Cytotoxic Mechanisms of ADRs

Most drugs undergo metabolism into inactive metabolites in the liver and/or other tissues. Other drugs are pro-drugs, they 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. For example, therapeutic doses of acetaminophen (APAP) are metabolized by conjugation into APAP-glucuronide and APAP-sulfate; these compounds are nontoxic and are readily excreted.

A small percentage of APAP undergoes oxidation by CYP450 isoenzyme 2E1 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 dosages glutathione stores are depleted. As NAPQI accumulates, it attacks cellular and mitochondrial proteins in the liver.6 This, in a dose-dependent manner may lead to hepatic fibrosis or necrosis.

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 Moderate doses of a toxic drug or metabolite activate mechanisms that result in programmed cell death (apoptosis) and tissue fibrosis. High doses of a toxic drug or metabolite activate mechanisms that lead to uncontrolled cell death and tissue necrosis.