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Decreased constitutive murine cytochromes P450 by staphyloccocal enterotoxin-b (SEB).

Shedlofsky-SI; Tosheva-R; Scheurer-J; Snawder-JE

Hepatology 1995 Oct; 22(4)(Suppl S Part 2):246A

http://www3.interscience.wiley.com/cgi-bin/jtoc/106570044/

20035137

Inflammation caused by gram-negative endotoxin (LPS) is associated with impaired hepatic P450-mediated drug metabolizing activity. However, gram-positive bacteria also commonly cause the sepsis syndrome. To evaluate effects of the gram-positive inflammatory stimulant SEB, C3H/HeN mice (male, 25g) were injected ip with either saline, LPS (0.5mg/kg), or SEB (3mg/kg), and hepatic microsomes prepared and serum harvested 24h later. Serum amyloid A (SAA) measured the intensity of the hepatic acute phase response. Total spectral P450, ethoxyresorufin-O-deethylase (EROD, -CYP1A1/2), paranitrophenol-OHase (PNP -CYP2El), and benzyloxy-O-deethylase (BROD -CYP3A) were assayed and immunoblots for each P450 isoform prepared using commercial antibodies. Data are mean +/-SD for 4-7 mice in each group. SEB increased SAA and decreased total P450 to the same ex­tent as LPS and also depressed activities of each specific P450 isoform and amount of specific protein > or = LPS. 3mg/kg was as effective as 6mg/kg and a time course showed maximal depression at 24h. Conclusion: The gram-positive inflammatory stimulant SEB depresses hepatic P450s as well as LPS. This suggests that patients with gram-positive sepsis are likely to have impaired hepatic drug metabolism.

Biological-effects; Biological-monitoring; Biological-factors; Biochemistry; Cell-biology; Cellular-reactions; Dose-response; Drug-interaction; Exposure-assessment; Exposure-methods; Endotoxins; Hepatic-microsomal-enzymes; Hepatocytes; Hepatotoxicity; Hepatotoxins; Laboratory-animals; Laboratory-testing; Liver-cells; Liver-disorders; Liver-microsomal-metabolism; Metabolic-disorders; Metabolic-study; Molecular-biology

HPTLD9

19951001

Abstract

1996

4

0270-9139

DBBS

Hepatology

OH