MetaPath: an electronic knowledge base for collating, exchanging and analyzing case studies of xenobiotic metabolism.

The MetaPath knowledge base was developed for the purpose of archiving, sharing and analyzing experimental data on metabolism, metabolic pathways and crucial supporting metadata. The MetaPath system grew out of the need to compile and organize the results of metabolism studies into a systematic database to facilitate data comparisons and evaluations. Specialized MetaPath data evaluation tools facilitate the review of pesticide metabolism data submitted for regulatory risk assessments as well as exchange of results of complex analyses used in regulation and research. Customized screen editors called Composers were developed to automate data entry into MetaPath while also streamlining the production of agency specific study summaries such as the Data Evaluation Records (DER) used by the US EPA Office of Pesticide Programs. Efforts are underway through an Organization for Economic Co-operation and Development (OECD) work group to extend the use of DER Composers as harmonized templates for rat metabolism, livestock residue, plant residue and environmental degradation studies.

Investigating the relationship between in vitro-in vivo genotoxicity: derivation of mechanistic QSAR models for in vivo liver genotoxicity and in vivo bone marrow micronucleus formation which encompass metabolism.

Strategic testing as part of an integrated testing strategy (ITS) to maximize information and avoid the use of animals where possible is fast becoming the norm with the advent of new legislation such as REACH. Genotoxicity is an area where regulatory testing is clearly defined as part of ITS schemes. Under REACH, the specific information requirements depend on the tonnage manufactured or imported. Two types of test systems exist to meet these information requirements, in vivo genotoxicity assays, which take into account the whole animal, and in vitro assays, which are conducted outside the living mammalian organism using microbial or mammalian cells under appropriate culturing conditions. Clearly, with these different broad experimental categories, results for a given chemical can often differ, which presents challenges in the interpretation as well as in attempting to model the results in silico. This study attempted to compare the differences between in vitro and in vivo genotoxicity results, to rationalize these differences with plausible hypothesis in concert with available data. Two proof of concept (Q)SAR models were developed, one for in vivo genotoxicity effects in liver and a second for in vivo micronucleus formation in bone marrow. These "mechanistic models" will be of practical value in testing strategies, and both have been implemented into the TIMES software platform ( http://oasis-lmc.org ) to help predict the genotoxicity outcome of new untested chemicals.

Quantitative structure-activity relationship modeling of dermatomyositis activity of drug chemicals.

Dermatomyositis (DM) is an idiopathic inflammatory disorder consisting of skin and skeletal muscle involvement. Some drugs induce DM or dermatomyositis-like syndrome (DM-LS), the others provoke polymoysitis (PM) or cause elevation of serum levels of muscle enzymes (SE) or give muscle damage (M). The unexpected adverse reactions to drugs causing myositis are not a solved contemporary problem. The aim of this study was to determine the structural requirements of eliciting drug-induced DM as compared with drug induced PM. The Common Reactivity Pattern (COREPA) approach was used to describe the structural requirements for eliciting side effects of 20 drugs, such as DM and combined activities as DM+DM-LS and PM+M+SE. The specific atoms (atomic groups) defined to have characteristic ranges for their electronic properties (atomic charges) were found to be indicative for the possible active centers responsible for eliciting the adverse effects. Reduced sulphur in the charge range of -0.07 < Qs < -0.450 a.u. and a nitrogen atom (in a cyclical fragment or anticyclical in a sp3-hybridization) in a charge range of -0.390 < QN < -0.140 a.u. were found as active centers for DM and DM+DM-LS side effects. In other group of drugs, the oxygen atoms of carbonyl and hydroxyl groups in the charge range of -0.350 < Qo < -0.320 a.u. were found to induce PM+M+SE side effects. It was found that DM requires moderate electrophilicity as compared with other chemical in the training set, whereas DM+DM-LS effect needs higher electrophilicity in the range of -0.220 < ELUMO < 0.250 eV for lowest unoccupied molecular orbital ELUMO. Similarly, PM+M+SE effect required higher electrophilicity, however, defined differently--in terms of lower values of nucleophilicity parameter EHOMO, i.e., highest occupied molecular orbital.