6-formylpterin, a xanthine oxidase inhibitor, intracellularly generates reactive oxygen species involved in apoptosis and cell proliferation.
The chemical property of 6-formylpterin and its biological functions were examined. Polarographic studies revealed that 6-formylpterin reacted with NAD(P)H and consumed oxygen. In contrast, other conjugated pterins, such as biopterin and neopterin, showed no consumption of oxygen. The production analysis using high-performance liquid chromatography documented that 6-formylpterin catalyzes the conversion from NADH to NAD. Electroparamagnetic resonance spin trapping experiments demonstrated that this reaction is accompanied with the generation of reactive oxygen species (ROS), superoxide anion and hydrogen peroxide. When 6-formylpterin was administered to HL-60 cells, intracellular ROS generation was observed and apoptosis was induced. In contrast, other conjugated pterins induced neither intracellular ROS generation nor apoptosis in HL-60 cells. The intracellular ROS generation by 6-formylpterin was observed in other cells, such as PanC-1 cells and Jurkat cells. 6-formylpterin suppressed cell proliferation in PanC-1 cells and inhibited Fas-mediated apoptosis in Jurkat cells. These findings indicate that, among conjugated pterins, 6-formylpterin has the unique property to transfer electron from NAD(P)H to oxygen and that the property brings about intracellular ROS generation, which exerts various biological functions such as induction of apoptosis, suppression of cell proliferation, and inhibition of Fas-mediated apoptosis.
Arai
T
T
Department of Anesthesia, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. arai@kuhp.kyoto-u.ac.jp
Endo
N
N
Yamashita
K
K
Sasada
M
M
Mori
H
H
Ishii
H
H
Hirota
K
K
Makino
K
K
Fukuda
K
K
D017209:Apoptosis / Q000187:drug effects*; D002374:Catalase / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects*; D002614:Chelating Agents / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003676:Deferoxamine / Q000494:pharmacology; D004563:Electrochemistry; D004578:Electron Spin Resonance Spectroscopy; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D019169:Jurkat Cells; D009243:NAD / Q000378:metabolism; D009711:Nucleotides / Q000032:analysis; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D011621:Pteridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011622:Pterins; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*; D019014:fas Receptor / Q000502:physiology
D002614:Chelating Agents; D004791:Enzyme Inhibitors; D009711:Nucleotides; D011621:Pteridines; D011622:Pterins; D017382:Reactive Oxygen Species; D019014:fas Receptor; D009243:NAD; D013481:Superoxides; C005926:2-amino-4-hydroxy-6-formylpteridine; D006861:Hydrogen Peroxide; D002374:Catalase; D014969:Xanthine Oxidase; D003676:Deferoxamine