title: Efficacy of theanine is connected with theanine metabolism by any enzyme, not only drug metabolizing enzymes.
abstract: Theanine increases the antitumor effect of doxorubicin (DOX) with decreasing adverse reaction. We clarified the mechanism by which theanine decreases the adverse reaction of DOX on any metabolizing enzymes of theanine. There was no change in the activity of any CYPs and the cytochrome P450 content by theanine treatment. Namely, it was considered that the decrease of DOX adverse reactions by theanine was not connected with CYP activity. In other words, it is shown that theanine has no effect on the metabolism of other medicines and is safe as a food (tea) or supplement. Glutathione S-transferase activity did not change in the theanine-alone group whereas increased in the theanine and DOX-combined group. These results suggested that theanine combination increased the conjugate with DOX and GSH, promoted the efflux of GS-DOX conjugates from the liver, and decreased DOX concentration in the liver. In medium containing theanine with glutaminase in vitro, glutamate gradually generated, showing that glutaminase reacted with theanine. Furthermore, the generation of glutamate increased by reaction of theanine and gamma-glutamyltranspeptidase (gamma-GTP), showed that gamma-GTP converted theanine to glutamate. It is expected that theanine metabolism occurred by hydrolysis and rearrangement reaction by gamma-GTP in the liver. Namely, it is suggested that the metabolism of theanine mediated by glutaminase and gamma-GTP and the increase of glutamate mediated GSH is important for theanine-induced action. In conclusion, it appeared that theanine does not change the biodistribution of combined drugs but it modulates biodistribution or damage to the relative site of GSH, and shows preventive effects in tissue.
authors.affiliation: School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. sadzuka@u-shizuoka-ken.ac.jp
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sadzuka
authors.forename: Tomomi
authors.initials: T
authors.lastname: Sugiyama
authors.forename: Makiko
authors.initials: M
authors.lastname: Nagamine
authors.forename: Keizo
authors.initials: K
authors.lastname: Umegaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Sonobe
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D003580:Cytochromes / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004317:Doxorubicin / Q000633:toxicity; D005971:Glutamates / Q000378:metabolism* / Q000627:therapeutic use*; D005972:Glutaminase / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D003580:Cytochromes; D005971:Glutamates; D004364:Pharmaceutical Preparations; D004317:Doxorubicin; C026166:theanine; D006160:Guanosine Triphosphate; D006899:Mixed Function Oxygenases; D005972:Glutaminase