Liver xenobiotic bioactivation

Researchers focused on the metabolically competent human hepatoma cell line HepG2 as a model of human liver. HepG2 cells are a well-known hepatoma cell line that retains many of the morphological characteristics of liver parenchymal cells. This model is often used as a useful tool for HRA/ERA-oriented chemical risk assessment due to the expression of antioxidant and xenobiotic metabolizing enzymes (in particular phase I and phase II enzymes responsible for the bioactivation/detoxification of various xenobiotics) that can be induced or inhibited by dietary and non-dietary agents [28-30]. 

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... 

It should also be noted that although metabolism usually decreases the toxicity as well as activity of most drugs and xenobiotic agents, this is not always the case, for certain chemicals, a process called bioactivation can occur in which one or more of the metabolites are more active or more toxic than the parent compound. Acetaminophen, one of the most commonly taken drugs on the market, has a metabolite that can be extremely toxic to liver tissues at high concentrations. The levels of this metabolite are normally too low to cause problems, but if a person takes a high dose of acetaminophen, such as ingesting several types of cold or flu medicines that each contain their own dose of acetaminophen, then it can cause severe health complications. 

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. 

All of the following statements r atding liver bioactivation of xenobiotics to a more toxic fbtm are true exc f ... 

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

Mechanisms of liver injury have been divided into two categories intrinsic and idiosyncratic. Intrinsic injury may lead to steatosis, necrosis, cholestasis, or a mixed form of damage, often with minimal inflammation (Sturgill and Lambert, 1997). Intrinsic liver injury is a predictable, reproducible, dose-dependent reaction to a toxicant (Dahm and Jones, 1996 Sturgill and Lambert, 1997 Zimmerman, 1999 Pineiro-Carrero and Pineiro, 2004). A threshold dose exists for xenobiotics causing intrinsic liver injury. There is commonly a predictable latent period between the time of exposure and clinical evidence of liver injury. This type of liver injury accounts for the vast majority of toxic liver injury and is often caused by reactive products of xenobiotic metabolism, most commonly electrophiles and free radicals. A few drugs cause intrinsic liver injury without bioactivation. An abbreviated summary of mechanisms of intrinsic liver injury is illustrated in Figure 42.1. 

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