Antibiotics suppress Cyp3a in the mouse liver by reducing lithocholic acid-producing intestinal flora.
We previously demonstrated that ciprofloxacin (CPX), a new quinolone antibiotic, suppresses Cyp3a in the mouse liver by reducing the hepatic level of lithocholic acid (LCA) produced by intestinal flora. The present study investigated the possibility that other antibiotics with antibacterial activity against LCA-producing bacteria also cause a decrease in the LCA level in the liver, leading to reduced expression of Cyp3a11. While the mRNA expression of Cyp3a11 in the liver was significantly reduced when SPF mice were administered antibiotics such as ampicillin, CPX, levofloxacin, or a combination of vancomycin and imipenem, no significant changes were observed after antibiotic treatment of GF mice lacking intestinal flora. LCA-producing bacteria in the feces as well as the hepatic level of the taurine conjugate of LCA were significantly reduced in the antibiotic-treated SPF mice, suggesting that the decrease in Cyp3a11 expression can be attributed to the reduction in LCA-producing intestinal flora following antibiotic administration. These results suggest that the administration of antibiotics with activity against LCA-producing bacteria can also cause a decrease in the LCA level in humans, which may lower CYP3A4 expression. The intestinal flora are reported to be altered not only by drugs, such as antibiotics, but also by stress, disease, and age. The findings of the present study suggest that these changes in intestinal flora could modify CYP expression and contribute to the individual differences in pharmacokinetics.
Toda
Takahiro
T
Department of Clinical Pharmacokinetics, Hoshi University, Tokyo, Japan.
Ohi
Kanna
K
Kudo
Toshiyuki
T
Yoshida
Tomoyuki
T
Ikarashi
Nobutomo
N
Ito
Kiyomi
K
Sugiyama
Kiyoshi
K
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001441:Bacteroides fragilis / Q000378:metabolism; D047989:Paraclostridium sordellii / Q000378:metabolism; D015169:Colony Count, Microbial; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007422:Intestines / Q000382:microbiology*; D008095:Lithocholic Acid / Q000096:biosynthesis / Q000378:metabolism*; D008099:Liver / Q000201:enzymology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014229:Triazolam / Q000378:metabolism; D008565:Membrane Proteins
D000900:Anti-Bacterial Agents; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D008095:Lithocholic Acid; D014229:Triazolam; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins