Analysis of Mitochondrial Function in Cell Membranes as Indicator of Tissue Vulnerability to Drugs in Humans

Abstract

Drug side effects are one of the main reasons for treatment withdrawal during clinical trials. Reactive oxygen species formation is involved in many of the drug side effects, mainly by interacting with the components of the cellular respiration. Thus, the early detection of these effects in the drug discovery process is a key aspect for the optimization of pharmacological research. To this end, the superoxide formation of a series of drugs and compounds with antidepressant, antipsychotic, anticholinergic, narcotic, and analgesic properties was evaluated in isolated bovine heart membranes and on cell membrane microarrays from a collection of human tissues, together with specific inhibitors of the mitochondrial electron transport chain. Fluphenazine and PB28 promoted similar effects to those of rotenone, but with lower potency, indicating a direct action on mitochondrial complex I. Moreover, nefazodone, a drug withdrawn from the market due to its mitochondrial hepatotoxic effects, evoked the highest superoxide formation in human liver cell membranes, suggesting the potential of this technology to anticipate adverse effects in preclinical phases.

Mitochondrial Metabolism in Major Depressive Disorder: From Early Diagnosis to Emerging Treatment Options

“…In terms of molecular mechanisms, it has been demonstrated that chronic inflammation induces the release of proinflammatory cytokines, such as TNF-α and interleukins, which can trigger the production of ROS in cells [ 115 ]. These ROS can have detrimental effects on mitochondrial function by damaging critical components of the mitochondrial machinery, such as electron transport chain proteins, thereby compromising the energy efficiency of mitochondria [ 122 ]. Anti-inflammatory agents, such as COX inhibitors, may counteract these effects by reducing ROS production and preserving the functional integrity of mitochondria, which potentially could mitigate the progression of mitochondrial dysfunction associated with chronic inflammation [ 121 ].…”