Modulation of hepatic mRNA levels after administration of lipopolysaccharide and diphtheria and tetanus toxoids and pertussis vaccine adsorbed (DTP vaccine) to mice.
Administration of whole-cell diphtheria and tetanus toxoids and pertussis vaccine adsorbed (DTP vaccine) caused marked depression in the expression of mRNA for isozymes of cytochrome P-450 in the livers of endotoxin-responsive and nonresponsive mice. The levels of expression of mRNA for a polycyclic aromatic hydrocarbon-inducible (CYP1A2) and an ethanol-inducible (CYP2E1) form of P-450 were reduced by 70% to 80% 8 to 12 hr after vaccination or Bordetella pertussis endotoxin administration. These effects are preceded by marked increases (threefold to sixfold) in mRNA expression for interleukin-6, interleukin-1 and tumor necrosis factor in both strains of mice, with maximal increases 1 to 2 hr after injection. This is the first demonstration that levels of cytokine mRNA are altered in the liver in response to DTP vaccine administration. The finding of increased cytokine mRNA in the livers of mice injected with vaccine supports a role for cytokines as mediators of the decreased levels of cytochrome P-450. In addition, inducible nitric oxide synthase mRNA expression is also increased after vaccine administration, with a peak at 4 hr. The temporal relationship of the increased cytokine mRNA expression, increased nitric oxide synthase and decreased expression of P-450 mRNAs suggests a mechanism by which cytokines mediate the induction of nitric oxide synthase, which increases nitric oxide and decreases the activities of some cytochromes P-450.
Ansher
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SS
Laboratory of Bacterial Toxins, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892.
Thompson
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D000594:Amino Acid Oxidoreductases / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D015721:Diphtheria-Tetanus-Pertussis Vaccine / Q000494:pharmacology*; D004731:Endotoxins / Q000494:pharmacology; D005260:Female; D007375:Interleukin-1 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase; D012333:RNA, Messenger / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D015721:Diphtheria-Tetanus-Pertussis Vaccine; D004731:Endotoxins; D007375:Interleukin-1; D015850:Interleukin-6; D007527:Isoenzymes; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D003577:Cytochrome P-450 Enzyme System; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases