Doxorubicin (DOX) is a highly potent anti-neoplastic agent widely used in clinical practice, but its dosage and duration of administration are strictly limited due to dose-related organ damage. In the present study, we examined whether theanine, an amino acid derivative found in green tea leaves, can protect against DOX-induced acute nephrotoxicity in rats. Decreases in the creatinine clearance by DOX administration were attenuated by concurrent treatment with theanine, which was consistent with the change in histological renal images assessed by microscopic examination. Theanine had no effect on the distribution of DOX to the kidney. The production of lipid peroxide in the kidney after DOX administration was suppressed by concurrent treatment with theanine. Reduced glutathione content, but not superoxide dismutase activity, was decreased following DOX administration, whereas this change was suppressed when theanine was given in combination with DOX. These results suggest that theanine prevents DOX-induced acute nephrotoxicity through its antioxidant properties.

1.
Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y: 4’-O-tetrahydropyranyl- adriamycin as a potential new antitumor agent. Cancer Res 1982; 42: 1462–1467.
2.
Shan K, Lincoff AM, Young JB: Anthracycline-induced cardiotoxicity. Ann Intern Med 1996; 125: 47–58.
3.
Zhang Y, Shi J, Li Y, Wei L: Cardiomyocyte death in doxorubicin-induced cardiotoxicity. Arch Immunol Ther Exp (Warsz) 2009; 57: 435–445.
4.
Kimura T, Fujita I, Itoh N, Muto N, Nakanishi T, Takahashi K, Azuma J, Tanaka K: Metallothionein acts as a cytoprotectant against doxorubicin toxicity. J Pharm Exp Ther 2000; 292: 299–302.
5.
Segeren CM, Sonneveld P, van der Holt B, Baars JW, Biesma DH, Cornellissen JJ, Croockewit AJ, Dekker AW, Fibbe WE, Löwenberg B, van Marwijk Kooy M, van Oers MH, Richel DJ, Schouten HC, Vellenga E, Verhoef GE, Wijermans PW, Wittebol S, Lokhorst HM: Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma. Br J Haematol 1999; 105: 127–130.
6.
Waga N, Ogasawara N, Okada K, Chiyokawa C, Wano Y: Analysis of adverse events and risk factors of febrile neutropenia in patients receiving CHOP or THP-COP chemotherapy for non-Hodgkin’s lymphoma. Health Care Sci 2010; 36: 375–381.
7.
Simmons TW, Jamall IS: Relative importance of intracellular glutathione peroxidase and catalase in vivo for prevention of peroxidation to the heart. Cadiovasc Res 1989; 23: 774–779.
8.
Saad SY, Najjar TA, Al-Rikabi AC: The preventive role of deferoxamine against acute doxorubicin-induced cardiac, renal and hepatic toxicity in rats. Pharmacol Res 2001; 43: 211–218.
9.
Kimura R, Murata T: Influence of alkylamides of glutamic acid and related compounds on the central nervous system. I. Central depressant effect of theanine. Chem Pharm Bull (Tokyo) 1971; 19: 1257–1261.
10.
Graham HN: Green tea composition, consumption, and polyphenol chemistry. Prev Med 1992; 21: 334–350.
11.
Rogers PJ, Smith JE, Heatherley SV, Pleydell-Pearce CW: Time for tea: mood, blood pressure and cognitive performance effects of caffeine and theanine administered alone and together. Psychopharmacology (Berl) 2008; 195: 569–577.
12.
Vuong QV, Stathopoulos CE, Golding JB, Nguyen MH, Roach PD: Optimum conditions for the water extraction of L-theanine from green tea. J Sep Sci 2011; 34: 2468–2474.
13.
Kim TI, Lee YK, Park SG, Choi IS, Ban JO, Park HK, Nam SY, Yun YW, Han SB, Oh KW, Hong JT: L-Theanine, an amino acid in green tea, attenuates beta-amyloid-induced cognitive dysfunction and neurotoxicity: reduction in oxidative damage and inactivation of ERK/p38 kinase and NF-kappaB pathways. Free Rad Biol Med 2009; 47: 1601–1610.
14.
Li G, Ye Y, Kang J, Yao X, Zhang Y, Jiang W, Gao M, Dai Y, Xin Y, Wang Q, Yin Z, Luo L: L-Theanine prevents alcoholic liver injury through enhancing the antioxidant capability of hepatocytes. Food Chem Toxicol 2012; 50: 363–372.
15.
Nagai K, Oda A, Konishi H: Theanine prevents doxorubicin-induced acute hepatotoxicity by reducing intrinsic apoptotic response. Food Chem Toxicol 2015; 78: 147–152.
16.
Heeba GH, Mahmound ME: Dual effects of quercetin in doxorubicin-induced nephrotoxicity in rats and its modulation of the cytotoxic activity of doxorubicin on human carcinoma cells. Environ Toxicol 2016; 31: 624–636.
17.
Nagai K, Nogami S, Egusa H, Konishi H: Pharmacokinetic evaluation of intraperitoneal doxorubicin in rats. Pharmazie 2014; 69: 125–127.
18.
Poontawee W, Natakankitkul S, Wongmekiat O: Protective effect of cleistocalyx nervosum var. paniala fruit extract against oxidative renal damage caused by cadmium. Molecules 2016; 21: 133.
19.
Kim YS, Sung SH, Tang Y, Choi EJ, Choi EJ, Choi YJ, Hwang YJ, Park PJ, Kim EK: Protective effect of taurine on mice with doxorubicin-induced acute kidney injury. Adv Exp Med Biol 2017; 975: 1191–1201.
20.
Ramakrishnan G, Raghavendran HR, Vinodhkumar R, Devaki T: Suppression of N-nitrosodiethylamine induced hepatocarcinogenesis by silymarin in rats. Chem Biol Interact 2006; 161: 104–114.
21.
Vasquez-Garzon VR, Arellanes-Robledo J, Garcia-Roman R, Aparicio-Rautista DI, Villa-Trevino S: Inhibition of reactive oxygen species and pre-neoplastic lesions by quercetin through an antioxidant defense mechanism. Free Radic Res 2009; 43: 128–137.
22.
Nagai K, Fukuno S, Oda A, Konishi H: Protective effects of taurine on doxorubicin-induced acute hepatotoxicity through suppression of oxidative stress and apoptotic responses. Anticancer Drugs 2016; 27: 17–23.
23.
Desai MJ, Gill MS, Hsu WH, Armstrong DW: Pharmacokinetics of theanine enantiomers in rats. Chirality 2005; 17: 154–162.
24.
Bertino JR, Sawicki WI, Lindquist CA, Gupta VS: Schedule-dependent antitumor effects of methotrexate and 5-fluorouracil. Cancer Res 1977; 37: 327–328.
25.
Fernández Hidalgo O, Gonzalez F, Gil A, Campbell W, Barrajon E, Lacave AJ: 120 hours simultaneous infusion of cisplatin and fluorouracil in metastatic breast cancer. Am J Clin Oncol 1989; 12: 397–401.
26.
Ichinose Y, Takanashi N, Yano T, Asoh H, Yokoyama H, Tayama K, Hara N, Ohta M: A phase II trial of oral tegafur and uracil plus cisplatin in patients with inoperable nonsmall cell lung cancer. Cancer 1995; 75: 2677–2680.
27.
O’Connel MJ: A phase III trial of 5-fluorouracil and leucovorin in the treatment of advanced colorectal cancer. A Mayo Clinic/North Central Cancer Treatment Group study. Cancer 1998; 63: 1026–1030.
28.
Sadzuka Y, Sugiyama T, Miyagishima A, Nozawa Y, Hirota S: The effects of theanine, as a novel biochemical modulator, on the antitumor activity of Adriamycin. Cancer Lett 1996; 105: 203–209.
29.
Sugiyama T, Sadzuka Y: Combination of theanine with doxorubicin inhibits hepatic metastasis of M5076 ovarian sarcoma. Clin Cancer Res 1999; 5: 413–416.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.