Mechanisms of Pathogenesis in Drug Hepatotoxicity Putting the Stress on Mitochondria

Thresholds for the precipitation of idiosyncratic drug-induced liver injury (DILI) in susceptible patients. The molecular mechanisms that contribute to idiosyncratic DILI can be considered in terms of oxidative injury to mitochondria. A. Hypothetical relationship between cumulative mitochondrial injury and manifestation of liver injury. The dotted line (threshold) represents the “no-apparent-effect level.” (See text for details.) B. Sources and consequences of oxidative/nitrative stress in hepatic mitochondria. Upon deficiencies in components of the electron transport chain (ETC), or by experimentally decreasing the expression of superoxide dismutase-2 (SOD2), the steady-state levels of superoxide anion radical will rise, leading to inactivation of sensitive proteins, such as aconitase or other iron-sulfur cluster-containing proteins (ETC subunits). Alternatively, increased levels of nitric oxide (NO) will readily produce peroxynitrite (ONOO⁻), which can compromise sensitive proteins including aconitase, complex I, SOD2, and cytochrome c; ONOO⁻ can also produce ultra-reactive hydroxyl radicals. Certain drugs associated with DILI can enhance mitochondrial stress through a number of modes, including an increase in cytosolic (free) Ca²⁺ levels, which among other actions can activate mitochondrial nitric oxide synthase (NOS). Oxidative/nitrative stress in mitochondria can damage mitochondrial DNA, initiating a catastrophic cycle of dysfunction as abnormal expression of ETC subunits results in further oxidative damage. (MOMP, mitochondrial outer membrane permeabilization; OM, outer membrane; IM, inner membrane.) C. Hypothetical scheme depicting the differential exposure-toxic response relationship against the threshold for inducing overt liver injury. The concept implies that, in normal individuals, drug-mediated injury to mitochondria is mild and does not reach the threshold for liver injury (lower curve; see text for details). In contrast, genetic and environmental factors may impair mitochondrial function, so that the drug-related cumulative mitochondrial injury is more severe, crossing the threshold to overt hepatocellular injury, and DILI may ensue (upper curve). The dotted lines represent possible resolution of the injury after discontinuation of drug exposure.