Quinone Methide Bioactivation Pathway: Contribution to Toxicity and/or Cytoprotection?

Area of Science:

• Biochemistry
• Toxicology
• Medicinal Chemistry

Background:

• Quinone methides (QMs) are reactive intermediates implicated in the biological activity of various compounds.
• Their formation can occur through oxidation, isomerization, or elimination reactions.

Purpose of the Study:

• To explore the diverse roles of quinone methides in the mechanisms of action of drugs, natural products, and endogenous compounds.
• To elucidate the connection between QM formation and both cytotoxic and cytoprotective effects.

Main Methods:

• Review of literature on quinone methide formation and its biological consequences.
• Analysis of specific examples involving drugs (nevirapine, troglitazone, phencyclidine, SERMs), endogenous compounds (estrogens), and natural products (eugenol, hydroxychavicol, quercetin).

Main Results:

• Quinone methide formation is linked to idiosyncratic hepatotoxicity (nevirapine, troglitazone) and psychological side effects (phencyclidine).
• Metabolism of SERMs and estrogens to quinone methides may contribute to carcinogenesis or chemoprevention.
• Natural product QMs can cause toxicity (eugenol, hydroxychavicol) or require risk-benefit assessment (quercetin).

Conclusions:

• Quinone methides are crucial mediators of both adverse and beneficial effects of xenobiotics and endogenous molecules.
• Understanding QM formation is essential for evaluating drug safety, natural product efficacy, and cancer risk.