ABSTRACT
The Liver Toxicity Biomarker Study is a systems toxicology approach to discover biomarkers that are indicative of a drug's potential to cause human idiosyncratic drug-induced liver injury. In phase I, the molecular effects in rat liver and blood plasma induced by tolcapone (a "toxic" drug) were compared with the molecular effects in the same tissues by dosing with entacapone (a "clean" drug, similar to tolcapone in chemical structure and primary pharmacological mechanism). Two durations of drug exposure, 3 and 28 days, were employed. Comprehensive molecular analysis of rat liver and plasma samples yielded marker analytes for various drug-vehicle or drug-drug comparisons. An important finding was that the marker analytes associated with tolcapone only partially overlapped with marker analytes associated with entacapone, despite the fact that both drugs have similar chemical structures and the same primary pharmacological mechanism of action. This result indicates that the molecular analyses employed in the study are detecting substantial "off-target" markers for the two drugs. An additional interesting finding was the modest overlap of the marker data sets for 3-day exposure and 28-day exposure, indicating that the molecular changes in liver and plasma caused by short- and long-term drug treatments do not share common characteristics.
Subject(s)
Benzophenones/toxicity , Catechols/toxicity , Chemical and Drug Induced Liver Injury/metabolism , Nitriles/toxicity , Nitrophenols/toxicity , Animals , Biomarkers/analysis , Blood Proteins/analysis , Chemical and Drug Induced Liver Injury/blood , Female , Gene Expression Profiling , Liver/chemistry , Liver/metabolism , Male , Metabolome/drug effects , Metabolomics , Proteome/analysis , Proteome/drug effects , Proteomics , Rats , Research Design , Tolcapone , Toxicity Tests, Acute/methods , Toxicity Tests, Chronic/methodsABSTRACT
Drug-induced liver injury (DILI) is the primary adverse event that results in withdrawal of drugs from the market and a frequent reason for the failure of drug candidates in development. The Liver Toxicity Biomarker Study (LTBS) is an innovative approach to investigate DILI because it compares molecular events produced in vivo by compound pairs that (a) are similar in structure and mechanism of action, (b) are associated with few or no signs of liver toxicity in preclinical studies, and (c) show marked differences in hepatotoxic potential. The LTBS is a collaborative preclinical research effort in molecular systems toxicology between the National Center for Toxicological Research and BG Medicine, Inc., and is supported by seven pharmaceutical companies and three technology providers. In phase I of the LTBS, entacapone and tolcapone were studied in rats to provide results and information that will form the foundation for the design and implementation of phase II. Molecular analysis of the rat liver and plasma samples combined with statistical analyses of the resulting datasets yielded marker analytes, illustrating the value of the broad-spectrum, molecular systems analysis approach to studying pharmacological or toxicological effects.
Subject(s)
Antiparkinson Agents/toxicity , Benzophenones/toxicity , Biomarkers/metabolism , Catechols/toxicity , Chemical and Drug Induced Liver Injury/metabolism , Liver/metabolism , Nitriles/toxicity , Nitrophenols/toxicity , Animals , Antiparkinson Agents/pharmacokinetics , Chemical and Drug Induced Liver Injury/etiology , Dose-Response Relationship, Drug , Female , Gene Expression/drug effects , Liver/drug effects , Male , Metabolomics , Oligonucleotide Array Sequence Analysis , Proteomics , Rats , Rats, Sprague-Dawley , TolcaponeABSTRACT
The advent of the "-omics revolution" has forced us to reevaluate our ability to acquire, measure, and handle large data sets. Omic platforms such as expression arrays and mass spectrometry, with their exquisite selectivity, sensitivity, and specificity, are unrivaled technologies for detection, quantitation, and identification of DNA, messenger RNA, proteins, and metabolites derived from complex body tissue and fluids. More recently, attempts have been made to capture the utility of these platform technologies and combine them under the umbrella of systems biology, also referred to as pathway, network, or integrative biology. Applied systems biology is the integrated analysis of genetic, genomic, protein, metabolite, cellular, and pathway events that are in flux and interdependent. It necessitates the use of a variety of analytic platforms as well as biostatistics, bioinformatics, data integration, computational biology, modeling, and knowledge assembly protocols. Such sophisticated analyses may provide new insight into the understanding of disease processes and mechanisms of action of pharmaceutical agents. Ultimately, this requires a perspective on how complex systems behave and are modulated. In this regard, systems biology, more appropriately considered as a process containing a series of modules, aims to provide tools and capabilities to carry out such tasks. We describe the essentials required to carry out systems biology experiments, the method in which integrated data in the form of a systems biology correlation network affords new insight into understanding disease, and the vista of developing more efficient biomarkers and therapeutic agents.
