To the editor:

In 2 interesting articles published in the June 4, 2009 issue of Blood, attention was focused on the possibility for green tea derivatives to inhibit the therapeutic activity of bortezomib, an anticancer agent very effective in multiple myeloma and mantle cell lymphoma.1,2  However, the interaction with boronic acid–based proteasome inhibitors is not the only important interaction between green tea and drugs. In fact, both green tea and black tea derivatives have been shown to modulate the activity of several drug metabolizing enzymes, and this effect could be responsible for undesired variations in plasma concentration of many drugs. Catechins, the main polyphenol constituents of green tea, inhibited the activity of the isoforms 3A4, 2A6, 2C19, and 2E1 whereas they increased the activity of the isoforms 1A2 and 2B of human and rodent cytochrome P-450 (CYP).3-6  The inhibition by green tea of CYP3A4 could be harmful, particularly in case of prolonged consumption of this beverage. With regard to antineoplastic drugs, epigallocatechin-3-gallate (EGCG) augmented the toxicity of cyclophosphamide5  and doxorubicin7  likely because it increased the activity of rat and human CYP2B and NADPH-Cyt-P-450 reductase and the further formation of noxious by-products.5,7  Also worthy of mention are the possible interactions between catechins and drugs that could be administered to cancer patients for the treatment of concomitant diseases. In fact, it has been shown that EGCG, by inhibiting both CYP3A4 and P-glicoprotein activities, increased the bioavailability of the calcium channel blockers verapamil and diltiazem,8,9  thus raising the risk for patients to undergo atrioventricular block. The inhibition of CYP3A4 activity by green tea extracts could increase the plasma concentrations of midazolam4  and, therefore, amplify the risk of prolonged sedation. On the contrary, the up-regulation of CYP1A2 could result in reduced bioavailability of the antipsychotic drug clozapine.6  Furthermore, both green and black tea extracts inhibited the activity of the isoforms 1A1 and 1A3 of sulfotransferases,10,11  a family of enzymes involved in the metabolism of drugs such as methyldopa or β2-adrenoceptor agonists, thus increasing their plasma concentrations and side effects. With regard to the plasma concentrations of EGCG in people drinking green tea, it is interesting to note that the values found by Chow and colleagues and quoted by Shah et al2  could be underestimated. In fact, Chow et al measured plasma EGCG after a single administration of green tea to healthy volunteers. Considering that catechins are metabolized by sulfotransferases and the latter is inhibited by the former,10,11  catechin plasma concentration could significantly increase in people consuming a large amount of green tea.

Finally, the rationale for use of green tea as an adjuvant in cancer therapy has been contradicted by recent clinical studies that demonstrated the inconsistent effect of green tea in preventing the occurrence of esophageal, stomach, liver, colorectal, and breast cancers.12,13  In our opinion, it is a matter of public health to refrain from providing people with confusing information about the unproven therapeutic potential of tea derivatives without consistent information on their toxicity.

Acknowledgment: C.M. thanks the Istituto Biochimico Italiano-Giovanni Lorenzini s.p.a. for support.

Contribution: C.M. and E.B. analyzed literature and wrote the letter.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Cesare Mancuso, Institute of Pharmacology, Catholic University School of Medicine, Largo F. Vito, 1-00168 Rome, Italy; e-mail: cmancuso@rm.unicatt.it.

1
Golden
 
EB
Lam
 
PY
Kardosh
 
A
, et al. 
Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors.
Blood
2009
, vol. 
113
 (pg. 
5927
-
5937
)
2
Shah
 
JJ
Kuhn
 
DJ
Orlowski
 
RZ
Bortezomib and EGCG: no green tea for you?
Blood
2009
, vol. 
113
 (pg. 
5695
-
5696
)
3
Wanwimolruk
 
S
Wong
 
K
Wanwimolruk
 
P
Variable inhibitory effect of different brands of commercial herbal supplements on human cytochrome P-450 CYP3A4.
Drug Metabol Drug Interact
2009
, vol. 
24
 (pg. 
17
-
35
)
4
Muto
 
S
Fujita
 
K
Yamazaki
 
Y
Kamataki
 
T
Inhibition by green tea catechins ofmetabolic activation of procarcinogens by human cytochrome P450.
Mutat Res
2001
, vol. 
479
 (pg. 
197
-
206
)
5
Park
 
D
Jeon
 
JH
Shin
 
S
, et al. 
Green tea extract increases cyclophosphamide-induced teratogenesis by modulating the expression of cytochrome P-450 mRNA.
Reprod Toxicol
2009
, vol. 
27
 (pg. 
79
-
84
)
6
Jang
 
EH
Choi
 
JY
Park
 
CS
, et al. 
Effects of green tea extract administration on the pharmacokinetics of clozapine in rats.
J Pharm Pharmacol
2005
, vol. 
57
 (pg. 
311
-
316
)
7
Dudka
 
J
Jodynis-Liebert
 
J
Korobowicz
 
E
, et al. 
Activity of NADPH-cytochrome P-450 reductase of the human heart, liver and lungs in the presence of (-)-epigallocatechin gallate, quercetin and resveratrol: an in vitro study.
Basic Clin Pharmacol Toxicol
2005
, vol. 
97
 (pg. 
74
-
79
)
8
Chung
 
JH
Choi
 
DH
Choi
 
JS
Effects of oral epigallocatechin gallate on the oral pharmacokinetics of verapamil in rats.
Biopharm Drug Dispos
2009
, vol. 
30
 (pg. 
90
-
93
)
9
Li
 
C
Choi
 
JS
Effects of epigallocatechin gallate on the bioavailability and pharmacokinetics of diltiazem in rats.
Pharmazie
2008
, vol. 
63
 (pg. 
815
-
818
)
10
Nagai
 
M
Fukamachi
 
T
Tsujimoto
 
M
, et al. 
Inhibitory effects of herbal extracts on the activity of human sulfotransferase isoform sulfotransferase 1A3 (SULT1A3).
Biol Pharm Bull
2009
, vol. 
32
 (pg. 
105
-
109
)
11
Nishimuta
 
H
Ohtani
 
H
Tsujimoto
 
M
Ogura
 
K
Hiratsuka
 
A
Sawada
 
Y
Inhibitory effects of various beverages on human recombinant sulfotransferase isoforms SULT1A1 and SULT1A3.
Biopharm Drug Dispos
2007
, vol. 
28
 (pg. 
491
-
500
)
12
Myung
 
SK
Bae
 
WK
Oh
 
SM
, et al. 
Green tea consumption and risk of stomach cancer: a meta-analysis of epidemiologic studies.
Int J Cancer
2009
, vol. 
124
 (pg. 
670
-
677
)
13
Liu
 
J
Xing
 
J
Fei
 
Y
Green tea (Camellia sinensis) and cancer prevention: a systematic review of randomized trials and epidemiological studies.
Chin Med
2008
, vol. 
3
 pg. 
12
 

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