Exposure and toxicity of green tea polyphenols in fasted and non-fasted dogs
Introduction
Tea is one of the most commonly consumed beverages worldwide, especially in Asian countries where it has been believed for centuries to posses a number of health promoting and curative properties. Green tea, like black and Oolong teas, is manufactured from dried leaves of Camelia sinensis, a species of Theaceae family. It differs from the other tea types by the processing method. Green tea is obtained by dry heat treatment of freshly harvested leaves to inactivate oxidative enzymes and by omitting fermentation, thereby preserving polyphenolic catechins with their high antioxidant activities. Four polyphenolic compounds, (−)-epigallocatechin gallate (EGCG), (−)-epigallocatechin (EGC), (−)-epicatechin gallate (ECG), and (−)-epicatechin (EC), constitute the main polyphenolic components of green tea (Fig. 1). Green tea products are commonly available, marketed and used as dietary supplements (nutraceuticals) in the United States, mainly for purported weight loss and antioxidant properties. A number of different health benefits have been attributed to green tea, including prevention and/or control of atherosclerosis, hypertension, coronary heart disease, diabetes, metabolic syndrome, obesity, and cancer as well as having antibacterial, antiviral, antifungal, and neuroprotective activities (Cabrera et al., 2006, Cheng, 2006, Cooper et al., 2005a, Cooper et al., 2005b, Crespy and Williamson, 2004, Friedman, 2007, Fujiki, 2005, Khan and Mukhtar, 2007, Pham-Huy et al., 2008, Shankar et al., 2007, Shukla, 2007, Zaveri, 2006). Due to potential public health benefits, green tea products have been and continue to be a subject of considerable attention from the general public and the scientific community.
Green tea polyphenolic catechins have shown promising cancer chemopreventive activities in a variety of animal tumor models, including lung, urinary bladder, mammary gland, prostate and skin (Lubet et al., 2007, Shukla, 2007, Yan et al., 2006, Yang et al., 2007). A highly purified and standardized green tea extract (Polyphenon E®; PPE) is in drug development, presently Phase 2 testing, as a candidate cancer chemopreventive agent in the Division of Cancer Prevention at the National Cancer Institute. PPE contains 85–95% total catechins and the main component is EGCG. EGCG accounts for 56–72% of the material and the other major ingredients EGC, ECG, and EC are present at approximately 3%, 8%, and 8%, respectively. PPE may also contain small amounts of caffeine (<1%), theobromine (<1%), and gallic acid (<0.5%). PPE as a topical antiviral cream was the first botanical drug approved (http://www.fda.gov/cder/foi/label/2006/021902lbl.pdf) under the FDA's new Botanical Drug Products guidance (http://www.fda.gov/cder/guidance/4592fnl.htm).
Chronic 9-month and the follow-up 13-week subchronic dog studies of PPE were carried out at different laboratories. Doses for the 9-month chronic study (0, 200, 500 and 1000 mg/kg/day) were selected on the basis of an earlier 13-week subchronic oral toxicity study in dogs in which the no-observed-adverse-effect-level (NOAEL) was >600 mg/kg body weight (highest dose tested) in fed dogs (Johnson et al., 1999). However, in view of the recognized low oral bioavailability of green tea catechins (Cai et al., 2002, Walle, 2007) and increased oral bioavailability of free catechins following administration of Polyphenon E® capsules to human volunteers on an empty stomach (Chow et al., 2005), dosing under fasted conditions was selected for the chronic study. Unexpected high morbidity and mortality in the chronic study led to its premature termination at 6.5 months. Due to high morbidity and mortality in the chronic study, it was not possible to ascertain causes for the unexpected severe toxicity that was observed. Therefore, the 13-week follow-up study was initiated to determine if the results could be replicated in another laboratory and to attempt to identify and characterize toxicities of Polyphenon E® following oral capsule dosing in dogs and examine confounding factors such as dosing under fed or fasted conditions.
Section snippets
Materials and methods
Prior to initiation of in vivo experimentation, study protocols were reviewed and approved by the institutional Animal Care and Use Committee. All aspects of animal care, use, and welfare were performed in compliance with United States Department of Agriculture regulations and the Guide for the Care and Use of Laboratory Animals (National Research Council, 1996). All studies were conducted in full compliance with the Good Laboratory Practice Regulations of the United States Food and Drug
Chronic study
Unexpected morbidity and mortality were encountered in the chronic 9-month dog toxicology study with PPE. Doses selected for this study (200, 500 and 1000 mg/kg/day) were based on an earlier 13-week study where NOAEL was > 600 mg/kg/day, the highest dose tested (Johnson et al., 1999). Unlike in that earlier study, PPE was administered on an empty stomach in the chronic study and food was provided for 2 h starting 2 h after dosing. Toxicity was evident by day 9 when clinical signs, including one
Discussion
Green tea extracts have been implicated in control, mitigation or prevention of a number of different diseases or conditions (Cabrera et al., 2006, Cheng, 2006, Cooper et al., 2005a, Cooper et al., 2005b, Crespy and Williamson, 2004, Friedman, 2007, Fujiki, 2005, Khan and Mukhtar, 2007, Pham-Huy et al., 2008, Shankar et al., 2007, Shukla, 2007, Zaveri, 2006), including in the area of cancer prevention (Lubet et al., 2007, Shukla, 2007, Yan et al., 2006, Yang et al., 2007). However,
Conflict of interest statement
The authors have no personal or financial conflicts of interest.
Acknowledgement
The work was conducted under contract N01-CN-43306.
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