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INVOLVEMENT OF INTERLEUKIN-6 AND TUMOR NECROSIS FACTOR IN CYP3A11 AND 2C29 DOWN-REGULATION BY BACILLUS CALMETTE-GUÉRIN AND LIPOPOLYSACCHARIDE IN MOUSE LIVER

Department of Biochemical Toxicology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan (T.A., S.N., T.Y); Japan Development, R&D Alcon Research, Ltd., Fort Worth, Texas (T.O.); Department of Anatomy, School of Medicine, Showa University, Tokyo, Japan (S.S.); Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan (R.H., Y.I.); Department of Transgenic Animal Science, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan (M.A.); and Department of Molecular Biology and Immunology, National Institute of Agrobiological Sciences, Ibaraki, Japan (K.S.)

Bacillus Calmette-Guérin (BCG) and lipopolysaccharide (LPS) are well known potent activators of the cell-mediated immune system and thus lead to the decreases in cytochrome P450 (P450). In this study we used interleukin (IL)-1/ß, IL-6, or tumor necrosis factor (TNF) knockout (KO) mice to investigate how each cytokine is involved in P450 down-regulation, especially CYP3A11 and 2C29. BCG (40 mg/kg) was found to reduce both CYP3A11 and 2C29 mRNAs at 24 h after treatment in IL-1/ß KO mice in a manner similar to that seen in wild-type mice. CYP3A11 mRNA, but not CYP2C29 mRNA, was significantly decreased by BCG treatment in the TNF KO mice, although the decrease was less than that of wild-type or IL-1/ß KO mice. In contrast, BCG showed no significant effect on CYP3A11 and 2C29 mRNAs in IL-6 KO mice. On the other hand, LPS was able to decrease CYP3A11 and 2C29 mRNA levels in all of the cytokine KO mice and markedly increased systemic levels of TNF; BCG (40 mg/kg) lacked such activity. The present study has shown that IL-6 and TNF are likely to be major factors involved in the down-regulation of CYP3A11 and 2C29 mRNAs in mice. In addition, there exist differences in the amount and/or kind of cytokines released by BCG or LPS, the latter being more potent than the former. This will be a possible reason for differential capability of P450 down-regulation between BCG and LPS.

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