title: Gastrectomy increases the expression of hepatic cytochrome P450 3A by increasing lithocholic acid-producing enteric bacteria in mice.
abstract: We had previously revealed that drug metabolism, as well as the expression level of hepatic CYP3A, a drug-metabolizing enzyme, increase 12 weeks after gastrectomy in mice. In this study, we elucidated the mechanism of the increased CYP3A expression. The levels of lithocholic acid (LCA)-producing bacteria (Bacteroides fragilis) and LCA in the colon did not show a significant increase up to 4 weeks after gastrectomy compared to the sham operation group. In contrast, at 12 and 24 weeks post-gastrectomy, the levels of Bacteroides fragilis and LCA were significantly higher in the gastrectomy group than in the sham operation group. At 12 and 24 weeks after gastrectomy, the hepatic nuclear translocation of pregnane X receptor (PXR) had also increased. The hepatic CYP3A11 mRNA expression and nuclear translocation of PXR after intraperitoneal administration of LCA to normal mice was significantly higher than those of the control group. The intraperitoneal administration of taurolithocholic acid (TLCA), a taurine conjugate of LCA, caused no change in the expression level of CYP3A11. We suggest that the increase in the expression level of CYP3A after gastrectomy is caused by an increase in the nuclear translocation of PXR, which is triggered by an increase in LCA-producing bacteria.
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ishii
authors.forename: Takahiro
authors.initials: T
authors.lastname: Toda
authors.forename: Nobutomo
authors.initials: N
authors.lastname: Ikarashi
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kusunoki
authors.forename: Risako
authors.initials: R
authors.lastname: Kon
authors.forename: Wataru
authors.initials: W
authors.lastname: Ochiai
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Machida
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Sugiyama
mesh_terms: D000818:Animals; D001441:Bacteroides fragilis / Q000378:metabolism*; D001692:Biological Transport; D003106:Colon / Q000378:metabolism / Q000382:microbiology*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D004755:Enterobacteriaceae / Q000378:metabolism*; D005743:Gastrectomy; D008658:Inactivation, Metabolic; D008095:Lithocholic Acid / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D008095:Lithocholic Acid; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A