12.3 Proteomics in drug toxicity and safety assessment

Proteomics revolutionizes drug safety assessment by identifying protein changes, uncovering toxicity mechanisms, and discovering safety biomarkers. This powerful approach enables early detection of adverse effects, personalized medicine applications, and comprehensive analysis of cellular responses to drugs.

Case studies showcase proteomics' ability to elucidate toxicity pathways for common drugs like acetaminophen and doxorubicin. By providing mechanistic insights and identifying novel biomarkers, proteomics enhances our understanding of drug-induced cellular changes and improves toxicity prediction.

Proteomics in Drug Toxicity and Safety Assessment

Application of proteomics in drug safety

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• Identification of protein changes in response to drug exposure reveals altered protein expression levels, post-translational modifications (phosphorylation, glycosylation), and protein-protein interactions (complexes, signaling pathways)
• Elucidation of toxicity mechanisms uncovers cellular pathways affected by drugs (apoptosis, oxidative stress) and molecular targets of drug action (enzymes, receptors)
• Safety biomarker discovery pinpoints proteins indicative of organ-specific toxicity (liver enzymes, kidney proteins) and early markers of adverse drug reactions (inflammation, cellular stress)
• Dose-response relationships analyze protein changes at different drug concentrations and determine threshold levels for toxic effects

Proteomic biomarkers for toxicity prediction

• Early detection of toxicity identifies protein changes before clinical symptoms appear and allows intervention before irreversible damage occurs
• Organ-specific toxicity markers include liver (alanine aminotransferase, aspartate aminotransferase), kidney (kidney injury molecule-1, neutrophil gelatinase-associated lipocalin), and heart (troponin, B-type natriuretic peptide)
• Monitoring treatment efficacy and safety tracks biomarker levels during drug administration and adjusts dosage based on proteomic profiles
• Personalized medicine applications identify patient-specific susceptibility to drug toxicity and tailor treatment plans based on individual proteomic profiles (genetic variants, metabolic differences)

Advantages and Case Studies

Advantages of proteomics vs traditional toxicology

• Comprehensive analysis of cellular responses examines multiple proteins and pathways simultaneously and provides unbiased approach to toxicity assessment
• Increased sensitivity and specificity detects subtle protein changes and differentiates between adaptive and adverse responses
• Time and cost efficiency utilizes high-throughput screening capabilities and reduces animal testing requirements
• Integration of multiple data types combines proteomic data with genomics and metabolomics for systems biology approach to toxicity assessment
• Mechanistic insights identify novel toxicity pathways and enhance understanding of drug-induced cellular perturbations (oxidative stress, mitochondrial dysfunction)

Case studies of proteomics in toxicity identification

• Acetaminophen-induced liver toxicity identified mitochondrial protein alterations and discovered early biomarkers for liver damage (glutathione depletion, protein adducts)
• Doxorubicin-induced cardiotoxicity profiled heart tissue proteome and elucidated oxidative stress and energy metabolism disruption (ATP synthase, electron transport chain proteins)
• Cisplatin-induced nephrotoxicity identified renal tubular injury markers and characterized protein oxidation and cellular stress responses (heat shock proteins, antioxidant enzymes)
• Idiosyncratic drug-induced liver injury analyzed patient samples and discovered personalized biomarkers for susceptibility (HLA proteins, drug-metabolizing enzymes)