title: Inverse gene expression patterns for macrophage activating hepatotoxicants and peroxisome proliferators in rat liver.
abstract: Macrophage activation contributes to adverse effects produced by a number of hepatotoxic compounds. Transcriptional profiles elicited by two macrophage activators, LPS and zymosan A, were compared to those produced by 100 paradigm compounds (mostly hepatotoxicants) using cDNA microarrays. Several hepatotoxicants previously reported to activate liver macrophages produced transcriptional responses similar to LPS and zymosan, and these were used to construct a gene signature profile for macrophage activators in the liver. Measurement of cytokine mRNAs in the same liver samples by RT-PCR independently confirmed that these compounds are associated with macrophage activation. In addition to expected effects on acute phase proteins and metabolic pathways that are regulated by LPS and inflammation, a strong induction was observed for many endoplasmic reticulum-associated stress/chaperone proteins. Additionally, many genes in our macrophage activator signature profile were well-characterized PPARalpha-induced genes which were repressed by macrophage activators. A shared gene signature profile for peroxisome proliferators was determined using a training set of clofibrate, WY 14643, diethylhexylphthalate, diisononylphthalate, perfluorodecanoic acid, perfluoroheptanoic acid, and perfluorooctanoic acid. The signature profile included macrophage activator-induced genes that were repressed by peroxisome proliferators. NSAIDs comprised an interesting pharmacological class in that some compounds, notably diflunisal, co-clustered with peroxisome proliferators whereas several others co-clustered with macrophage activators, possibly due to endotoxin exposure secondary to their adverse effects on the gastrointestinal system. While much of these data confirmed findings from the literature, the transcriptional patterns detected using this toxicogenomics approach showed relationships between genes and biological pathways requiring complex analysis to be discerned.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, LLC, Raritan, NJ, USA. mmcmilli@prdus.jnj.com
authors.forename: Michael
authors.initials: M
authors.lastname: McMillian
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Nie
authors.forename: J Brandon
authors.initials: JB
authors.lastname: Parker
authors.forename: Angelique
authors.initials: A
authors.lastname: Leone
authors.forename: Michael
authors.initials: M
authors.lastname: Kemmerer
authors.forename: Stewart
authors.initials: S
authors.lastname: Bryant
authors.forename: Judy
authors.initials: J
authors.lastname: Herlich
authors.forename: Lynn
authors.initials: L
authors.lastname: Yieh
authors.forename: Anton
authors.initials: A
authors.lastname: Bittner
authors.forename: Xuejun
authors.initials: X
authors.lastname: Liu
authors.forename: Jackson
authors.initials: J
authors.lastname: Wan
authors.forename: Mark D
authors.initials: MD
authors.lastname: Johnson
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D020025:Peroxisome Proliferators; D012333:RNA, Messenger