Involvement of interleukin-6 and tumor necrosis factor alpha in CYP3A11 and 2C29 down-regulation by Bacillus Calmette-Guerin and lipopolysaccharide in mouse liver.
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)-1alpha/beta, IL-6, or tumor necrosis factor alpha (TNFalpha) 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-1alpha/beta 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 TNFalpha KO mice, although the decrease was less than that of wild-type or IL-1alpha/beta 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 TNFalpha; BCG (40 mg/kg) lacked such activity. The present study has shown that IL-6 and TNFalpha 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.
Ashino
Takashi
T
Department of Biochemical Toxicology, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
Oguro
Takiko
T
Shioda
Seiji
S
Horai
Reiko
R
Asano
Masahide
M
Sekikawa
Kenji
K
Iwakura
Yoichiro
Y
Numazawa
Satoshi
S
Yoshida
Takemi
T
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000235:genetics; D001500:BCG Vaccine / Q000008:administration & dosage / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005260:Female; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis; D013045:Species Specificity; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D001500:BCG Vaccine; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C400322:cytochrome P-450 CYP2C subfamily; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; C022657:steroid hormone 6-beta-hydroxylase; D010089:Oxidoreductases, N-Demethylating