Which metabolic pathway becomes saturated during acetaminophen overdose leading to hepatotoxicity?

During an acetaminophen overdose, the Phase I cytochrome P450 metabolic pathway becomes saturated. Under normal circumstances, acetaminophen is primarily metabolized through conjugation pathways (such as Phase II glucuronidation and sulfation), which are generally safe, producing non-toxic metabolites. However, in an overdose scenario, the capacity of these pathways is overwhelmed.

As a result, more of the drug is directed towards the cytochrome P450 system, particularly the isoform CYP2E1, which produces a reactive metabolite known as N-acetyl-p-benzoquinone imine (NAPQI). This metabolite is highly toxic and can lead to hepatotoxicity, causing liver damage due to its ability to interact with cellular components, ultimately resulting in cell death.

Understanding this saturation of the cytochrome P450 pathway is crucial because it highlights the risk factors associated with acetaminophen use and the importance of early intervention, such as administering N-acetylcysteine, which can help replenish glutathione and neutralize the toxic NAPQI.