Structure-Activity Relationship of Hepatotoxicity

Drug induced liver injury is a major cause for withdrawing a drug from development or more dramatically from the market. In a recent article, Dr. Dennis J. Pelletier et Al. performed a SAR study of hepatotoxicity. They used the data from literature and built a structure searchable database. The resulting database was analyzed to identify the chemical structures associated with liver toxicity. Data from over 1266 compounds were collected and a SAR of 38 chemical structures was developed. An interesting chemical structure highlighted as a potential liver toxin is the thiophene ring. Metabolic activation of thiophene leads to a reactive intermediate that can undergo Michael type addition with cellular nucleophiles. See figure below.

 

Interestingly, hepatotoxicity is often due to an activation of the drug resulting from Phase I metabolization. Moreover, this kind of reactive metabolite is present at low levels in the blood stream which makes them difficult to be detected.
Biomimetic technology can allow for the production of such metabolites for biological and toxicology studies which could reduce the drug development attrition due to liver toxicity.
Dennis J. Pelletier et Al.; Chem. Res. Toxicol., 2010, 23, 1215-1222