miércoles, 23 de mayo de 2018

NCTR Publications > NCTR Research Highlights ► FDA/NCTR Research Highlights: Understanding Liver Toxicity

NCTR Publications > NCTR Research Highlights

NCTR... Improving Understanding of Liver Toxicity

Role of Cytochromes in Dronedarone-Induced Liver ToxicityDronedarone, a drug used to treat patients with cardiac arrhythmias, is associated with liver injury. Research scientists in NCTR’s Division of Biochemical Toxicology investigated the role of drug metabolism in dronedarone-induced liver toxicity. Cytochrome P450s (CYPs) are enzymes that metabolize external substances, such as medications that are ingested and internal substances, such as toxins that are formed within cells. In this NCTR study, a panel of 14 HepG2-derived human cell lines that stably express individual CYPs was used to identify the metabolic activity of each CYP toward dronedarone.  A key finding of the study was that three CYP isoforms, or protein variants — CYP3A4, 3A5, and 2D6 — were involved in the metabolism of dronedarone and that metabolism by these CYPs decreased dronedarone’s toxic effects on human cells. Thus, implying that individuals with low levels of CYP3A4, 3A5, and 2D6 enzymes may be more susceptible to dronedarone-induced liver toxicity. An article on this study was recently published in Archives of Toxicologydisclaimer icon.
For more information, please contact Lei Guo, Ph.D., Division of Biochemical Toxicology, FDA/NCTR. 

Therapeutic Bile Acids and the Risks for Liver Toxicity
Bile acids have long been used to treat many disorders, such as gallstones, cholestatic liver disease (when substances normally excreted into bile are retained), and more recently used to treat diabetes and obesity. Several bile-acid derivatives (e.g., obeticholic acid) have been recently approved or submitted to FDA for approval. However, the use of bile acids also carries risk, particularly toxicity to the liver. Scientists from FDA’s NCTR and Center for Drug Evaluation and Research and the Hannover Medical School in Germany have published a review article that presents the uses of bile acids in therapy, as well as the associated toxicity risks. The authors discuss toxicity observed in clinical trials data, and data mined from surveillance programs designed to detect toxicity of drugs on the market. The authors further discuss the variation of molecular mechanisms of action of bile acids across different species, illuminating the difficulties of predicting effects in one species from those observed in others. The article is now available online at Alimentary Pharmacology & Therapeuticsdisclaimer icon
For more information, please contact Minjun Chen, Ph.D., Division of Bioinformatics and Biostatistics, FDA/NCTR.

Monograph Published on Drug-Induced Liver Toxicity 
Drug-induced liver injury (DILI) has been one of the most vexing problems in toxicology for the pharmaceutical industry and their regulators for many decades. Many drugs fail in development due to DILI, and others are taken off the market after regulatory approval when DILI appears. When a drug fails, people who would not experience toxicity are denied its potential therapeutic benefits. Monographs such as this work edited by DILI experts Minjun Chen, Ph.D. from NCTR and Yvonne Will, Ph.D. from Pfizer are paramount in moving the field forward by summarizing the most current, relevant science. The book is not only a comprehensive review, but encompasses DILI over a drug’s life cycle — from drug discovery to clinical trials to post-market and clinical settings. The methodologies to test DILI risk are systematically discussed, including those in cells, animals, emerging genetic methods, and human clinical trials. The book, titled Drug-Induced Liver Toxicitydisclaimer icon was published by Humana Press, a part of Springer Nature in hard copies and online. 
For more information, please contact Minjun Chen, Ph.D., Division of Bioinformatics and Biostatistics, FDA/NCTR.
Early and Sensitive Biomarkers of Liver Toxicity Discovered
NCTR scientists used a well-known chemical toxic to the liver – thioacetamide (TAA) –  which could be a liver carcinogen in humans, to discover microRNA biomarkers of liver toxicity. After administering the chemical to rats, scientists used next-generation sequencing to discover early and sensitive microRNA biomarkers for liver injury and tumor progression. These biomarkers could improve cancer diagnosis, prognosis, and management. A paper summarizing the findings of this study can be found in Scientific Reportsdisclaimer icon  and research on this topic continues in 2018.
For more information, please contact Weida Tong, Ph.D., Director, Division of Bioinformatics and Biostatistics, FDA/NCTR.

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