title: Intestinal and hepatic expression of cytochrome P450s and mdr1a in rats with indomethacin-induced small intestinal ulcers.
abstract: BACKGROUND
  Non-steroidal anti-inflammatory drugs induce the serious side effect of small intestinal ulcerations (SIUs), but little information is available regarding the consequences to drug metabolism and absorption.
  
  
  OBJECTIVE
  We examined the existence of secondary hepatic inflammation in rats with indomethacin (INM)-induced SIUs and assessed its relationship to the cytochrome P450 (CYP) and P-glycoprotein (mdr1a), the major drug-metabolizing factors in the small intestine and the liver.
  
  
  METHODS
  Gene expression of the CYP family of enzymes and mdr1a was measured with quantitative real-time polymerase chain reaction (qPCR). Vancomycin (VCM), a poorly absorbed drug, was administered intraduodenally to rats with SIUs.
  
  
  RESULTS
  INM induced SIUs predominantly in the lower region of the small intestine with high expression of inflammatory markers. Liver dysfunction was also observed, which suggested a secondary inflammatory response in rats with SIUs. In the liver of rats with SIUs, the expression of CYP2C11, CYP2E1, and CYP3A1 was significantly decreased, and loss of CYP3A protein was observed. Although previous studies have shown a direct effect of INM on CYP3A activity, we could not confirm any change in hepatic CY3A4 expression (major isoform of human CYP3A) in vitro. The plasma VCM concentration was increased in rats with SIUs due to partial absorption from the mucosal injury, but not in normal mucosa.
  
  
  CONCLUSIONS
  INM-induced SIUs had a subtle effect on intestinal CYP expression, but had an apparent action on hepatic CYP, which was influenced, at least in part, by the secondary inflammation. Furthermore, drug absorption was increased in rats with SIUs.
authors.affiliation: 1. Department of Medical Pharmaceutics, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan; ; 2. Educational Center for Clinical Pharmacy, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan;
authors.forename: Shoji
authors.initials: S
authors.lastname: Kawauchi
authors.affiliation: 3. Department of Pharmaceutical Health Care, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 7-2-1 Kamiohno, Himeji, 670-8524, Japan;
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: 4. Department of Analytical and Bioinorganic Chemistry, Division of Analytical and Physical Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan;
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yasui
authors.affiliation: 4. Department of Analytical and Bioinorganic Chemistry, Division of Analytical and Physical Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan;
authors.forename: Chikako
authors.initials: C
authors.lastname: Nishikawa
authors.affiliation: 1. Department of Medical Pharmaceutics, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan; ; 5. Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Ikuya
authors.initials: I
authors.lastname: Miki
authors.affiliation: 1. Department of Medical Pharmaceutics, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan; ; 5. Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Inoue
authors.affiliation: 1. Department of Medical Pharmaceutics, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan;
authors.forename: Sayo
authors.initials: S
authors.lastname: Horibe
authors.affiliation: 2. Educational Center for Clinical Pharmacy, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan;
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Hamaguchi
authors.affiliation: 1. Department of Medical Pharmaceutics, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan; ; 5. Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Toshihito
authors.initials: T
authors.lastname: Tanahashi
authors.affiliation: 1. Department of Medical Pharmaceutics, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan;
authors.forename: Shigeto
authors.initials: S
authors.lastname: Mizuno
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072467:Cytochrome P450 Family 2; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007213:Indomethacin / Q000633:toxicity*; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase / Q000235:genetics; D014456:Ulcer / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D014640:Vancomycin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000894:Anti-Inflammatory Agents, Non-Steroidal; D012333:RNA, Messenger; D014640:Vancomycin; D003577:Cytochrome P-450 Enzyme System; C095122:multidrug resistance protein 3; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D007213:Indomethacin
keywords: P-glycoprotein; cytochrome P450; indomethacin; secondary inflammation; small intestine.