Shigeo Nakamura

Ipso substitution of bisphenol A catalyzed by microsomal cytochrome P450 and enhancement of estrogenic activity

Bisphenol A (BPA), an industrial chemical with estrogenic activity, was investigated as a substrate for the ipso-metabolism catalyzed by microsomal cytochrome P450 (P450). BPA was expected to be transformed to a quinol via an ipso-addition reaction; however, hydroquinone (HQ) was detected as a metabolite via an ipso-substitution reaction. Isopropenylphenol (IPP) and hydroxycumyl alcohol (HCA) were also produced as eliminated metabolites by C-C bond scission via ipso-substitution. Incorporation of the ¹⁸O atom to HCA from H₂¹⁸O suggested the presence of a carbocation intermediate. Bulkiness of p-substituted group of BPA and/or stability of the eliminated carbocation intermediate may cause ipso-substitution of BPA. CYP3A4 and CYP3A5 showed higher activity for ipso-substitution. CYP2D6*1 also showed the activity; however, the other 9 isozymes did not. IPP showed ER-binding activity in the same degree of BPA. Furthermore, the ER-binding activity of HCA was about a hundred times greater than that of BPA. These results suggested that this new metabolic pathway contributes to the activation of the estrogenic activity of BPA.

Pyrrolidinium-type fullerene derivative-induced apoptosis by the generation of reactive oxygen species in HL-60 cells

The biological activities of C(60)-bis(N,N-dimethylpyrrolidinium iodide), a water-soluble cationic fullerene derivative, on human promyeloleukaemia (HL-60) cells were investigated. The pyrrolidinium fullerene derivative showed cytotoxicity in HL-60 cells. The characteristics of apoptosis, such as DNA fragmentation and condensation of chromatin in HL-60 cells, were observed by exposure to the pyrrolidinium fullerene derivative. Caspase-3 and -8 were activated and cytochrome c was also released from mitochondria. The generation of reactive oxygen species (ROS) by the pyrrolidinium fullerene derivative was observed by DCFH-DA, a fluorescence probe for the detection of ROS. Pre-treatment with alpha-tocopherol suppressed cell death and intracellular oxidative stress caused by the pyrrolidinium fullerene derivative. The apoptotic cell death induced by the pyrrolidinium fullerene derivative was suggested to be mediated by ROS generated by the pyrrolidinium fullerene derivative.

C60 Nanowhisker Field-Effect-Transistor Application for Nano-Electronics

Various kinds of field-effect transistor (FET) have been fabricated with C60 nanowhisker (NW) and also studied for nano-electronics application. Especially, pure and solvated C60 NWs have been synthesized in N2 environment so as to clarify the best device performance of C60 NW-FET. The FET works not only under vacuum but also in N2 environment when kept in the solvated condition. The solvated C60 NW-FET shows a clear improvement of their on/off ratio in the solvated condition, and the highest electron mobility after annealing. Although further study is needed, our results demonstrate the possibility, by appropriate choice of the solvent, of achieving good improvements in FET performance. Moreover, new kinds of C60 NW, such as derivative-based and nanotube-type one, have also been studied with regards to their fundamental FET characteristics.

2,2′-Pyridoin derivatives protect HL-60 cells against oxidative stress

Focusing on 2,2-pyridoin (1, 1,2-di(2-pyridyl)-1,2-ethenediol) and its synthetic derivatives as the lead compound of the potent antioxidative enediol, their protective effect against oxidative stress was evaluated on the HL-60 cell system. 2,2-Pyridoins showed no remarkable cytotoxic effect on HL-60 cells. The derivatives 1, 2, 3, 5, and 6 inhibited H(2)O(2)-induced cell death and intracellular oxidative stress more significantly than ascorbic acid. Since 2,2-pyridoins are oxidized to the diketones, 2,2-pyridils, in a protic solvent, the antioxidant activity of 2,2-pyridils was also investigated. 2,2-Pyridils showed antioxidant activity in the cell; however, the activity was lower than that of 2,2-pyridoins. These results suggested that 2,2-pyrdoin derivatives can be good cytoprotective agents against oxidative stress.