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Biological markers (biomarkers) are used to recognize, characterize and monitor treatment-related responses following exposure to xenobiotics. Biomarkers serve three primary applications in toxicology: 1) to confirm exposure to a deleterious agent, 2) to provide a system for monitoring individual susceptibility to a toxicant, and 3) to quantitatively assess deleterious effects of a toxicant to an organism or individual. Because the liver is a general target for adverse effects of drugs and other chemicals, biomarkers of untoward hepatic response to xenobiotics are of particular interest to the pharmaceutical toxicologist. General requirements for the latter category of biomarkers are sample availability, target organ specificity, sensitivity for the toxicity of interest, accessibility, a relatively short half-life, and available detection systems. Biomarkers that can be assayed in biological fluids from both human and animal subjects are particularly desirable. Histologically, acute and subacute hepatic toxicity commonly involves necrosis, steatosis, cholestasis, vascular disorders, or multiple lesions. The purpose of this review is to summarize reported applications using clinical analytes and biochemical indicators of hepatic dysfunction with emphasis on those that show promise of supplementing or improving upon standard laboratory procedures. Liver function markers refer to peripheral indicators of hepatic synthetic and secretory activities, enterohepatic function, or perturbations of the hepatic uptake and clearance of circulating biomolecules. Liver injury biomarkers include various peripheral proteins released in response to a cellular damage or locally, proteins that are significantly altered within the liver. These include both circulating cytosolic, mitochondrial, or canalicular membrane markers, and the up-regulation or depletion of radical scavengers, modulators, and stabilizers of intracellular damage. Subsequent recovery from a toxic insult involves repair, regenerative, and proliferative responses that constitute the third class of biomarkers. Of these, protein markers found either in sera, plasma, or urine either during or just prior to the early manifestation of histological hepatic lesions are of greatest interest. Examples of a number of these markers, their documented applications in humans or animals, and potential advantages as well as limitations are presented.

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Background: Our objectives were to identify serum marker proteins in rats that might serve as sensitive indicators of hepatomegaly, hepatocellular necrosis, or hepatobiliary injury and to use them to analyze data from a collaborative proteomics project. Methods: In each of 4 studies comprising the collaborative project, rats were given 1 of 4 compounds that target the liver through different mechanisms. Sera and liver samples were collected by terminal bleeds at 1 of 3 postdose time points. Sera were depleted of major secretory proteins and then separated into protein features by 2-dimensional gel electrophoresis (2DGE). Liver specimens were also processed and subjected to 2DGE. Protein spots that significantly increased or decreased in quantity after drug treatment were recovered, digested, analyzed by mass spectroscopy, and compared with available databases for identification. Criteria for further consideration were (a) temporal expression (i.e., increase or decrease at early, fulminant, or recovery periods), (b) known biological function, (c) probable hepatic origin, and (d) any previous association with toxicity in published studies. Markers that changed significantly at the early time point were important because of their potential sensitivity for signaling minimal damage. Results: Vitamin D-binding protein, paraoxonase, cellular retinol-binding protein, malate dehydrogenase, F-protein, and purine nucleoside phosphorylase were

Adverse drug reactions (ADRs) can involve all tissues and organs, but liver injuries are considered among the most serious. A number of prospective, multicenter studies have confirmed a higher risk of ADRs in general among female subjects compared to a male cohort. Although drug-induced liver injury (DILI) is infrequently encountered, the preponderance of evidence suggests that women appear to be more susceptible than men to fulminate hepatic/acute liver failure especially in response to some anti-infective drugs and to autoimmune-like hepatitis following exposure to certain other therapeutic drugs. A number of hypotheses have been proposed to explain this sex difference in susceptibility to DILI. Collectively, these hypotheses suggest three basic sex-dependent mechanisms that include differences in various aspects of drug pharmacokinetics (PK) or pharmacodynamics following the administration of certain drugs; specific hormonal effects or interactions with immunomodulating agents or signaling molecules; and differences in the adverse response of the immune system to some drugs, reactive drug metabolites, or drug-protein adducts. At the preclinical drug safety stage, there is a need for more research on hormonal effects on drug PK and for additional research on gender differences in aberrant immune responses that may lead to idiosyncratic DILI in some female patients. Because the detection of rare but serious hepatic ADRs requires the exposure of very large patient populations, pharmacovigilance networks will continue to play a key role in the postmarketing surveillance for their detection and reporting.