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.