Comparative Hepatic Toxicity: Prechronic/Chronic Liver Toxicity in Rodents

Abstract

The morphologic assessment of the gross and microscopic appearance of the liver can provide a broad base of knowledge concerning the potential toxicity of a drug or chemical. This information may either lead to an understanding of the underlying mechanism of toxicity or guide further study to discern the mode of action of the hepatotoxicity. In standard regulatory bioassays, toxicity studies are conducted during phase 1 and phase 2 of the development process to define the acute, subchronic and chronic toxicity of the test compound. In the liver, there are a limited number of morphologic changes that can be identified using conventional light microscopy. These morphologic alterations are often characterized as "adaptive," consisting of an exaggerated normal physiologic response; "pharmacologic," consisting of an expected alteration in response to the desired action of the test article; or "adverse," consisting of morphologic alterations that are generally undesired, progressive and deleterious to the normal function of the cell(s) involved. Morphologic evidence of adverse effects may involve hepatocytes, the biliary system, hepatic vasculature, Kupffer cells, or stellate cells (Ito cells). In drug discovery and development programs, it is necessary to utilize a multidisciplinary approach, using different endpoints, to investigate the same or similar biological responses in the liver. This results in large amounts of data that must be organized in a retrievable fashion. In order for such a multidisciplinary approach to succeed, each discipline must organize and generate their data in a manner that is easily used by others in the process. The toxicologic pathologist must develop and use standardized nomenclature and diagnostic criteria when examining the liver so that data from various investigators can be compared in a useful manner.

Hepatoprotective activity of exogenous RNA

“…These results demonstrate the decrease of lesions in the liver parenchyma and inflammatory infiltration of liver by neutrophils under Nuclex administration and correlate well with data concerning anti-inflammatory effect of yeast RNA investigated on local inflammation model [21]. Moreover, the decreased levels of TBA-reactive substances do not contradict membrane-stabilizing properties of oli-goribonucleotides as had been described on in vitro model systems [22]. In contrast to this, in the in vivo model system, which was used in our experiment, not just the hepatocytes take part in hepatotoxic processes in the role of the primary effector cells, but various populations of non-parenchymal cells are also involved [22,23].…”

Microengineered cell and tissue systems for drug screening and toxicology applications: Evolution ofin-vitroliver technologies

“…Among all organs, the liver plays the most central role in human-drug interactions and is also the most common target for drug-induced toxicity 5,13 . Liver toxicity results in costly, late stage drug failures as 25–40% of drugs are found to cause hepatic injuries by phase III clinical studies 5,14 .…”

Characterizing the Network of Drugs and Their Affected Metabolic Subpathways

“…Interestingly, both drug therapeutic and side effects had an impact on the liver. The critical synthetic, metabolic, and detoxifying function of the liver may partly explain its therapeutic importance and arguably its vulnerability to be injured by drugs [76]. In summary, therapeutic subpathways and non-therapeutic subpathways had significant tissue specific differences including the ratio of TEGs and HKGs in drug-affected genes, the TH coefficient and affected tissues.…”