Editorial pubs.acs.org/crt
Introduction: Mass Spectrometry and Emerging Technologies for Biomarker Discovery in the Assessment of Human Health and Disease his issue of Chemical Research in Toxicology, “Mass Spectrometry and Emerging Technologies for Biomarker Discovery in the Assessment of Human Health and Disease,” is dedicated to mass spectrometry and emerging technologies to understand the health risk of exposures to chemicals and to detect disease or predisposition to disease, and to evaluate the safety of new drug candidates. Historically, chemicals under investigation were given to rodents or nonhuman primates at substantially high doses, and overt toxicities were measured to extrapolate acceptable margins of exposures of toxic or carcinogenic chemicals to humans. The technological advancements in mass spectrometry combined with new in vitro, in vivo, and in silico models have enabled the researchers in the chemical toxicology field and pharmaceutical industry to increase their confidence in the safety of new drug molecules, by developing increasingly sensitive methods to detect biomarkers of xenobiotic exposure and disease, with earlier onset markers of toxicity. In this special issue, excellent contributions from nine eminent researchers in the field provide reviews on emerging technologies and their application to biomarker discovery in chemical exposures, human health, and disease, as well as safety assessment of drugs and drug candidates. Mass spectrometry has played a key role in the characterization of biotransformation pathways of chemicals to reactive metabolites that form covalent adducts to proteins, which can provoke allergenicity and other toxicities.1,2 Some xenobiotics induce oxidative stress leading to oxidative damage to DNA, and the reactive intermediates of certain xenobiotics may form covalent DNA adducts, possibly leading to mutations and the development of cancer.3,4 Advances have also been made in cell and animal-based models to elucidate the mechanisms of action of drugs. Mass spectrometry has played a key role in identifying and quantifying biomarkers in these studies. With highly sensitive triple quadrupole, ion trap and high-resolution accurate mass spectrometer instrumentation, it is now possible to screen for thousands of environmental and endogenous chemicals, oxidative stress biomarkers, and to employ metabolomic approaches to study drug metabolism, cell homeostasis, pathology, and disease status.5,6 With the enormous amount of data generated from metabolomics studies, computational approaches are required to assist in the assembly and harmonization of analytical data to reliably identify compounds and for interpreting metabolic pathways in disease states.6 The extraordinary sensitivity of accelerator mass spectrometry (AMS), an instrument historically used for radiocarbon dating, has been employed in a number of human studies to assess metabolism and biodisposition of toxicants at minute levels.4 These studies have bridged the gap in extrapolation of biomarkers and toxicities formed at high dose studies in animal models to relevant human exposures.
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© 2016 American Chemical Society
AMS has also played an important role for clinical applications and the safety of drugs. One of the major challenges in the pharmaceutical industry is the safety assessment of candidate drugs prior to first time in human studies to minimize the risk for adverse drug reactions. Traditionally, the assessment has been done via in vitro models and preclinical toxicology studies. Various efforts have been attempted to improve the human relevance of these approaches and to increase the confidence in predicting safety of drug candidates. One of the technological advances is the development of 3D cell cultures to overcome the limitations of the 2D models in drug metabolism and toxicology testing.7 A complementary approach to cell based models is application of high content screening where multiple refined readouts at the molecular and cellular levels are combined to predict organ toxicities, an important tool in the field of predictive toxicology.8 In addition to the advances in the utilization of in vitro models in safety testing of drug candidates, the application of chimeric mice in drug metabolism and disposition predictions in humans is a key approach to overcome the complexities arising from species differences in drug metabolism.9 All together, this special issue provides the chemical toxicology community a timely update on the technological advances to tackle the various challenges in studying the risk of chemical exposure to xenobiotics including drug molecules and relevance to human health and disease.
Emre M. Isin*,† Robert J. Turesky*,‡
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† Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal SE-431 83, Sweden ‡ Masonic Cancer Center and Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, United States
AUTHOR INFORMATION
Corresponding Authors
*(E.I.) UCB BioPharma Sprl Chemin du Foriest, B-1420 Braine-l’Alleud, Belgium. Phone: +32 2 3861814. E-mail: Emre.
[email protected]. *(R.T.) 2231 6th Street SE, CCRB, University of Minnesota, Minneapolis, MN 55455, USA. Phone: 612-626-0141. E-mail:
[email protected]. Special Issue: Mass Spectrometry and Emerging Technologies for Biomarker Discovery in the Assessment of Human Health and Disease Published: December 19, 2016 1901
DOI: 10.1021/acs.chemrestox.6b00429 Chem. Res. Toxicol. 2016, 29, 1901−1902
Chemical Research in Toxicology
Editorial
ORCID
Robert J. Turesky: 0000-0001-7355-9903 Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
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REFERENCES
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DOI: 10.1021/acs.chemrestox.6b00429 Chem. Res. Toxicol. 2016, 29, 1901−1902
