Specific Hepatic Toxins

Acetaminophen

Acetaminophen is a popular over-the-counter pain reliever that also has anti-inflammatory and antipyretic properties. It is usually a safe drug unless taken in large quantity or when used by individuals whose alcohol drinking behavior is excessive. The mechanism of acetaminophen toxicity is an excellent example of liver pathology. Figure 7.5 shows the metabolism of acetaminophen. It is important to note that several metabolic fates are possible for acetaminophen but over 90% of the drug is excreted as conjugates with glucuronic acid or sulfate. In normal use, less than 5% of acetaminophen will be converted to a reactive electrophilic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). That portion which is converted to NAPQI will be inactivated readily by reduced glutathione under normal conditions. However, when NAPQI accumulates, it is toxic and binds to nucleophilic macromolecules in the hepatocyte causing cell necrosis. If high amounts of acetaminophen are ingested, then the glutathione detoxification mechanism is overwhelmed. NAPQI achieves high concentrations.

The role of alcohol in the whole process is interesting. Alcohol induces the P450 oxidase system enzymes. Therefore, a relatively larger quantity of the acetaminophen will take the metabolic pathway to NAPQI. Alcoholics have suffered acetaminophen overdose on as little as 4 acetaminophen tablets per day.

Acetaminophen

Acetaminophen

Mixed-function oxidases I O

Glucuronide

NHCOCH3

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