PRINCIPLES OF TOXICOLOGY - Biology East Borneo

REFERENCES AND SUGGESTED READING 127assays that are rapid and inexpensive. In fact, the concentrations of each of these proteins are typicallymeasured as an enzyme activity rate, rather than a true concentration per se.Aminotransferase activities [alanine aminotransferase (ALT) and aspartate aminotransferase(AST)], alkaline phosphatase activity, and gamma glutamyltransferase transpeptidase (GGTP) areincluded in nearly all standard clinical test suites to assess potential hepatotoxicity. The value ofperforming a battery of these tests is that each test responds slightly differently in the various formsof liver injury, and evaluating the pattern of responses can offer insight into the type of injury that hasoccurred. For example, severe hepatic injury from acetaminophen can result in dramatic increases inserum ALT and ALT activities (up to 500 times normal values), but only modest increases in alkalinephosphatase activity. Pronounced increases in alkaline phosphatase is characteristic of cholestaticinjury, where increases in ALT and AST may be limited or nonexistent. In alcoholic liver disease, ASTactivity is usually greater than ALT activity, but for most other forms of hepatocellular injury ALTactivities are higher. Serum GGTP is an extremely sensitive indicator of hepatobiliary effects, and maybe elevated simply by drinking alcoholic beverages. It is not a particularly specific indicator (it isincreased by both hepatocellular and cholestatic injury) and is best utilized in combination with othertests. Serum levels of enzymes such as lactate dehydrogenase have been used to evaluate liver toxicity,but this enzyme has such low specificity for the liver that interpretation of these results is impossiblewithout other confirming tests. Other enzymes such as sorbitol dehydrogenase (SDH) and ornithinecarbamoyltransferase (OCT) are quite specific to the liver.5.4 SUMMARYBoth the anatomic location and its role as a primary site for biotransformation make the liver uniquelysusceptible to drug- and chemical-induced injury. Many chemicals encountered in the workplace andenvironment are capable of producing toxic effects in the liver:• There are many types of liver injury, including hepatocellular degeneration and death(necrosis), fatty liver, cholestasis (decreased or arrested bile flow), vascular injury, cirrhosis,and tumor development.• Hepatic injury from drugs and chemicals can arise from a variety of mechanisms. While themechanism of toxicity for some chemicals is reasonably well established, many aspects oftoxic mechanisms for most chemicals remain unclear.• Hepatotoxic chemicals can attack a variety of subcellular targets. Principal organelles andstructures affected include the plasma membrane, mitochondria, the endoplasmic reticulum,the nucleus, and lysosomes.• Liver injury can be evaluated morphologically (microscopic examination of liver tissue) orthrough blood tests. Blood tests are designed to either measure the functional capacity ofthe liver or the appearance of intracellular hepatic contents in the blood.REFERENCES AND SUGGESTED READINGCullen, J. M., and B. H. Ruebner, “A histopathologic classification of chemical-induced injury of the liver,” inHepatotoxicity, R. G. Meeks, S. D. Harrison, and R. J. Bull, eds., CRC Press, Boca Raton, FL, 1991, pp. 67–92.Delaney, K., “Hepatic principles,” in Goldfrank’s Toxicologic Emergencies, L. R. Goldfrank, N. E. Flomenbaum,N. A. Lewin, R. S. Weisman, M. A. Howland, and R. S. Hoffman, eds., Appleton & Lange, Stamford, CT, 1998,pp. 213–228.Kedderis, G. L. “Biochemical Basis of Hepatocellular Injury.” Toxicologic Pathology, 24 (1): 77–83 (1996).