Ciprofloxacin Suppresses Cyp3a in Mouse Liver by Reducing Lithocholic Acid-producing Intestinal Flora

CYP2D6 plays an important role in the metabolism of many drugs such as opioids and antidepressants. Polymorphisms of the CYP2D6 gene are widely observed in the Japanese population, and can affect the firstpass metabolism of orally administered drugs. Several CYP enzymes have been identified in the small intestine of Caucasians, but intestinal CYP enzymes have not been reported in the Japanese population, except for CYP3A4 and CYP2C19. In this study, we evaluated the CYP2D6 metabolic capacity by measurement of CYP2D6 mRNA and protein levels and activity in the small intestine of Japanese individuals. Normal jejunal tissues were obtained from 31 patients who had undergone pancreaticoduodenectomy, and the CYP2D6*10 variant was identified in these tissues. CYP2D6 mRNA and CYP2D6 protein levels were analyzed using realtime RT-PCR and Western blotting, respectively. Bufuralol 1′-hydroxylation, a marker of CYP2D6 activity, was analyzed using HPLC. Frequencies of the CYP2D6*1/*1, *1/*10, and *10/*10 genotypes in the jejunal tissue were 29.0% (n 9), 35.5% (n 11), and 35.5% (n 11), respectively. CYP2D6 protein and activity levels did not differ significantly between the genotypes. A positive correlation was found between CYP2D6 protein and activity levels. Furthermore, CYP2D6 protein levels and activity in the small intestine were significantly lower than those in the liver. These findings suggest that the metabolic capacity of CYP2D6 in the small intestine of the Japanese population has a relatively small effect on drug metabolism. Key words CYP 2D6; small intestine; Japanese; polymorphism; bufuralol CYP enzymes are present in most tissues in the body, but are most abundant in the liver. There, they play a pivotal role in the metabolism of endogenous substrates and of exogenous compounds such as xenobiotics.1) Their presence in extrahepatic tissues, such as the esophagus, stomach, and small intestine, 2-4) also contributes to drug metabolism. 5-7) Paine et al. reported a significant contribution of CYP enzymes in the small intestine to the first-pass metabolism of midazolam, specifically by intestinal CYP3A4.7) Expressions of CYP3A, CYP2C9, CYP2C19, CYP2D6, CYP2J2, and CYP4F proteins have been demonstrated in the small intestine of Caucasians. 4,8) Of these, CYP2D6 plays a particularly important role in drug metabolism. Although CYP2D6 accounts for only 2% of the total CYP protein in the liver, it is a very important isoform because it metabolizes approximately 20-25% of commonly used drugs, including codeine, tramadol, and tamoxifen. 9) However, CYP2D6 expression and activity have not yet been characterized in the small intestine of the Japanese population.CYP2D6 gene polymorphisms are produced from over 109 allelic variants.10) The phenotypes resulting from these polymorphisms are associated with abolished, decreased, and increased enzyme activity, and the resulting phenotypes can be classified as a poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM), or ultra-rapid metabolizer (UM), based ...

Section: Discussionmentioning

confidence: 99%

Evaluation of CYP2D6 Protein Expression and Activity in the Small Intestine to Determine Its Metabolic Capability in the Japanese Population

Kawakami

Takenoshita-Nakaya

Takeba

et al. 2017

“…We have previously reported that the expression of CYP3A in the livers increases when there is an increase in lCA produced by enteric bacteria. 24,37) Therefore, the amount of enteric bacteria (Bacteroides fragilis) that produced lCA was measured in infant male mice in the HF group. No differences were observed in the amount of Bacteroides fragilis between the control group and the HF group (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…24,25) Therefore, we examined the amount of enteric bacteria (Bacteroides fragilis) that produce lCA in the large intestines of infant males born to mothers that consumed a high-fat diet during pregnancy. As a result, no differences were observed in the amount of enteric bacteria between the control group and the HF group (Fig.…”

Section: The Effect Of High-fat Diet Consumption During Pregnancy On mentioning

confidence: 99%

Consumption of a High-Fat Diet during Pregnancy Changes the Expression of Cytochrome P450 in the Livers of Infant Male Mice

Tajima

Ikarashi

Okaniwa

et al. 2013

Self Cite

It has been recently reported that the consumption of a high-fat diet during pregnancy exerts various effects on fetuses and newborn mice. The purpose of this study was to determine the effects of a high-fat diet during pregnancy on the expression of cytochrome P450 (CYP) in the livers of offspring. Mouse dams were fed a high-fat diet during pregnancy from the time of conception. After their birth, the newborn mice were fed a normal diet until 12 weeks of age. In the livers of the infant male mice that consumed a high-fat diet, the protein expression of CYP3A and CYP2C was decreased, and the protein expression of CYP1A and CYP2E was increased at 6 and 12 weeks of age. However, almost no changes were observed in the CYP proteins at 6 and 12 weeks of age in the livers of the infant female mice that consumed a high-fat diet. The amount of pregnane X receptor (PXR) translocated into the nucleus was reduced in the livers of infant male mice that consumed a high-fat diet. However, there was neither an increase in tumor necrosis factor-α or interleukin-1β nor a decrease in lithocholic acid. These data suggested that CYP3A and CYP2C might decrease as a result of the decrease in the amount of nuclear PXR in infant male mice that consumed a high-fat diet. The results of this study suggested that the consumption of a high-fat diet by pregnant mothers may be one explanation for individual differences in pharmacokinetics.Key words high-fat diet; cytochrome P450; pregnane X receptor; pharmacokinetics Studies have reported that consumption of a high-fat diet during pregnancy exerts various effects on offspring.1-4) For example, rats born to mothers that were given a high-fat diet during pregnancy showed an increased number of galaninproducing brain cells (galanin is an orexigenic peptide in the brain), which leads to obesity at 10 weeks of age.1) Additionally, the level of brain-derived neurotrophic factor in the brain decreases, which can lead to the development of neurodegenerative diseases such as Alzheimer's disease. 4)Cytochrome P450 (CYP) is major drug-metabolizing enzyme that is known to metabolize approximately 70% of the drugs used in clinical practice.5) The role of the CYP3A subfamily is important because approximately 50% of all drugs are metabolized by CYP3A. 5) In humans, the expression level of CYP3A accounts for more than 30% and 70% of total CYP protein expression in the liver and the intestine, respectively. 6)Therefore, changes in CYP3A expression and activity exert significant effects on drug therapy. 7-9) It has been reported that there are sex differences in the expression of CYP. For example, in mice, CYP2D9 and CYP4A12 are specifically expressed in males, and CYP2A4, CYP2B9, CYP3A41, and CYP3A44 are specifically expressed in females. 10-12)There have been many reports suggesting that the consumption of a high-fat diet differentially affects the expression and activity of CYP. 13,14) It has also been reported that obesity in mothers affects the expression of CYP1A1 in fetuses. 15) We have demonstrated th...

“…We have revealed that when the amount of lithocholic acid (LCA)-producing bacteria, such as Bacteroides fragilis, increased, the hepatic expression of CYP3A increased, [9][10][11] resulting in the decreased efficacy of drugs. It is known that the enterobacterial flora changes with the decrease in or lack of secretion of gastric acid in patients who have received a gastrectomy.…”

mentioning

confidence: 99%

Gastrectomy Increases the Expression of Hepatic Cytochrome P450 3A by Increasing Lithocholic Acid-Producing Enteric Bacteria in Mice

Ishii

Toda

Ikarashi

et al. 2014

Self Cite

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.