Cytotoxic Mechanisms of ADRs

Most drugs undergo metabolism into inactive metabolites in the liver and/or other tissues. Other drugs are prodrugs, tthat must be metabolized into active metabolites to produce an effect; subsequently, these may undergo further metabolism into inactive metabolites. In some cases however, the metabolites are unstable or reactive. Moderate doses of a toxic drug or metabolite activate mechanisms that may result in programmed cell death (apoptosis) and tissue fibrosis. High doses of a toxic drug or metabolite may activate mechanisms that lead to uncontrolled cell death and tissue necrosis.

For example, therapeutic (APAP) doses are metabolized by conjugation into APAP-glucuronide and APAP-sulfate; these compounds are nontoxic and readily excreted.

A small percentage of APAP undergoes oxidation by cytochrome P450 isoenzyme CYP2E1 into N-acetyl-p-benzoquinoneimine (NAPQI), a highly reactive metabolite. This toxic metabolite must undergo conjugation by glutathione. The APAP-glutathione conjugate is nontoxic and is readily cleared from the body. However, with supratherapeutic dosing glutathione stores are depleted. As NAPQI accumulates, it attacks cellular and mitochondrial proteins in the liver causing hepatic fibrosis or necrosis⁶

The main mechanisms responsible for fibrosis or necrosis include an oxidative pathway, which leads to the formation of reactive oxygen species (ROS), and a reductive pathway, which leads to the formation of reactive nitrogen intermediates (RNI).⁶