Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

Abstract

Mitochondria are critical cellular organelles for energy generation and are now also recognized as playing important roles in cellular signaling. Their central role in energy metabolism, as well as their high abundance in hepatocytes, make them important targets for drug-induced hepatotoxicity. This review summarizes the current mechanistic understanding of the role of mitochondria in drug-induced hepatotoxicity caused by acetaminophen, diclofenac, anti-tuberculosis drugs such as rifampin and isoniazid, anti-epileptic drugs such as valproic acid and constituents of herbal supplements such as pyrrolizidine alkaloids. The utilization of circulating mitochondrial-specific biomarkers in understanding mechanisms of toxicity in humans will also be examined. In summary, it is well-established that mitochondria are central to acetaminophen-induced cell death. However, the most promising areas for clinically useful therapeutic interventions after acetaminophen toxicity may involve the promotion of adaptive responses and repair processes including mitophagy and mitochondrial biogenesis, In contrast, the limited understanding of the role of mitochondria in various aspects of hepatotoxicity by most other drugs and herbs requires more detailed mechanistic investigations in both animals and humans. Development of clinically relevant animal models and more translational studies using mechanistic biomarkers are critical for progress in this area.

Diclofenac impairs autophagic flux via oxidative stress and lysosomal dysfunction: Implications for hepatotoxicity

“…Other serious adverse effects include kidney and liver toxicity. Diclofenac is the NSAID most frequently reported to induce side effects predominantly related to hepatocellular and cholestatic types of liver injury, which leads to liver failure [ 31 , 32 ]. Diclofenac-induced hepatotoxicity in humans is idiosyncratic.…”

“…The influences of diclofenac and its metabolites on mitochondrial function are well characterized. Diclofenac induces hepatic mitochondrial dysfunction through several mechanisms: the uncoupling of oxidative phosphorylation and increases in cytosolic calcium and ROS facilitate mitochondrial permeability transition pore opening and the collapse of mitochondrial transmembrane potential followed by ATP depletion [ 32 ]. However, signal amplification is required for diclofenac-induced mitochondrial dysfunction to lead to hepatotoxicity.…”

Role of Natural Phenolics in Hepatoprotection: A Mechanistic Review and Analysis of Regulatory Network of Associated Genes

“…Several mechanisms are involved in the initiation of liver cell damage and aggravate ongoing injury processes (Guan et al, 2014; Ju and Tacke, 2016). Dysfunction of these vital cell organelles results in the impairment of dynamic equilibrium in homeostatic condition, thus resulting in intracellular oxidative stress with excessive formation of reactive oxygen species (Cannistrà et al, 2016; Ramachandran et al, 2018). Major causes of the hepatotoxic reactions by drugs are elevated ROS generation, oxidative stress and suppressed immune responses.…”

A prospective study on associations between superoxide dismutase gene polymorphisms and antituberculosis drug‐induced liver injury in a Chinese Han population

“…SOD is an enzyme mainly responsible for scavenging reactive oxygen species (ROS), such as superoxide radical (O 2 •− ), and preventing many types of cellular damage . Therefore, SOD provides antioxidant defence against oxidative stress.…”