Role of Kupffer cells in pathogenesis of sepsis-induced drug metabolizing dysfunction.

The present study aimed to determine the role of Kupffer cells (KCs) in cytochrome P450 (CYP) isozyme activity and the expression of its gene during polymicrobial sepsis. For ablation of KCs, rats were pretreated with gadolinium chloride (GdCl) at 48 and 24 h before cecal ligation and puncture (CLP). The depletion of KCs was confirmed by measuring the mRNA level of the KC marker gene CD163. Serum aminotransferase levels and lipid peroxidation showed an increase and hepatic glutathione content showed a decrease at 24 h after CLP. These changes were prevented by GdCl pretreatment. Catalytic activities of CYP1A1, 1A2 and 2E1 showed a significant reduction at 24 h after CLP but were prevented by GdCl. A reduction in the levels of CYP2E1 protein and CYP2B1 and CYP2E1 mRNA expression was prevented by GdCl. Phosphorylation of CYP1A1/1A2 markedly increased 24 h after CLP, which was prevented by GdCl. The increased serum level of high mobility group box 1, hepatic level of Toll-like receptors 2 and 4, and inducible nitric oxide synthase protein expression were prevented by GdCl. In addition, elevated serum concentrations of tumor necrosis factor-α and interleukin-6, and increased hepatic mRNA levels of tumor necrosis factor-α and interleukin-6 were decreased by depletion of KCs. Our findings suggest that ablation of KCs protects against hepatic drug-metabolizing dysfunction by modulation of the inflammatory response. The cytochrome P450 (CYP) enzyme contributes to the metabolism and elimination of exogenous and endogenous substances. In this study, we have demonstrated that Kupffer cells differentially regulate the expression of each form of cytochrome P450 (CYP) among various CYP subfamilies, and these differential regulations were attributable to the ability of Kupffer cells to develop exaggerated inflammatory responses [ABSTRACT FROM AUTHOR]