PerspectivesAre you interested in submitting a Perspective Article? Be sure to read The Science Advisory Board's Editorial Guides for Perspective Articles. Click here. Drug-Induced Hepatotoxicity by Ravi Shankar Nagarajan, M.V.Sc There are numerous pharmacy companies working furiously to innovate new chemical entities (NCEs) for many of the diseases and disorders known to the man. These new chemical entities fall into specific classes of drugs. There is no drug without toxic effects. And toxicity to the liver is reported to be the second most common cause of drug failure through adverse effects in clinical trials of potential drugs. There are several in silico software programs like TOPKAT, DEREK and all to detect such potential adverse effects. But all of these software concentrate mainly on the carcinogenic and mutagenic potential of the NCEs and little is known about the hepatotoxicity. In vitro hepatotoxicity assays have been developed and standardized which are able to predict the hepatotoxicity of the NCEs. Following this assessment, preclinical toxicity testing in rodents and non-rodents is done to predict the adverse hepatic effects in the clinic. In approximately 50% of NCEs evaluated, preclinical studies were ignored and compounds progressed into human clinical trials in spite of adverse hepatic effects in preclinical studies. Evaluation of the relative predictivity of the rodent versus nonrodent studies for the prediction of human hepatotoxicity suggests that nonrodent species had a concordance of 63% between laboratory results and those obtained in the clinic, while rodent studies alone were only able to predict approximately 43% of subsequent hepatotoxic events in the clinic. However, together studies conducted in both nonrodent and rodent species were able to predict approximately 71% of subsequent hepatotoxic events in man. It should be noted however, that considerable differences exist between the calculated predictivity of the preclinical studies for clinical hepatotoxicity. These differences depend upon the therapeutic class under investigation, with anticancer therapy consistently outperforming other therapy areas in this respect. Regulatory authorities throughout the world require preclinical toxicity testing in both a rodent and a nonrodent species before the potential drug is administered to humans. These studies establish the expected dose-limiting toxicity in humans and give therapeutic ratios between the toxicity seen in these species with reference to the expected therapeutic levels needed to elicit the desired pharmacological action of the drug. As such they are an essential part of the drug development process in ensuring the best method of limiting predictable toxicity in the initial clinical studies in humans. Pharmaceutical companies have various policies with respect to which second species they routinely use as the nonrodent, but the beagle dog, the marmoset, and the Cynomolgus macaque are the three most common, nonrodent species used. Various considerations are evaluated when making this decision including similarity of biochemical response to humans, similar pharmacological distribution and behavior of the target protein, similar absorption, metabolic, pharmacokinetic, and distribution profile for the chemical. The liver is centrally located between the gastrointestinal tract where absorption of ingested drugs occurs and the organs that are targets of these drugs. It is also the central site for the metabolism of nearly all xenobiotics. Most drugs are lipophilic, which enables them to be absorbed by the mucosal surfaces of the intestinal mucosa. Biochemical processes in the hepatocyte metabolize many drugs, so they are more hydrophilic, resulting in metabolites that are water-soluble and excretable in the bile or urine. 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 lead to an understanding of the underlying mechanism of toxicity or guide further study that will assist in determining 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 acute and subchronic bioassays, a range of doses is commonly used to establish a “no-observed-effect level” (NOEL), to establish maximum tolerated doses (MTD) for chronic toxicity studies, and to aid in the prediction of potential effects of long-term exposure to the test article. Toxic injury to the liver can be expressed in several parameters and is routinely measured during the course of pre-chronic toxicity studies. These studies include clinical examinations; clinical chemistry of the blood, serum, and urine; absolute and relative organ weights; necropsy observations; light microscopic examination; ultrastructural examinations using transmission and scanning electron microscopy; histochemical and immunohistochemical staining; and molecular investigations for changes in gene expression. It is very important to consider all available information when evaluating the potential for a drug or chemical to induce hepatic injury. Clinical observations, changes in clinical chemistry data and necropsy findings, in combination with the pathologist’s observations when examining the liver at the light microscopic level, may lead to a proposed pathogenesis of the mechanism of injury or provide critical information to direct further investigations. The following are the various mechanisms of hepatocellular injury and toxicity: Cytochrome P450 activation Alcohol dehydrogenase activation Inhibition of _-oxidation, respiration or both, leading to oxidative stress Membrane lipid peroxidation Protein synthesis inhibition Cytoskeletal actin filament aggregation Disruption of calcium homeostasis Activation of proapoptotic receptor enzymes Nonhepatocyte mediated injury In the liver, there are a limited number of morphologic changes that can be discerned using conventional light microscopy. These morphologic alterations are often characterized as either “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. While a few of the morphologic changes observed in the liver are unique and may be considered pathognomic for a specific mode of action, many of the changes observed by the morphologic toxicologic pathologist are relatively nonspecific and often require additional study to determine the exact nature of the observed change. There are many sophisticated tools available to aid the toxicologic pathologist in the characterization of histomorphologic changes observed in routine hematoxylin and eosin stained sections. These retrospective techniques include the use of special staining procedures, electron microscopy, molecular investigations, and more recently, the use of automated pathology systems. However despite all the new techniques available, a trained toxicologic pathologist still represents the most discerning and accurate tool available for identification and interpretation of hepatic pathology. There is a great need for experienced toxicologic pathologists to interpret and record hepatic lesions consistently, within studies and between studies. ### Ravi Shankar Nagarajan, M.V.Sc is a member of The Science Advisory Board Steering Committee. He invites you to read his other Web site contribution: Telemicroscopy over the Internet ### << Previous Next >> [ View All Perspectives ] |
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