The Role of Drug Metabolism in Toxicity

State-of-the-Art Metabolic Toxicity Screening and Pathway Evaluation

“…In the majority of cases, toxic chemistry is caused by the actions of these reactive metabolites rather than by the parent chemicals. 10,11 This complicates toxicity assays since they often need to incorporate representative metabolic enzymes into their protocols to produce the reactive metabolites. 4,12 …”

“…Reactive oxygen species (ROS) are byproducts of some metabolic process, and these ROS can oxidize biomolecules and trigger other toxicity pathways. 11 When metabolites damage DNA, 13,14 they are termed genotoxic . Thus, DNA damage and DNA damage products can be used as end points for genotoxicity assays.…”

“…Although metabolic enzymes have evolved to convert parent chemicals to more soluble metabolites that can be easily cleared from our bodies, in some case the metabolites that form are dangerously reactive to biomolecules in our bodies. In the majority of cases, toxic chemistry is caused by the actions of these reactive metabolites rather than by the parent chemicals. , This complicates toxicity assays since they often need to incorporate representative metabolic enzymes into their protocols to produce the reactive metabolites. , …”

Simultaneous Electrochemical Speciation of Oxidized and Reduced Glutathione. Redox Profiling of Oxidative Stress in Biological Fluids with a Modified Carbon Electrode

“…Oxidative stress has been recognized as a factor in aging and lifespan and in several diseases, including schizophrenia . Oxidative stress has been defined as a disruption in the antioxidant defense against prooxidants such as reactive oxygen species (ROS). , The antioxidant cellular defense mechanism is governed significantly in vivo by reduced glutathione (GSH), which is oxidized continuously, generating disulfide glutathione (GS-SG) . Therefore, more than 90% of glutathione species is in the GSH form in healthy cells .…”

Modern approaches to chemical toxicity screening

“…6 Parent chemicals are converted to metabolites for excretion, but metabolites can be dangerously reactive toward DNA, RNA, and proteins. Metabolic generation of reactive species is called bioactivation , and can result in genotoxic, or covalent adducts, reactive oxidation species (ROS), 5,7 , or so-called idiosyncratic drug reactions (IDR). 8 Major sources of bioactivated metabolites are cytochrome (cyt) P450 enzymes that are present in all human organs and involved in 75% of metabolic reactions of existing drugs.…”