Abstract
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.
Keywords
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
