title: Elevated cardiac 3-deoxyglucosone, a highly reactive intermediate in glycation reaction, in doxorubicin-induced cardiotoxicity in rats.
abstract: 3-Deoxyglucosone (3-DG) is a highly reactive carbonyl intermediate in glycation reaction (also known as Maillard reaction) and plays an important role in diabetic complications. We investigated the potential involvement of 3-DG in doxorubicin (DXR)-induced cardiotoxicity. Male Crl:CD(SD) rats received intravenous injections of DXR at 2mg/kg, once weekly, for 6 weeks, with/without daily intraperitoneal treatment with 3-DG scavenging agents, i.e., aminoguanidine (AG, 25mg/kg/day) and pyridoxamine (PM, 60mg/kg/day). Cardiac levels of 3-DG, thiobarbituric acid reactive substances (TBARS), fructosamine, and pentosidine, plasma glucose levels and cardiac troponin I (cTnI), echocardiography, and histopathology were assessed at 4 and 6 weeks after treatment. Cardiac 3-DG levels were significantly increased by DXR treatment at 4 and 6 weeks. Cardiac fructosamine levels and plasma glucose were not altered by DXR; however, TBARS levels in the heart were significantly increased at 4 and 6 weeks, suggesting that the enhanced generation of 3-DG is not attributed to any abnormal glycemic status, but may be related to oxidative stress by DXR. An advanced glycation end-product, pentosidine, was significantly increased by DXR treatment at 6 weeks. Intervention by AG and PM ameliorated the DXR-induced echocardiographic abnormalities, increased cTnI in plasma, and histopathological lesion as well as normalizing the elevation of 3-DG and pentosidine levels. These results suggest that 3-DG is generated by DXR and involved, at least in part, in the pathogenesis of DXR-cardiotoxicity through glycation reaction.
authors: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan. Electronic address: tomoyuki_moriyama@eisai.com.
authors: Tomoyuki
authors: T
authors: Moriyama
authors: Tsukuba Research Institute, BOZO Research Center Inc., 8 Okubo, Tsukuba, Ibaraki, 300-2611, Japan.
authors: Masayuki
authors: M
authors: Kemi
authors: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors: Toshiharu
authors: T
authors: Horie
keywords: 3-Deoxyglucosone; Advanced glycation end-products; Cardiotoxicity; Doxorubicin