Effects of intravenous administration of lipopolysaccharide on cytochrome P450 isoforms and hepatic drug metabolizing enzymes in swine.
OBJECTIVE
To investigate effects of bacteria-mediated inflammation on hepatic drug metabolizing enzymes (DMEs) in swine via a lipopolysaccharide (LPS) challenge technique.


METHODS
22 Poland China-Landrace crossbred barrows.


METHODS
In experiment 1, 10 market-weight swine were treated with LPS (20 microg/kg, IV [n = 5 swine]) or sham-injected (5) 24 hours before slaughter. In experiment 2, 12 growing and finishing swine were treated with LPS at 2 or 20 microg/kg, IV (n = 3 swine/age group/treatment) 24 hours before slaughter. Hepatic DMEs, cytochrome P450 (CYP) isoforms, and CYP-mediated reactions were measured.


RESULTS
In experiment 1, LPS administered at 20 microg/kg decreased most hepatic DME components and inhibited enzymatic activities. In experiment 2, both doses reduced protein content in subcellular fractions and inhibited some DME- and CYP-mediated activities. In growing and finishing swine, CYP2A and CYP2B isoforms were not detected after treatment with LPS; the CYP1A2 isoform was eliminated in growing but not in finishing swine. Lipopolysaccharide also reduced CYP2D6 content in growing and finishing swine but increased CYP2E content. Lipopolysaccharide had no effect on swine CYP2C11, CYP2C13, or CYP3A content. The CYP2B-mediated 7-pentoxyresorufin O-dealkylase activity in growing and finishing swine was totally eliminated, and 7-ethoxyresorufin (indicating CYP1A activity) and aniline (mediated by CYP2E) metabolism was decreased.


CONCLUSIONS
Effect of LPS treatment on swine CYPs appeared to be isoform specific; age-related metabolic status of the swine and the LPS dose modified this effect. Lipopolysaccharide-induced inflammation may affect metabolism of drugs and xenobiotics in swine.
Myers
Michael J
MJ
Division of Animal Research, Office of Research, Center for Veterinary Medicine, Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708, USA. michael.myers@fda.hhs.gov
Farrell
Dorothy E
DE
Howard
Karyn D
KD
Kawalek
Joseph C
JC
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D007275:Injections, Intravenous; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009919:Orchiectomy; D013552:Swine
D007527:Isoenzymes; D008070:Lipopolysaccharides; D003577:Cytochrome P-450 Enzyme System