Intestinal flora induces the expression of Cyp3a in the mouse liver.
In order to determine the effects of intestinal flora on the expression of cytochrome P450 (CYP), the mRNA expression of CYP was compared between specific pathogen-free (SPF) and germ-free (GF) mice. Most of the major CYP isozymes showed higher expression in the livers of SPF mice compared with GF mice. Nuclear factors such as pregnane X receptor (PXR) and constitutive androstane receptor (CAR), as well as transporters and conjugation enzymes involved in the detoxification of lithocholic acid (LCA), also showed higher expression in SPF mice. The findings suggest that in the livers of SPF mice, LCA produced by intestinal flora increases the expression of CYPs via activation of PXR and CAR. Drugs such as antibiotics, some diseases and ageing, etc. are known to alter intestinal flora. The present findings suggest that such changes also affect CYP and are one of the factors responsible for individual differences in pharmacokinetics.
Department of Clinical Pharmacokinetics, Hoshi University, Ebara, Shinagawa-ku, Tokyo, Japan.
T
T
Toda
N
N
Saito
N
N
Ikarashi
K
K
Ito
M
M
Yamamoto
A
A
Ishige
K
K
Watanabe
K
K
Sugiyama
D000818:Animals; D001419:Bacteria / Q000737:chemistry; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005856:Germ-Free Life; D007422:Intestines / Q000382:microbiology*; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008095:Lithocholic Acid / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013047:Specific Pathogen-Free Organisms; D014157:Transcription Factors / Q000378:metabolism; D008565:Membrane Proteins
D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D017931:DNA Primers; D007527:Isoenzymes; D008095:Lithocholic Acid; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins