毒理学相关资料,第六章内容参考文献1.docVIP

Calcium Signaling and Cytotoxicity Abstract1School of Biological Sciences, University of Surrey, Guildford, Surrey, United Kingdom2Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden Abstract The divalent calcium cation Ca2+ is used as a major signaling molecule during cell signal transduction to regulate energy output, cellular metabolism, and phenotype. The basis to the signaling role of Ca2+ is an intricate network of cellular channels and transporters that allow a low resting concentration of Ca2+ in the cytosol of the cell ([Ca2+]i) but that are also coupled to major dynamic and rapidly exchanging stores. This enables extracellular signals from hormones and growth factors to be transduced as [Ca2+]i spikes that are amplitude and frequency encoded. There is considerable evidence that a number of toxic environmental chemicals target these Ca2+ signaling processes, alter them, and induce cell death by apoptosis. Two major pathways for apoptosis will be considered. The first one involves Ca2+-mediated expression of ligands that bind to and activate death receptors such as CD95 (Fas, APO-1). In the second pathway, Ca2+ has a direct toxic effect and its primary targets include the mitochondria and the endoplasmic reticulum (ER). Mitochondria may respond to an apoptotic Ca2+ signal by the selective release of cytochrome c or through enhanced production of reactive oxygen species and opening of an inner mitochondrial membrane pore. Toxic agents such as the environmental pollutant tributyltin or the natural plant product thapsigargin, which deplete the ER Ca2+ stores, will induce as a direct result of this effect the opening of plasma membrane Ca2+ channels and an ER stress response. In contrast, under some conditions, Ca2+ signals may be cytoprotective and antagonize the apoptotic machinery. -- Environ Health Perspect 107(Suppl 1):25-35 (1999). /docs/1999/Suppl-1/25-35kass/abstract.html Key words: apoptosis, necrosis, Ca2+-ATPase,