Quinones represent a class of toxicological intermediates, which can create a variety of hazardous effects in vivo including, acute cytotoxicity, immunotoxicity, and
carcinogenesis. In contrast,
quinones can induce cytoprotection through the induction of detoxification
enzymes, anti-inflammatory activities, and modification of redox status. The mechanisms by which
quinones cause these effects can be quite complex. The various biological targets of
quinones depend on their rate and site of formation and their reactivity.
Quinones are formed through a variety of mechanisms from simple oxidation of
catechols/
hydroquinones catalyzed by a variety of oxidative
enzymes and
metal ions to more complex mechanisms involving initial P450-catalyzed hydroxylation reactions followed by two-electron oxidation.
Quinones are Michael acceptors, and modification of cellular processes could occur through alkylation of crucial cellular
proteins and/or
DNA. Alternatively,
quinones are highly redox active molecules which can redox cycle with their semiquinone radical
anions leading to the formation of
reactive oxygen species (ROS) including
superoxide,
hydrogen peroxide, and ultimately the
hydroxyl radical. Production of ROS can alter redox balance within cells through the formation of oxidized cellular macromolecules including
lipids,
proteins, and
DNA. This perspective explores the varied biological targets of
quinones including GSH,
NADPH,
protein sulfhydryls [
heat shock proteins, P450s,
cyclooxygenase-2 (COX-2),
glutathione S-transferase (GST),
NAD(P)H:
quinone oxidoreductase 1, (NQO1),
kelch-like ECH-associated protein 1 (Keap1), IκB
kinase (IKK), and arylhydrocarbon receptor (AhR)], and
DNA. The evidence strongly suggests that the numerous mechanisms of
quinone modulations (i.e., alkylation versus oxidative stress) can be correlated with the known pathology/cytoprotection of the parent compound(s) that is best described by an inverse U-shaped dose-response curve.