Hepatotoxicity: A scheme for generating chemical categories for read-across, structural alerts and insights into mechanism(s) of action

Abstract

The ability of a compound to cause adverse effects to the liver is one of the most common reasons for drug development failures and the withdrawal of drugs from the market. Such adverse effects can vary tremendously in severity, leading to an array of possible drug-induced liver injuries (DILIs). As a result, it is not surprising that drug development has evolved into a complex and multifaceted process including methods aiming to identify potential liver toxicities. Unfortunately, hepatotoxicity remains one of the most complex and poorly understood areas of human toxicity; thus it is a significant challenge to identify potential hepatotoxins. The performance of existing methods to identify hepatotoxicity requires improvement. The current study details a scheme for generating chemical categories and the development of structural alerts able to identify potential hepatotoxins. The study utilized a diverse 951-compound dataset and used structural similarity methods to produce a number of structurally restricted categories. From these categories, 16 structural alerts associated with observed human hepatotoxicity were developed. Furthermore, the mechanism(s) by which these compounds cause hepatotoxicity were investigated and a mechanistic rationale was proposed, where possible, to yield mechanistically supported structural alerts. Alerts of this nature have the potential to be used in the screening of compounds to highlight potential hepatotoxicity, whilst the chemical categories themselves are important in applying read-across approaches. The scheme presented in this study also has the potential to act as a knowledge generator serving as an excellent starting platform from which to conduct additional toxicological studies.

Ado-Trastuzumab Emtansine Targets Hepatocytes Via Human Epidermal Growth Factor Receptor 2 to Induce Hepatotoxicity

“…Hepatotoxicity is widely regarded as the leading cause of failure of drug development programs and a serious safety concern in clinical studies and postmarketing surveillance (36,37). In the analysis of drugs withdrawn for toxicity reasons in the period between 1992 and 2002, hepatotoxicity was identified in 27% of cases (36).…”

“…The samples were blocked with 10% goat serum (Jackson ImmunoResearch) in TBS at 37 C for 30 minutes and then incubated with the purified human IgG (Life Technologies), trastuzumab, or T-DM1 antibodies (each at 50 mg/mL) at 37 C for 1 hour. After washing with TBS containing 1% goat serum three times (10 minutes for each wash), the samples were incubated with Alexa Fluor 488-conjugated anti-human secondary antibody (1:100 dilution, Life Technologies) diluted in TBS at 37 C for 30 minutes. The samples were washed with TBS containing 1% goat serum at room temperature three times and then mounted on glass slides as described above.…”

Development of an in Silico Profiler for Mitochondrial Toxicity

“…When utilised together, multiple structural alerts pertaining to the same MIE form the basis of an in silico profiler. [13][14][15][16] The information within an in silico profiler can, in turn, be used to develop chemical categories centred on a common MIE (note that multiple MIEs can be initiated by a single chemical). This allows for read-across and data gap filling to be applied.…”

“…[10][11][16][17][18] A number of in silico profilers have been developed for a variety of organ-level toxicities, such as skin sensitisation, respiratory sensitisation, genotoxicityand hepatotoxicity. [13][14][15][19][20][21] However, very few profilers have dealt with toxicity induced by mitochondrial dysfunction. 1,22,23 This is, in part, due to the number of mechanisms by which a chemical could induce mitochondrial dysfunction 24 .…”

Toxicidad hepática causada por medicamentos: revisión estucturada

“…Aunque unos 1100 fármacos, excluidas sustancias de abuso y productos naturales, se han asociado con hepatotoxicidad (19); la identificación de este evento adverso es un proceso complejo. Por esto, se requiere de una minuciosa indagación, orientada a identificar cualquier sustancia y a descartar otras causas de hepatopatía (3,8,34).…”