Tachikawa H

References (2)

Title : Ab initio model study on acetylcholinesterase catalysis: potential energy surfaces of the proton transfer reactions - Tachikawa_2005_J.Photochem.Photobiol.B_79_11
Author(s) : Tachikawa H , Igarashi M , Nishihira J , Ishibashi T
Ref : J Photochem Photobiol B , 79 :11 , 2005
Abstract : Ab initio molecular orbital (MO) and hybrid density functional theory (DFT) calculations have been applied to the initial step of the acylation reaction catalyzed by acetylcholinesterase (AChE), which is the nucleophiric addition of Ser200 in catalytic triads to a neurotransmitter acetylcholine (ACh). We focus our attention mainly on the effects of oxyanion hole and Glu327 on the potential energy surfaces (PESs) for the proton transfer reactions in the catalytic triad Ser200-His440-Glu327. The activation barrier for the addition reaction of Ser200 to ACh was calculated to be 23.4 kcal/mol at the B3LYP/6-31G(d)//HF/3-21G(d) level of theory. The barrier height under the existence of oxyanion hole, namely, Ser200-His440-Glu327-ACh-(oxyanion hole) system, decreased significantly to 14.2 kcal/mol, which is in reasonable agreement with recent experimental value (12.0 kcal/mol). Removal of Glu327 from the catalytic triad caused destabilization of both energy of transition state for the reaction and tetrahedral intermediate (product). PESs calculated for the proton transfer reactions showed that the first proton transfer process is the most important in the stabilization of tetrahedral intermediate complex. The mechanism of addition reaction of ACh was discussed on the basis of theoretical results.
ESTHER : Tachikawa_2005_J.Photochem.Photobiol.B_79_11
PubMedSearch : Tachikawa_2005_J.Photochem.Photobiol.B_79_11
PubMedID: 15792875

Title : Role of oxidant stress and antioxidant protection in acephate-induced renal tubular cytotoxicity - Poovala_1998_Toxicol.Sci_46_403
Author(s) : Poovala VS , Kanji VK , Tachikawa H , Salahudeen AK
Ref : Toxicol Sci , 46 :403 , 1998
Abstract : Acephate (AT) is an organophosphate (OP) insecticide. Due to their reputation for low environmental persistence, OP pesticides are often used indiscriminately resulting in detrimental exposure to humans and other nontarget species. Although the toxicity of OP compounds is primarily through blockade of neural transmission via inhibition of acetylcholinesterase, studies have revealed histopathological alterations in the renal proximal tubules, suggesting a role for additional mechanisms in renal toxicity. It is our hypothesis that Reactive Oxygen Species (ROS) may play a role in OP-induced renal tubular injury for the following reasoning. Renal tubular cells concentrate many nephrotoxic chemicals including OPs, and renal injury from many of these compounds has been shown to arise from excessive ROS production. Furthermore, it has been established that many phosphorothiolates, which are sulfur-containing OPs and constitute the class of OP compounds to which AT belongs, are S-oxidized to highly reactive intermediates within cells and tissues. Because of these considerations, we examined whether ROS play a role in OP-induced renal tubular epithelial cell (LLC-PK1) toxicity using AT as a prototype. AT produced a concentration- and time-dependent increase in cell damage in LLC-PK1 cells, measured by lactate dehydrogenase (LDH, % of total) leakage. The cytotoxicity (LDH) induced by 2500 ppm of AT over 72 h was significantly suppressed by antioxidants 2-methylaminochroman (2-MAC) and desferrioxamine (DFO). H2O2 levels were significantly elevated following exposure of LLC-PK1 cells to 2500 ppm of AT. Malondialdehyde (MDA) formation was also significantly increased in AT-exposed cells compared to the control cells, indicating the occurrence of enhanced lipid peroxidation. 2-MAC and DFO, in addition to providing cytoprotection, inhibited AT-induced MDA generation in a significant and concentration-dependent manner. Results from this study, which is the first to explore the toxic effects of AT on renal tubular cells, demonstrate that toxic action of AT on kidney cells is partly through an ROS-mediated mechanism. Based on these direct in vitro findings, we further hypothesize that oxidant stress may play a role in the pathogenesis of AT-induced acute tubular necrosis and renal dysfunction observed in cases of AT overdoses.
ESTHER : Poovala_1998_Toxicol.Sci_46_403
PubMedSearch : Poovala_1998_Toxicol.Sci_46_403
PubMedID: 10048144