Effects of bacterial lipopolysaccharide on phenobarbital-induced CYP2B expression in mice.
Models of inflammation and infection, such as bacterial lipopolysaccharide (LPS), cause suppression of cytochrome P450 expression in various species, although the mechanisms involved are poorly understood. The effects of LPS on expression of phenobarbital (PB)-induced CYP2B1/2 in rats have been well characterized, but less is known about the effects of LPS on PB-induced CYP2B in mice. Since genetically manipulated mice represent an attractive model to study the mechanisms involved in the down-regulation of CYP2B expression by LPS, we investigated the effects of LPS on PB-induced CYP2B expression in mouse liver. Female C57BL/6 mice were injected with 100 mg/kg PB once daily for 4 days to induce CYP2B10 expression, and 1 mg/kg LPS was injected i.p. with the last PB dose. LPS inhibited the mRNA expression of CYP2B10 and CYP2B9 at 6 and 12 h of treatment, with the inhibitory effect more profound at 12 h. LPS also suppressed the CYP2B9 mRNA level at 24 h. However, CYP2B10 mRNA levels in mice treated with PB alone had declined markedly by 24 h after the last PB injection; therefore, no effect of LPS could be discerned. Further experiments showed that injections of 33 mg/kg PB every 8 h produced more stable CYP2B10 mRNA and enzymatic activity. Suppression of CYP2B protein level was found in LPS-treated animals at 24 h of treatment, although no significant effects were noticed at 6 and 12 h of treatment. This study suggests that LPS suppresses the expression of phenobarbital-induced CYP2B expression in mice, which resembles its effects in rats.
Li-Masters
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Department of Pharmacology, Emory University, Atlanta, GA 30322, USA.
Morgan
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D000818:Animals; D000918:Antibody Specificity; D001189:Aryl Hydrocarbon Hydroxylases; D015152:Blotting, Northern; D015153:Blotting, Western; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D065702:Cytochrome P-450 CYP2B6; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D015345:Oligonucleotide Probes / Q000235:genetics; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
D007527:Isoenzymes; D008070:Lipopolysaccharides; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D010634:Phenobarbital