Xenobiotics induced liver injury

Xenobiotic-induced liver injury has become the most frequent cause of acute liver failure in humans in the USA and around the world, exceeding all other causes combined (Watkins and Seef, 2006). Owing to its detoxification mechanisms, the liver protects the individual against xenobiotic-induced injury. Certainly, the liver toxicity caused by chemical warfare agents is a potential area of concern. 

Cytotoxicity. The liver is the primary target organ for a variety of drugs and chemicals (Hasemen et ah, 1984 Farland et ah, 1985). The prevalence of drug-and chemical-induced liver injury is of concern because some xenobiotics can produce liver damage at dose levels that are magnitudes below that which causes cell death (Plaa, 1976). Environmental and commercial chemicals can increase this effect by as much as 100-fold (Plaa and Hewitt, 1982 Plaa, 1976). Studies of early cell injury caused by exposure to a toxicant can be undertaken easily in monolayer cultures of hepatocytes, whereas early cell injury is very difficult to assess in vivo. 

Kidneys have relatively low xenobiotic-metabolizing enzyme activities, and chemically induced nephrotoxicity has been assumed to be produced by toxic intermediates generated in the liver and transported to the kidney. If a single hepatic metabolite of chloroform produced both kidney and liver injury, species, strain, and sex differences in susceptibility to chloroform nephro- and hepatotoxicity should be similar. However, species, strain and sex differences in susceptibility to chloroform nephrotoxicity are not consistent with those of chloroform hepatotoxicity. In addition, several modulators of tissue xenobiotic-metabolizing activities alter... 

FIGURE 37.1. Multiple metabolic pathways involved in the mediation of hepatic injury for any compound. The liver is central to xenobiotic (and some endogenous compounds) metabolism which produces water-soluble products amenable to urinary or biliary excretion. Some compounds undergo metabolic activation to produce free radicals, electrophiles, or other toxic products that may induce hepatic injury. 

Sturgill, M.G., Lambert, G.H. (1997). Xenobiotic-induced hepatotoxicity mechanisms of liver injury and methods of monitoring hepatic fimction. Clin. Chem. 43 1512-26. 

Sturgill, M. G., and G. H. Lambert. 1997. Xenobiotic-induced hepatotoxicity Mechanisms of liver injury and methods of monitoring hepatic function. Clinical Chemistry 43 1512-1526. 

The endoplasmic reticulum (ER) contributes to a variety of functions, including protein synthesis and detoxification of xenobiot-ics, and disturbance of these functions can be linked to cell injury (53). Prolonged exposure to ethanol induces proliferation of the ER of in the liver and enhanced activity of cytochrome P450 enzymes, which in turn can result in production of hepatotoxic or carcinogenic metabolites (54). 

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