tailieunhanh - Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2

Part 2 book “Mitochondrial dysfunction caused by drugs and environmental toxicants” has contents: Acylcarnitines as translational biomarkers of mitochondrial dysfunction, imaging of mitochondrial toxicity in the kidney, imaging mitochondrial membrane potential and inner membrane permeability, and other contents. | 373 23 Biomarkers of Mitochondrial Injury After Acetaminophen Overdose: Glutamate Dehydrogenase and Beyond Benjamin L. Woolbright and Hartmut Jaeschke Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA CHAPTER MENU  ­Introduction,  373  ­Acetaminophen Overdose as a Model for Biomarker Discovery,  373  ­Acetaminophen Overdose: Mechanisms of Toxicity in Mice and Man,  374  ­Biomarkers of Mitochondrial Injury,  375  ­Conclusions,  379 References, 379  ­Introduction In the drug discovery process, drug‐induced liver injury is one of the most common reasons for failure in preclini­ cal development and in clinical trials. In addition, idio­ syncratic hepatotoxicity leads to black box warnings or even withdrawal of approved drugs from the market. Whereas currently used biomarkers for liver injury (ala­ nine (ALT) and aspartate aminotransferases (AST)) and dysfunction (bilirubin) are sufficiently sensitive to detect dose‐dependent hepatotoxins, there are no biomarkers available that could alert to a potential idiosyncratic tox­ icity. Clinically, acetaminophen (APAP) overdose remains the most common source of both drug‐induced liver injury and acute liver failure (ALF) (Lee, 2013). Patients that develop ALF have a very poor outcome, with mortal­ ity up to 50% (Lee, 2013). Early identification of which patients will proceed to ALF is critical, as these patients can be treated more aggressively or listed for transplanta­ tion earlier. As such, biomarkers of patient outcome are of considerable clinical value for determining early during the patient’s hospitalization which patients will proceed to ALF and will die or need a liver transplant and which patients will recover spontaneously. The best biomarkers are those that are also informative of the mechanisms at play in the pathophysiology or ­valuable clinically due to prognostic capacity. Biomarkers present in the serum or urine of .