From the Guidelines
The area around the central vein is most susceptible to acetaminophen damage due to the high concentration of cytochrome P450 enzymes, particularly CYP2E1, which metabolize acetaminophen into its toxic metabolite NAPQI. This is because the centrilobular region has the highest concentration of these enzymes, leading to increased production of NAPQI when acetaminophen is taken in excessive doses 1. The normal detoxification pathways involving glutathione become saturated, allowing more NAPQI to accumulate, and since hepatocytes in the centrilobular region produce the most NAPQI, they experience the greatest oxidative stress and damage. Additionally, these cells receive blood that has already passed through other parts of the liver lobule, meaning they have the lowest oxygen concentration (relative hypoxia) and fewer nutrients, making them less resilient to toxic injury 1. Some of the key factors that contribute to this susceptibility include:
- High concentration of cytochrome P450 enzymes, particularly CYP2E1
- Increased production of NAPQI in the centrilobular region
- Saturation of normal detoxification pathways involving glutathione
- Relative hypoxia and fewer nutrients in the centrilobular region This explains why acetaminophen overdose typically causes centrilobular necrosis as the first and most severe manifestation of liver damage, which can then spread outward if the injury continues. It is essential to note that the management of acetaminophen overdose involves the use of N-acetylcysteine (NAC) as an antidote, which has been shown to limit hepatotoxicity by serving as a sulfhydryl group donor, conjugating NAPQI into a nontoxic metabolite, and blunting the hepatocellular toxicity of NAPQI 1.
From the Research
Mechanism of Acetaminophen Damage
- The area around the central vein is most susceptible to acetaminophen damage due to the high concentration of cytochrome P450 enzymes in this region 2, 3, 4.
- These enzymes are responsible for metabolizing acetaminophen into its toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI) 2, 3, 4.
- NAPQI is normally inactivated by glutathione, but in the case of an acetaminophen overdose, the hepatic stores of glutathione become depleted, leaving NAPQI free to damage liver tissue 2, 5.
Role of Cytochrome P450 Enzymes
- Several forms of cytochrome P450 enzymes, including CYP2E1, CYP1A2, CYP2A6, CYP3A4, and CYP2D6, have been shown to catalyze the oxidation of acetaminophen to NAPQI 2, 3, 4.
- CYP2E1 is the most efficient enzyme in converting acetaminophen to NAPQI, but CYP2D6 also contributes significantly to this process, especially in individuals with high CYP2D6 activity 4.
Regional Susceptibility
- The central vein region is particularly susceptible to acetaminophen damage due to the high concentration of cytochrome P450 enzymes and the resulting high levels of NAPQI formation 2, 3, 4.
- This regional susceptibility is thought to contribute to the centrilobular necrosis characteristic of acetaminophen-induced liver injury 2, 5.