Application of high-throughput Fourier-transform infrared spectroscopy in toxicology studies: contribution to a study on the development of an animal model for idiosyncratic toxicity.
An evaluation of high-throughput Fourier-transform infrared spectroscopy (FT-IR) as a technology that could support a "metabonomics" component in toxicological studies of drug candidates is presented. The hypothesis tested in this study was that FT-IR had sufficient resolving power to discriminate between urine collected from control rat populations and rats subjected to treatment with a potent inflammatory agent, bacterial lipopolysaccharide (LPS). It was also hypothesized that co-administration of LPS with ranitidine, a drug associated with reports of idiosyncratic susceptibility, would induce hepatotoxicity in rats and that this could be detected non-invasively by an FT-IR-based metabonomics approach. The co-administration of LPS with "idiosyncratic" drugs represents an attempt to develop a predictive model of idiosyncratic toxicity and FT-IR is used herein to support characterization of this model. FT-IR spectra are high dimensional and the use of genetic programming to identify spectral sub-regions that most contribute to discrimination is demonstrated. FT-IR is rapid, reagentless, highly reproducible and inexpensive. Results from this pilot study indicate it could be extended to routine applications in toxicology and to supporting characterization of a new animal model for idiosyncratic susceptibility.
Harrigan
George G
GG
HTS Metabolic Profiling, Pharmacia Corporation, Chesterfield, MO 63198, USA. george.g.harrigan@pharmacia.com
LaPlante
Roxanne H
RH
Cosma
Greg N
GN
Cockerell
Gary
G
Goodacre
Royston
R
Maddox
Jane F
JF
Luyendyk
James P
JP
Ganey
Patricia E
PE
Roth
Robert A
RA
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D016002:Discriminant Analysis; D004198:Disease Susceptibility; D006635:Histamine H2 Antagonists / Q000378:metabolism / Q000633:toxicity; D008070:Lipopolysaccharides / Q000633:toxicity; D008107:Liver Diseases / Q000652:urine; D008297:Male; D023421:Models, Animal; D010865:Pilot Projects; D011899:Ranitidine / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017550:Spectroscopy, Fourier Transform Infrared / Q000295:instrumentation / Q000379:methods* / Q000592:standards; D018675:Toxicity Tests / Q000379:methods*
D006635:Histamine H2 Antagonists; D008070:Lipopolysaccharides; D011899:Ranitidine