Xenobiotics hepatic bioactivation

Hepatic bioactivation of xenobiotics decreases Kver microsafiial proteins and reduces liver weight... 

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... 

For studies involving metabohsm-mediated effects of xenobiotics, cells that are known to contain the requisite mixed-function oxygenases should be selected. As an alternative, an S9 hepatic microsomal fraction (see Supplementary procedure bioactivation) can be included in the test medium (Borenfreund Puerner, 1987). Serum concentrations should be kept as low as tolerated (or eliminated as in a defined medium) to prevent binding of the test agent to serum components. 

This is often due to metabolites of a xenobiotic formed by bioactivation or biotransformation in the liver and not the parent compounds, and reactive metabolites are more likely to cause damage at the sites of phase I bioactivation reactions. Many different mechanisms cause hepatotoxicity and affect different cellular locations (Figures 3.3 and 3.4). Liver injury can be broadly classified as those injuries that are predictable and show a dose- and time-dependent pattern (type 1 lesions or intrinsic toxicity) and that occur in animals and are predictive of hepatic effects in man. Type... 

Although hepatic metabolism continues to be the most important route of metabolism tor xenobiotics, the ability of the liver and intestine to metabolize substances to either pharmacologically inactive or bioactive metabolites before reaching systemic blood levels is called prehepatic or presystemic first pass metabolism, which results in the low systemic availability tor susceptible drugs. Sulfation and glucuronidation are major pathways of presystemic intestinal first-pass metabolism in humans tor acetaminophen, phenylephrine, terbutaline, albuterol, tenoterol, and isoproterenol. 

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