Age-Related Changes in the Hepatic Pharmacology and Toxicology of Paracetamol

Figure 4

The effect of age on the hepatotoxic pathway for paracetamol-induced liver injury. At therapeutic doses, paracetamol metabolised primarily in the livervia the Phase II metabolism (conjugation). A small amount of drug undergoes Phase I CYP450- (CYP-)mediated N-hydroxylation to form N-acetyl-p-amino-benzoquinone immine (NAPQI), a toxic metabolite which is conjugated with hepatic glutathione (GSH) and is neutralised. The major metabolites are excreted via the urine or bile by Phase III transporters. Saturation of conjugation pathways results in increased use of the CYP450 pathway, increased NAPQI formation, and increased depletion of hepatic glutathione. NAPQI can cause injury through direct cell stress, direct mitochondrial inhibition, or through immune reactions. Initial injury leads to mitochondrial dysfunction leading to either apoptosis of damaged cells, or necrosis with recovery, chronic liver injury or actual liver failure, and death as potential outcomes. Additionally, necrosis can stimulate the inflammatory response leading to cytokine release and further potentiation of the immune reaction. Ageing can act at multiple parts of the pathway to either increase (↑) or decrease (↓) susceptibility to hepatotoxicity. It must be noted, however, that this is likely to vary between individuals. The effect of ageing on Phase III transporters is somewhat unknown (?) in humans. Picture adapted from Russmann et.al., 2009 [141].