| Comparison of metabolite profiles generated in Aroclor-induced rat liver and human liver subcellular fractions: considerations for in vitro genotoxicity hazard assessment. | |
| | |
MedLine Citation:
|
PMID: 18626997 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Because it is well known that metabolites of chemicals and drugs are frequently the ultimate species responsible for genotoxicity and carcinogenicity, in vitro testing to identify the human genotoxicity hazard potential of new chemicals and drugs routinely utilizes liver S-9 fraction from rats treated with Aroclor 1254 as a system that can generate metabolites. However, it is frequently questioned as to whether such an in vitro metabolite generation system is the most relevant for human risk, or whether the assay would be better served by using a human-derived in vitro system. To address this, 16 common drugs have been examined for profiles of metabolites in Aroclor-induced rat liver S-9 and pooled human liver S-9. Metabolite profiles were compared using high pressure liquid chromatography coupled with ion trap mass spectrometry, in line with ultraviolet or radiometric detection to help make semiquantitative comparisons. Results showed that, with few exceptions, metabolites generated in the human system were also generated in the rat system. Also, in several cases the rat system generated considerably more metabolites, suggesting that there is a potential that positive genotoxicity findings could be caused by metabolites that have no relevance to humans. These findings suggest that when conducting in vitro genotoxicity testing using the Aroclor-induced rat liver S-9 system, knowledge of the metabolite profile in the system is important, and a comparison to the profile generated in human liver S-9 could be of value when interpreting the genotoxicity results. |
| | |
Authors:
|
R Scott Obach; Krista L Dobo |
Related Documents
:
|
6517697 - Inhalation pharmacokinetics based on gas uptake studies. vi. comparative evaluation of ... 9463527 - The disposition of allyl isothiocyanate in the rat and mouse. 16956957 - Pharmacokinetics of berberine and its main metabolites in conventional and pseudo germ-... 6104307 - H-pro-[3h]leu-gly-nh2: metabolism in human and rat plasma investigated by high-pressure... 10788557 - Ethane sulfonate metabolite of alachlor: assessment of oncogenic potential based on met... 17220517 - Numerical modeling of odorant uptake in the rat nasal cavity. |
Publication Detail:
|
Type: Comparative Study; Journal Article |
Journal Detail:
|
Title: Environmental and molecular mutagenesis Volume: 49 ISSN: 1098-2280 ISO Abbreviation: Environ. Mol. Mutagen. Publication Date: 2008 Oct |
Date Detail:
|
Created Date: 2008-10-13 Completed Date: 2008-10-28 Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 8800109 Medline TA: Environ Mol Mutagen Country: United States |
Other Details:
|
Languages: eng Pagination: 631-41 Citation Subset: IM |
Copyright Information:
|
Copyright 2008 Wiley-Liss, Inc. |
Affiliation:
|
Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer, Inc., Groton, Connecticut 06340, USA. r.scott.obach@pfizer.com |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Aroclors / pharmacokinetics, toxicity* Biotransformation Cytochrome P-450 Enzyme System / metabolism Humans Liver / drug effects*, enzymology, ultrastructure Mutagenicity Tests Mutagens / toxicity* Rats Subcellular Fractions / drug effects* |
| Chemical | |
Reg. No./Substance:
|
0/Aroclors; 0/Mutagens; 9035-51-2/Cytochrome P-450 Enzyme System |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Development of an in vivo gene mutation assay using the endogenous Pig-A gene: II. Selection of Pig-...
Next Document: Faulty spindle checkpoint and cohesion protein activities predispose oocytes to premature chromosome...