat hepatocarcinogenesis model. Free Radic. Res. 42, 873–884. Nikaidou, S., Ishizuka, M., Maeda, Y., Hara, Y., Kazusaka, A., Fujita, S., 2005. Effect of components of green tea extracts, caffeine and catechins on hepatic drug metabolizing enzyme activities and mutagenic transformation of carcinogens. Jpn. J. Vet. Res. 52, 185–192. Niwattisaiwong, N., Luo, X.X., Coville, P.F., Wanwimolruk, S., 2004. Effects of Chinese, Japanese and Western tea on hepatic P450 enzyme activities in rats. Drug Metabol. Drug Interact. 20, 43–56. Omura, T., Sato, R., 1964. The carbon monoxide-binding pigment of liver microsomes. l. Evidence for its hemeprotein nature. J. Biol. Chem. 239, 2370– 2379. Park, D., Jeon, J.H., Shin, S., Joo, S.S., Kang, D.H., Moon, S.H., Jang, M.J., Cho, Y.M., Kim, J.W., Ji, H.J., Ahn, B., Oh, K.W., Kim, Y.B., 2009. Green tea extract increases cyclophosphamide-induced teratogenesis by modulating the expression of cytochrome P-450 mRNA. Reprod. Toxicol. 27, 79–84. Pascussi, J.M., Drocourt, L., Fabre, J.M., Maurel, P., Vilarem, M.J., 2000. Dexamethasone induces pregnane X receptor and retinoid X receptor-alpha expression in human hepatocytes: synergistic increase of CYP3A4 induction by pregnane X receptor activators. Mol. Pharmacol. 58, 361–372. Patel, R., Maru, G., 2008. Polymeric black tea polyphenols induce phase II enzymes via Nrf2 in mouse liver and lungs. Free Radic. Biol. Med. 44, 1897–1911. Phillips, A.H., Langdon, R.G., 1962. Hepatic triphosphopyridine nucleotide cytochrome c reductase: isolation, characterization, and kinetic studies. J. Biol. Chem. 237, 2652–2660. Rana, R., Chen, Y., Ferguson, S.S., Kissling, G.E., Surapureddi, S., Goldstein, J.A., 2010. Hepatocyte nuclear factor 4{alpha} regulates rifampicin-mediated induction of CYP2C genes in primary cultures of human hepatocytes. Drug Metab. Dispos. 38, 591–599. Rendic, S., 2002. Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab. Rev. 34, 83–448. Rodríguez-Fragoso, L., Martínez-Arismendi, J.L., Orozco-Bustos, D., Reyes-Esparza, J., Torres, E., Burchiel, S.W., 2011. Potential risks resulting from fruit/vegetabledrug interactions: effects on drug-metabolizing enzymes and drug transporters. J. Food Sci. 76, 112–124. Roncal-Jimenez, C.A., Lanaspa, M.A., Rivard, C.J., Nakagawa, T., Sanchez-Lozada, L.G., Jalal, D., Andres-Hernando, A., Tanabe, K., Madero, M., Li, N., Cicerchi, C., Mc Fann, K., Sautin, Y.Y., Johnson, R.J., 2011. Sucrose induces fatty liver and pancreatic inflammation in male breeder rats independent of excess energy intake. Metabolism 60, 1259–1270. Saracino, M.R., Lampe, J.W., 2007. Phytochemical regulation of UDPglucuronosyltransferases: implications for cancer prevention. Nutr. Cancer 59, 121–141. Shi, S.T., Wang, Z.Y., Smith, T.J., Hong, J.Y., Chen, W.F., Ho, C.T., Yang, C.S., 1994. Effects of green tea and black tea on 4-(methylnitrosamino)-1-(3-pyridyl)-1butanone bioactivation, DNA methylation, and lung tumorigenesis in A/J mice. Cancer Res. 54, 4641–4647. Srinivasan, P., Suchalatha, S., Babu, P.V., Devi, R.S., Narayan, S., Sabitha, K.E., Shyamala Devi, C.S., 2008. Chemopreventive and therapeutic modulation of green tea polyphenols on drug metabolizing enzymes in 4-nitroquinoline 1oxide induced oral cancer. Chem. Biol. Interact. 172, 224–234. Tian, J., Lin, X., Guan, R., Xu, J.G., 2004. The effects of hydroxyethyl starch on lung capillary permeability in endotoxic rats and possible mechanisms. Anesth. Analg. 98, 768–774. Tsvetkov, P., Asher, G., Reiss, V., Shaul, Y., Sachs, L., Lotem, J., 2005. Inhibition of NAD(P)H:quinone oxidoreductase 1 activity and induction of p53 degradation by the natural phenolic compound curcumin. Proc. Natl. Acad. Sci. 15, 5535– 5540. Uehiyama, M., Mihara, M., 1978. Determination of malonaldehyde precursor in tissue by thiobarbituric acid test. Anal. Biochem. 86, 271–278. Wu, J.J., Chiang, M.T., Chang, Y.W., Chen, J.Y., Yang, H.T., Lii, C.K., Lin, J.H., Yao, H.T., 2011. Correlation of major components and radical scavenging activity of commercial tea drinks in Taiwan. J. Food Drug Anal. 19, 289–300. Xu, C., Li, C.Y., Kong, A.N., 2005. Induction of phase I, II and III drug metabolism/ transport by xenobiotics. Arch. Pharm. Res. 28, 249–268. Yang, C.S., Pan, E., 2012. The effects of green tea polyphenols on drug metabolism. Expert Opin. Drug Metab. Toxicol. 8, 677–689.

Please cite this article in press as: Yao, H.-T., et al. Effect of commercially available green and black tea beverages on drug-metabolizing enzymes and oxidative stress in Wistar rats. Food Chem. Toxicol. (2014), http://dx.doi.org/10.1016/j.fct.2014.04.043

550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635

FCT 7959

No. of Pages 8, Model 5G

14 May 2014 8 636 637 638 639 640 641

H.-T. Yao et al. / Food and Chemical Toxicology xxx (2014) xxx–xxx

Yang, C.S., Chhabra, S.K., Hong, J.Y., Smith, T.J., 2001. Mechanisms of inhibition of chemical toxicity and carcinogenesis by diallyl sulfide (DAS) and related compounds from garlic. J. Nutr. 131, 1041S–1045S. Yao, H.T., Chang, Y.W., Lan, S.J., Yeh, T.K., 2008. The inhibitory effect of tannic acid on cytochrome P450 enzymes and NADPH-CYP reductase in rat and human liver microsomes. Food Chem. Toxicol. 46, 645–653.

Yao, H.T., Lin, J.H., Chiang, M.T., Chiang, W., Luo, M.N., Lii, C.K., 2011. Suppressive effect of the ethanolic extract of adlay bran on cytochrome p-450 enzymes in rat liver and lungs. J. Agric. Food Chem. 8, 4306–4314. Zheng, Z., Fang, J.L., Lazarus, P., 2002. Glucuronidation: an important mechanism for detoxification of benzo[a]pyrene metabolites in aerodigestive tract tissues. Drug Metab. Dispos. 30, 397–403.

642 643 644 645 646 647 648

Please cite this article in press as: Yao, H.-T., et al. Effect of commercially available green and black tea beverages on drug-metabolizing enzymes and oxidative stress in Wistar rats. Food Chem. Toxicol. (2014), http://dx.doi.org/10.1016/j.fct.2014.04.043