AASLD-FDA-NIH-PhRMA Hepatotoxicity Steering Group Meeting, 2006 Presentations: Liver tissue repair, survival factors, and adaptation to injury
Harihara M. Mehendale
Department of Toxicology, College of Pharmacy,
University of Louisiana at Monroe
Liver tissue repair, survival factors, and adaptation to injury [PDF]
Liver injury initiated by either the parent drug or its reactive metabolite(s), is known to progress in disease or other physiological states. While we know a great deal about how injury is initiated by drugs, a solid understanding of how injury may progress or regress is lacking. Recent studies reveal that many events driven by liver biology determine the latter. Progression can result due to destructive actions of hydrolytic enzymes, “death proteins” leaking out of necrosed cells on the neighboring partly affected or unaffected cells, thereby setting off a self-perpetuating expansion of injury. Once necrosis is initiated by mechanism-based events, this process occurs even in the absence of the necrogenic drug. Calpain and c-phospholiase A2 (cPLA2) are good examples of such hydrolytic ‘death proteins’. Compensatory mechanisms such as cell division and over-expression of survival factors by the newly dividing cells, can prevent this onslaught by the death proteins and expansion of injury. Failed or delayed cell division, as in the case of high doses, or in disease, leads to expansion of injury. Autoprotection and heteroprotection models indicate that stimulation of cell division and tissue repair are critical in overcoming life-threatening liver injury suggesting that adaptive mechanisms can be activated in the liver by priming. Diabetes is known to sensitize liver to hepatotoxicity. Diabetic rats (type I & type II) are highly sensitive to hepatotoxicity due to impaired compensatory cell division in the diabetic state. However, even in the diabetic state, animal experiments show that it is possible to stimulate efficient cell division by priming and protect the diabetic animals from life-threatening liver toxicity, by overcoming the acute liver failure (ARF)-bound injury. In stark contrast to the diabetic rats, diabetic mice (type 1 & type II) are resilient to drug-induced hepatotoxicity. Unfortunately, this model has not been investigated enough to find what we can learn from the mouse about survival strategies. Although much remains to be learned about the murine strategy for survival, what we know drug toxicity models is that mice are able to compensate rapidly by early and robust stimulation of cell division. Moreover, subchronic priming exposure to chloroform for 30 days protects mice from a subsequent dose of chloroform that normally causes ARF and death, due to prompt stimulation of cell division as an adaptive mechanism. What we learn from these experimental models provides us clues that may be exploited to modify our approaches in dealing with drug-associated liver toxicities.
Dr. Mehendale received his M.S. and Ph.D. degrees from the Toxicology Program at North Carolina State University. He received his postdoctoral training at the University of Kentucky and at the National Institute of Environmental Health Sciences (NIEHS), before joining NIEHS as a Staff Fellow. In 1975, he joined the University of Mississippi Medical Center as Assistant Professor, rose through the academic ranks to full Professor in 1980. He joined the University of Louisiana at Monroe (ULM) in 1992. His research interests span across pulmonary, hepatic, renal and general toxicology of medicinal, industrial and environmental chemicals. His current area of research emphasis involves understanding the role of tissue repair in the ultimate outcome of tissue injury, the mechanisms in control of cell division and tissue repair as well as the molecular events keying these mechanisms. Current research is focused on the impact of age, diabetes, and diet restriction on toxic effects, mechanisms of progression and regression of injuries, and potential adverse health effects of exposure to combinations of chemicals. He has authored over 275 original research and review articles, as well as book chapters. Dr. Mehendale has received several Honors and Awards for his research and scholarly contributions. In 1988, he received the "Burroughs Wellcome Scholar in Toxicology" award given by the Society of Toxicology, U.S.A. In 1993, he received the Zeneca International Travel Award. In 1995, he was named outstanding researcher at ULM and received the "Researcher of the Year" Award. In 1996, the American Association for the Advancement of Science (AAAS) elected him "Science Fellow". In 1999, he received the Best Paper Award for best paper published in Toxicology and Applied Pharmacology. In 2001, received the Society of Toxicology’s Education Award for his eminent contributions to education in toxicology.