RT Journal Article
SR Electronic
T1 INVOLVEMENT OF INTERLEUKIN-6 AND TUMOR NECROSIS FACTOR α IN CYP3A11 AND 2C29 DOWN-REGULATION BY BACILLUS CALMETTE-GUÉRIN AND LIPOPOLYSACCHARIDE IN MOUSE LIVER
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 707
OP 714
DO 10.1124/dmd.32.7.707
VO 32
IS 7
A1 Takashi Ashino
A1 Takiko Oguro
A1 Seiji Shioda
A1 Reiko Horai
A1 Masahide Asano
A1 Kenji Sekikawa
A1 Yoichiro Iwakura
A1 Satoshi Numazawa
A1 Takemi Yoshida
YR 2004
UL http://dmd.aspetjournals.org/content/32/7/707.abstract
AB 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)-1α/β, IL-6, or tumor necrosis factor α (TNFα) 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-1α/β 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 TNFα KO mice, although the decrease was less than that of wild-type or IL-1α/β 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 TNFα; BCG (40 mg/kg) lacked such activity. The present study has shown that IL-6 and TNFα 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. The American Society for Pharmacology and Experimental Therapeutics