NCTR Quarter Page

Research Highlights, Activities, and Publications

Jan 2017-Mar 2017

Book Edited by Recognized Experts from NCTR — Dr. Cheng Wang and Dr. William Slikker, Jr.

Neural Cell Biology reviews and　discusses approaches that can be used as effective tools to dissect mechanisms underlying pharmacological and toxicological phenomena associated with the exposure to drugs or environmental toxicants during development. The book intends to elaborate functional outcomes of component-to-component relationships using rodent and nonhuman primate in vitro and in vivo models that allow for the directional and quantitative description of the complete organism in response to environmental perturbations. In addition, attention has also been directed to some of the more recent methodologies, including genomics, proteomics and metabolomics, applied in the evolutionary neurobiological field. Preview Neural Cell Biology.

Epigenetic Mechanisms in Pathogenesis of Acute Kidney Injury (AKI)

Scientists from NCTR and Texas A&M University have identified an epigenetic mechanism in the pathogenesis of AKI that involves miR-1247 and SOX-9. In kidneys from a mouse alcoholic-liver fibrosis-associated AKI model, miR-1247 is over-expressed and targets Sox9 mRNA resulting in the down-regulation of SOX-9 protein, a key regulator of regeneration. This compromises cellular repair processes and contributes to the severity of AKI. This study suggests that miR-1247 may have value as a predictive and/or prognostic indicator of AKI severity; and may be a potential target for clinical intervention and management of AKI. A manuscript describing this study is available online at Toxicology.

For more information, please contact Igor Pogribny, Ph.D., Division of Biochemical Toxicology.

Effects of Small-Molecule Kinase Inhibitors on Isolated Rat Liver Mitochondria

Scientists from FDA's National Center for Toxicological Research and Center for Drug Evaluation and Research used isolated rat liver mitochondria to test 31 FDA-approved small-molecule kinase inhibitors (KIs) for mitochondrial toxicity in vitro and showed that only three (all of which are hepatotoxic in humans) caused mitochondrial toxicity at concentrations equivalent to the therapeutic maximal blood concentrations (Cmax). At this concentration, mitochondrial toxicity showed a 100% positive predictive value (PPV) and a negative predictive value (NPV) of 32%. Conversely, at 100-fold Cmax, mitochondrial toxicity had a PPV of 72% and a NPV of 33%. Although in vitro mitochondrial toxicity assessments have been proposed as a useful tool to predict the hepatotoxicity of chemicals, these findings suggest that its predictive power for KI-induced hepatotoxicity in humans is limited to positive predictions at Cmax concentrations. A manuscript reporting the results of this study is available online at Archives of Toxicology.

For more information, please contact Qiang Shi Ph.D., Innovative Safety and Technologies Branch/Division of Systems Biology or William Mattes Ph.D., DABT, Director, Division of Systems Biology.

FDA Liver Toxicity Working Group Workshop

NCTR hosted the FDA Liver Toxicity Working Group Workshop on January 9, 2017, at Jefferson Laboratories campus in Arkansas with additional online conferencing. The workshop provided a forum for toxicologists, clinicians, and regulators from government, academia, and industry to present and discuss current research from clinical, mechanistic, and in silico studies of drug-induced liver injury. The workshop concluded with a panel discussion that addressed the improvement of predictive models and the potential incorporation into regulatory and clinical practice.

For more information, please contact Weida Tong Ph.D., Director, Division of Bioinformatics and Biostatistics.

New Technologies to Supplement Animal Studies in Evaluating Drugs for Liver Toxicity Risk

Scientists from NCTR, Merck, and LifeNet Health published a review article in Institute for Laboratory Animal Research Journal on several new technological developments that might be used to identify drugs with human drug-induced liver injury (DILI) potential. One of the most critical safety issues confronted in drug development is the risk of causing DILI; particularly when traditional animal studies have sometimes failed to identify drugs that caused liver injury in humans. The authors review the history of this issue and discuss new technologies, such as:

human cell culture-based systems (e.g., human induced pluripotent stem cell-derived hepatocytes, 3D liver-tissue models, and microfluidic culture systems)
new animal models (e.g., humanized liver mouse models)
new translational biomarkers
computational/predictive models

While these emerging technologies are still in development, many seem to have promise in screening drugs for potential human DILI risk.

For more information, please contact William Mattes Ph.D., Director, Division of Systems Biology.

Effects of β-lactam Antibiotics on Resistance Development and Penicillin-Binding Proteins in Clostridium perfringens

NCTR scientists demonstrated that C. perfringens — a pathogenic bacterium — rapidly developed resistance to three different classes of β-lactams (penicillin G, cephalothin, and ceftriaxone) and all three antibiotics induced mutation in the penicillin-binding protein (PBP) genes. The largest PBP appeared to be the primary target of β-lactams. These results were consistent with the observed variation in the PBP amino acid sequences found in field isolates of β-lactam-resistant C.perfringens. A decrease in the affinity of PBPs for β-lactams is considered a potential mechanism of bacterial resistance to β-lactams. The results of this study are available online at Anaerobe.

For more information, please contact Fatemeh Rafii, Ph.D., Division of Microbiology.