Abstract
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 BaSO4. 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, BaSO4 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 BaSO4 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 BaSO4 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-α in the induction of hepatic CYP4As by inflammatory agents.
Footnotes
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Send reprint requests to: Edward T. Morgan, Ph.D., Department of Pharmacology, Emory University, Atlanta, GA 30322. E-mail: etmorga{at}bimcore.emory.edu
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This work was supported by Grant GM46897 from the National Institute of General Medical Sciences (to E.T.M.) and by a Howard Hughes Predoctoral Fellowship (to M.B.S.).
- Abbreviations used are::
- P450
- cytochrome P450
- GAP
- glyceraldehyde-3-phosphate dehydrogenase
- LPS
- bacterial lipopolysaccharide
- F344
- Fischer 344
- PPAR
- peroxisome proliferator-activated receptor
- S-D
- Sprague-Dawley
- SSC
- standard saline citrate
- Received May 10, 2000.
- Accepted August 28, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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