Characterization of CYP4A induction in rat liver by inflammatory stimuli: dependence on sex, strain, and inflammation-evoked hypophagia.
Acute treatment of rats with bacterial endotoxin or particulate irritants induces the expression of CYP4A mRNAs in rat liver and kidney. To determine whether all or part of these effects could be caused by hypophagia associated with the treatments, we pair-fed saline-injected rats to rats injected with endotoxin or the particulate irritant BaSO(4). The effects of endotoxin on hepatic or renal CYP4A1, CYP4A2, or CYP4A3 expression 24 h after injection were clearly distinguishable in kinetics and magnitude from those of pair feeding, indicating that the effects of endotoxin are not caused by hypophagia. Conversely, BaSO(4) treatment caused a more profound hypophagia, and pair feeding to these animals produced effects similar to those of the irritant treatment, indicating that CYP4A induction by BaSO(4) is mainly caused by reduced food intake. To gain further insight into the mechanism of induction of CYP4A by these inflammatory agents, we studied the sex dependence of their effects in Fischer 344 and Sprague-Dawley rats. No significant strain differences were observed, but the induction of hepatic CYP4A mRNAs by endotoxin or BaSO(4) was either absent in females or significantly lower than in males. This sex specificity of induction of hepatic CYP4As has been reported previously for peroxisome proliferators, and thus our results are consistent with a role for the peroxisome proliferator-activated receptor-alpha in the induction of hepatic CYP4As by inflammatory agents.
Mitchell
S R
SR
Department of Pharmacology, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, Georgia 30322, USA.
Sewer
M B
MB
Kardar
S S
SS
Morgan
E T
ET
D000818:Animals; D001466:Barium Sulfate / Q000494:pharmacology; D001483:Base Sequence; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D015342:DNA Probes; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D013045:Species Specificity
D015342:DNA Probes; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D001466:Barium Sulfate; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A