Transcriptional profiling of reactive metabolites for elucidating toxicological mechanisms: a case study of quinoneimine-forming agents

Abstract

Toxicogenomics can be broadly defined as the study of how the genetic material responds to toxicant exposure. This sub-discipline of toxicology utilizes numerous genomic technologies to relate adverse toxicologic effects with their associated changes in gene expression. The scope of this review will focus on microarray technology and its use in identifying key biomarkers at both the single gene and pathway levels to elucidate toxicologic mechanisms in the liver. Microarrays have been used to study global transcriptomic changes associated with toxicants for years; however, limited emphasis has been placed on what role their reactive metabolites play in this process. Reactive metabolites, which can be generated by normal oxidative metabolism, have the potential to react with endogenous biomolecules, alter their function, and elicit a toxicogenomic response. Quinoneimines are an example of such a species, eliciting toxicity through the generation of oxidative and electrophilic stress. Five compounds with differing toxicity profiles are evaluated herein that are capable of forming quinoneimine intermediates by cytochrome P450 enzymes. They include acetaminophen (APAP), amodiaquine, atorvastatin, carvedilol, and diclofenac. Perspectives on the consistency between the hepatic gene expression profiles of these quinoneimine-forming agents as well as the untapped value of structure-based transcriptome profiling are discussed in this review.

• Acetaminophen
• amodiaquine
• atorvastatin
• carvedilol
• diclofenac
• gene expression
• microarray
• reactive metabolites
• toxicogenomics

Acknowledgements

This review is dedicated to Sid Nelson, a brilliant scientist and dedicated teacher who was always eager to move in the direction that his students and scientific discoveries led him.

Declaration of interest

The author reports no declaration of interest.