Effects of xenobiotics on signal transduction and Ca2+ mediated processes in mammalian cells.
Cellular responses to hormones and growth factors that act through the hydrolysis of membrane-bound inositol phospholipid are mediated by at least two second messengers--diacylglycerol and inositol 1, 4, 5-trisphosphate. While diacylglycerol stimulates protein kinase C activity, inositol 1, 4, 5-trisphosphate mobilizes intracellular Ca2+. Studies in our laboratory have demonstrated that xenobiotics can interfere with signal transduction at different levels with a resulting loss of normal Ca2+ responses to hormones and growth factors. Effects of toxicants on ion channels, receptors, G proteins, and other enzymes involved in cell signalling have been investigated. Our recent studies have shown that mild oxidative stress can activate protein kinase C which may in turn stimulate cell proliferation. In addition, toxic agents can directly affect intracellular Ca2+ homeostasis by interfering with Ca2+ pumps and Ca2+ channels. This can compromise the ability of the cell to buffer Ca2+ changes and result in a sustained elevation of the cytosolic Ca2+ concentration with the subsequent activation of various Ca(2+)-dependent degradative processes. Thus, the alteration of cell signalling by toxicants may affect several important cell functions, including cell differentiation and proliferation, and may ultimately lead to cell death.
Kass
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GE
Department of Toxicology, Karolinska Institutet, Stockholm, Sweden.
Nicotera
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Orrenius
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D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism* / Q000493:pharmacokinetics; D015220:Calcium Channels / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002462:Cell Membrane / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D003603:Cytotoxins / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000502:physiology; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000378:metabolism; D008670:Metals / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*
D015220:Calcium Channels; D003603:Cytotoxins; D008670:Metals; D002118:Calcium