Document Detail


Hepatotoxicity: A scheme for generating chemical categories for read-across, structural alerts and insights into mechanism(s) of action.
MedLine Citation:
PMID:  23875763     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
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.
Authors:
M Hewitt; S J Enoch; J C Madden; K R Przybylak; M T D Cronin
Related Documents :
21075043 - Redox platforms in cancer drug discovery and development.
23108693 - Preparation and characterization of poly(ε-caprolactone) nanospheres containing the lo...
15878153 - The origins and spread of antimalarial drug resistance: lessons for policy makers.
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Critical reviews in toxicology     Volume:  43     ISSN:  1547-6898     ISO Abbreviation:  Crit. Rev. Toxicol.     Publication Date:  2013 Aug 
Date Detail:
Created Date:  2013-07-23     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8914275     Medline TA:  Crit Rev Toxicol     Country:  England    
Other Details:
Languages:  eng     Pagination:  537-58     Citation Subset:  IM    
Affiliation:
School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University , Liverpool, England , UK.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  A cross sectional survey of attitudes, awareness and uptake of the parental pertussis booster vaccin...
Next Document:  Sesquiterpene lactones: Adverse health effects and toxicity mechanisms.