The use of hepatocytes to investigate drug toxicity

Methods in Molecular Biology
M José Gómez-LechónM Teresa Donato

Abstract

The liver is very active in metabolizing foreign compounds and the major target for toxicity caused by drugs. Hepatotoxicity may be the result of the drug itself or, more frequently, a result of the bioactivation process and the production of reactive metabolites. Prioritization of compounds based on human hepatotoxicity potential is currently a key unmet need in drug discovery, as it can become a major problem for several lead compounds in later stages of the drug discovery pipeline. Therefore, evaluation of potential hepatotoxicity represents a critical step in the development of new drugs. Cultured hepatocytes are increasingly used by the pharmaceutical industry for the screening of hepatotoxic potential of new molecules. Hepatocytes in culture retain hepatic key functions and constitute a valuable tool to identify chemically induced cellular damage. Their use has notably contributed to the understanding of mechanisms responsible for hepatotoxicity (disruption of cellular energy status, alteration of Ca(2+) homeostasis, inhibition of transport systems, metabolic activation, oxidative stress, covalent binding, etc.). Assessment of current cytotoxicity and hepatic-specific biochemical effects is limited by the inability to mea...Continue Reading

Citations

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