Cell injury

The first is cell injury (cytotoxicity), which can be severe enough to result in cell death. There are many mechanisms by which xenobiotics injure cells. The one considered here is covalent binding to cell macromol-ecules of reactive species of xenobiotics produced by metabolism. These macromolecular targets include DNA, RNA, and protein. If the macromolecule to which the reactive xenobiotic binds is essential for short-term cell survival, eg, a protein or enzyme involved in some critical cellular function such as oxidative phosphorylation or regulation of the permeability of the plasma membrane, then severe effects on cellular function could become evident quite rapidly. 

Figure 53-1. Simplified scheme showing how metabolism of a xenobiotic can result in cell injury, immunologic damage, or cancer. In this instance, the conversion of the xenobiotic to a reactive metabolite is catalyzed by a cytochrome P450,and the conversion of the reactive metabolite (eg, an epoxide) to a nontoxic metabolite is catalyzed either by a GSH S-transferase or by epoxide hydrolase.

In liver cells the activity of GOT is higher than that of GPT, but most of the GPT activity is located in the cytoplasm and therefore leaks more readily into the blood stream with minor or reversible cell damage. Enzymes located in the mitochondria, such as one of the GOT isoenzymes appear in serum only when there has been more severe liver cell injury including cell death. 

Dreyer EB, Kaiser PK, Offermann JT, Lipton SA (1990) HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists. Science 248(4953) 364-367 Dreyer EB, Zurakowski D, Gorla M, Vorwerk CK, Lipton SA (1999) The contribution of various NOS gene products to HlV-1 coat protein (gpl20)-mediated retinal ganglion cell injury. Invest Ophthalmol Vis Sci 40(5) 983-989... 

Hyslop, P.A., Hinshaw, D.B., Halsey, W.A., Schraufttatter, I.U., Sauerheber, RD., Spragg, RG., Jackson, J.H. and Cochrane, C.G. (1988). Mechanisms of oxidant-mediated cell injury. The glycolytic and mitochondrial pathways of ADP phosphorylation as major intracellular targets inactivated by hydrogen peroxide. J. Biol. Chem. 263, 1665-1671. 

Recent studies by Crompton et al. have shown that oxidant stress may open a Ca-sensitive, non-selective pore in the inner mitochondrial membrane that is blocked by cyclosporin A (Crompton, 1990 Crompton and Costi, 1990). This pore opening results in massive mitochondrial swelling, dissipation of the transmembrane proton gradient and disruption of mitochondrial energy production (Crompton et al., 1992). Since mitochondria may play a role as a slow, high-capacity cytosolic calcium buffer (Isenberg et al., 1993), disruption of mitochondrial function may also contribute to calcium overload and cell injury. 

Whilst experimentally it is relatively easy to investigate the eflFect of the exogenous application of GSH and GSSG on cardiac Na/K ATPase activity, one further approach that has been exploited in many aspects of oxidant-induced cell injury has been the depletion of cellular glutathione levels. The hypothesized importance of GSH in the cell s antioxidant armoury would be expected to be reflected in an increased susceptibility to oxidant stress-... 

Sun, F.F., Taylor, B.M. and Fleming, W.E. (1993). Formation of intracellular reactive oxygen metabolites during irreversible cell injury. FASEB J. 7, A658. 

J. L. (1985). Oxygen-mediated cell injury in the killing of cultured hepatocytes by acetaminophen. Biochem. Biophys. Res. Commun. 126, 1129-1137. 

Marubayashi, S., Dohi, K., Ochi, K. and Kawasaki, T. (1986). Role of free radicals in ischaemic rat liver cell injury prevention of damagy by a-tocopherol administration. Surgery 99, 184-199. 

Farber, J.L. (1990). The role of calcium in lethal cell injury. Chem. Res. Toxicol. 3, 503-508. 

Cantin, A.M., North, S.L., Fells, G.A., Hubbard, R.C. and Crystal, R.G. (1987). Oxidant mediated epithelial cell injury in idiopathic pulmonary fibrosis. J. Clin. Invest. 79, 1665-1675. 

Farber, J.L., Kyle, M.E. and Coleman, J.B, (1990). Biology of disease mechanisms of cell injury by activated oxygen species. Lab. Invest. 62, 670-679. 

Grosso, M.A., Brown, J.M., Viders, D.E., Mulvin, D.W., Banerjee, A., Velasco, S.E. and Repine, J.E. (1989). Xanthine oxidase-derived oxygen radicals induce pulmonary edema via direct endothelial cell injury. J. Suig. Res. 46, 355-360. 

Recknagel, R.O. and Glende, E.A. (1992). Calcium, phospholipase Az and eicosanoids in toxigenic liver cell injury. In Free Radicals and Liver (eds. G. Csomos and J. Feher) pp. 43-62. Springer-Verlag, Berlin. 

Redl, H., Gasser, H., Schlag, G. and Marzi, I. (1993). Involvement of free radicals in shock-related cell injury. In Free Radicals in Medicine (eds. K.H. Cheeseman and T.F. Slater) pp. 556-565. Churchill-Livingstone, Edinbuigji. 

Reynolds, E.S. (1967). Liver parenchymal cell injury IV Pattern of incorporation of carbon and chlorine atoms from carbon tetrachloride into chemical constituents of liver in vivo. J. Pharmacol. Exp. Therap. 155, 117-126. 

Beckman, J.S., Beckman, T.W., Chen, J., Marshall, P.A. and Freeman, B.A. (1990). Apparent hydroxyl radical formation by peroxynitrite implications for endothelial cell injury from nitric oxide and superoxide anion. Proc. Natl Acad. Sci. USA 87, 1620-1624. 

The lead-induced nephropathy observed in humans and rodents shows a comparable early pathology (Goyer 1993). However, in rodents, proximal tubular cell injury induced by lead can progress to adenocarcinomas of the kidney (see Section 2.2.3.8). The observation of lead-induced kidney tumors in rats may not be relevant to humans. Conclusive evidence for lead-induced renal cancers (or any other type of cancer) in humans is lacking, even in populations in which chronic lead nephropathy is evident. 

Fowler BA. 1989. Biological roles of high affinity metal-binding proteins in mediating cell injury. Comments Toxicol 3 27-46. 

---