Comparison of metabolite profiles generated in Aroclor-induced rat liver and human liver subcellular fractions: considerations for in vitro genotoxicity hazard assessment.
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.
Obach
R Scott
RS
Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer, Inc., Groton, Connecticut 06340, USA. r.scott.obach@pfizer.com
Dobo
Krista L
KL
D000818:Animals; D001140:Aroclors / Q000493:pharmacokinetics / Q000633:toxicity*; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D013347:Subcellular Fractions / Q000187:drug effects*
D001140:Aroclors; D009153:Mutagens; D003577:Cytochrome P-450 Enzyme System