Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

Table 1 Mechanisms that favor high sensitivity of fatty liver to drug toxicity and necrotic cell death

Initial change	Intermediate effects	Consequences
Increased bioactivation (microsomal CYP 450s)	Higher amount of toxic metabolites	Consumption of antioxidants
	Increased release of ROS	Lipid peroxidation
Mitochondrial dysfunction	Decreased energy production (ATP) and cytochrome c content	Over-expression of uncoupling protein 2
		Increased Ca2+ efflux
	Increased release of ROS and NO derivatives	Protein oxidation and nitration
	Pores opening and increased membrane permeability	Expression of FAS ligands
		Calpain activation and protein cleavage
Impaired intracellular signaling and trafficking	Alterations of nuclear receptors and sensors	Defective transcription of repair mechanisms
	Increased DNA fragmentation rate
Activation of non-parenchymal cells (Kupffer cells) and enzymes	Increased release of transforming growth factor-β1, p53, TNF-α	Inflammation and pro-oxidant attack
	Increased NADPH oxidase activity

ROS: Reactive oxygen species; TNF: Tumor necrosis factor.