A toxicologist's guide to biomarkers of hepatic response

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.