Structural alerts for hepatotoxicity

COMP 188

William J. Egan, Modeling Methods, Modeling Methods, Vertex Pharmaceuticals, 130 Waverly Street, Cambridge, MA 02139
One review calculated that approx. 26% of drug withdrawls in the period 1960-1999 were initiated due to hepatotoxicity. We have created a structural database of hepatotoxic drugs and chemicals containing over 230 molecules, including 54 drugs which were withdrawn or whose use was abandoned due to hepatotoxicity. Besides name and structure, the database contains information on marketing status, type of injury, mechanism of injury, metabolism, and pertinent references. Analysis of the structural features, clinical and biochemical literature, and routes of metabolism shows that there are a number of structural features that are definitely or possibly associated with hepatotoxicity in humans. The presentation will summarize the database, review some of the identified structural features, and discuss the challenges involved in extracting useful alerts and rules applicable to the complex processes of liver toxicity.