Hepatotoxicity

The blood draining the stomach and small intestine is delivered directly to the liver via the hepatic portal vein, thus exposing the liver to relatively large concentrations of ingested drugs or toxicants (e.g., Fig. 7.1). Hepatic exposure to agents that undergo bioactivation to toxic species can be significant.

Hepatic necrosis can be classified by the zone of the liver tissue affected. Xenobiotics, such as acetaminophen or chloroform, that undergo bioactivation to toxic intermediates cause necrosis of the cells surrounding the central veins (centrilobular) because the components of the cytochrome P450 system are found in those cells in abundance. At higher doses or in the presence of agents that increase the synthesis of cytochrome P450 (inducers), the area of necrosis may incorporate the midzonal area (midway between the portal triad and central vein). Cells around the portal triad are exposed to the highest concentrations; necrosis occurs with direct-acting agents. A single large dose of a hepato-toxin may cause liver necrosis yet resolve with little or no tissue scarring. Continued exposure to the toxic agent, however, can result in hepatic cirrhosis and permanent scarring.

Allergic reactions to drugs produce foci of necrosis that are scattered throughout the liver. Other agents cause severe (chlorpromazine) or mild (estrogens) cholestatic liver damage, including cholestasis and inflammation of the portal triad and hepatocellular necrosis.

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