Procedures—In experiment 1, 10 market-weight swine were treated with LPS (20 μg/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 μg/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 μg/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 and Clinical Relevance—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.
Objective—To determine the effect of oral administration
of low doses of pentobarbital on cytochrome
P450 (CYP) isoforms and CYP-mediated reactions in
Animals—42 immature (12-week-old) Beagles.
Procedure—Dogs were grouped and treated orally as
follows for 8 weeks: low-dose pentobarbital (50 µg/d;
4 males, 4 females), mid-dose pentobarbital (150
µg/d; 4 males, 4 females), high-dose pentobarbital
(500 µg/d; 4 males, 4 females), positive-pentobarbital
control (10 mg/kg/d; 2 males, 2 females), positivephenobarbital
control (10 mg/kg/d; 2 males, 2
females), and negative control (saline [0.9% NaCl]
solution; 5 males, 5 females). Serum biochemical and
hematologic values were monitored. On necropsy
examination, organ weights were determined, and
histologic evaluation of tissue sections of liver, kidney,
small intestine, testes, epididymis, and ovaries was
performed. Hepatic and intestinal drug-metabolizing
enzyme activities were measured, and relative
amounts of CYP isoforms were determined by western
Results—The amount of a hepatic CYP2A-related isoform
in dogs from the high-dose pentobarbital treatment
group was twice that of dogs from the negative
control group. CYP2C was not detectable in small
intestinal mucosa of dogs from the negative control
group; measurable amounts of CYP2C were found in
dogs from the various (low-, mid-, and high-dose) pentobarbital
treatment groups and from positive-pentobarbital
and positive phenobarbital control groups.
Several CYP-mediated reactions increased in a dosedependent
manner. The lowest calculated effective
dose of pentobarbital ranged from 200 to 450 µg/d.
Conclusions and Clinical Relevance—Several CYP
isoforms and their associated reactions were induced
in dogs by oral administration of low amounts of pentobarbital.
(Am J Vet Res 2003;64:1167–1175)