ABSTRACT
The repeated dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect genotoxic hepatocarcinogens that can be integrated into a general toxicity study. The assay methods were thoroughly validated by 19 Japanese facilities. Methapyrilene hydrochloride (MP), known to be a non-genotoxic hepatocarcinogen, was examined in the present study. MP was dosed orally at 10, 30 and 100mg/kg/day to 6-week-old male Crl:CD (SD) rats daily for 14 days. Treatment with MP resulted in an increase in micronucleated hepatocytes (MNHEPs) with a dosage of only 100mg/kg/day. At this dose level, cytotoxicity followed by regenerative cell growth was noted in the liver. These findings suggest that MP may induce clastogenic effects indirectly on the liver or hepatotoxicity of MP followed by regeneration may cause increase in spontaneous incidence of MNHEPs.
Subject(s)
Carcinogens/toxicity , Hepatocytes/drug effects , Liver/drug effects , Methaqualone/toxicity , Micronucleus Tests , Administration, Oral , Age Factors , Animals , Body Weight/drug effects , Bone Marrow/drug effects , Chromosome Aberrations/drug effects , Cooperative Behavior , Dose-Response Relationship, Drug , Drug Administration Schedule , Hepatocytes/pathology , Humans , Japan , Liver/pathology , Male , Organ Specificity , Rats , Rats, Sprague-Dawley , Reticulocytes/drug effects , Societies, PharmaceuticalABSTRACT
We reviewed the effect of monosodium glutamate (MSG) on the development and healing of nonsteroidal anti-inflammatory drug (NSAID)-induced small intestinal lesions in rats. Loxoprofen (60 mg/kg, p.o.) induced lesions in the small intestine within 24 h, accompanied by a decrease of Muc2 expression and an increase in enterobacterial invasion and inducible nitric oxide synthase (iNOS) expression. These lesions were prevented when MSG was given as a mixture of powdered food for 5 days before the loxoprofen treatment. This effect of MSG was accompanied by an increase in Muc2 expression / mucus secretion as well as the suppression of bacterial invasion and iNOS expression. These intestinal lesions healed spontaneously within 6 days, but the process was impaired by the repeated administration of low-dose loxoprofen (30 mg/kg) for 5 days after the ulceration, with the decrease of vascular endothelial derived growth factor (VEGF) expression and angiogenesis. The healing-impairing effect of loxoprofen was prevented by feeding 5% MSG for 5 days after the ulceration. These results suggest that MSG not only prevents loxoprofen-induced small intestinal damage but also promotes a healing of these lesions; the former is functionally associated with the increase in Muc2 expression / mucus secretion and the suppression of bacterial invasion and iNOS expression, while the latter is associated with the stimulation of VEGF expression/angiogenesis.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/toxicity , Intestinal Diseases/drug therapy , Phenylpropionates/toxicity , Sodium Glutamate/pharmacology , Animals , Disease Models, Animal , Food Additives/pharmacology , Gene Expression Regulation/drug effects , Intestinal Diseases/chemically induced , Intestinal Diseases/pathology , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , Intestine, Small/drug effects , Intestine, Small/pathology , Mucin-2/genetics , Nitric Oxide Synthase Type II/genetics , Rats , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolismABSTRACT
BACKGROUND AND AIMS: We examined the effect of lafutidine, a histamine H(2) receptor antagonist with a mucosal protective action mediated by capsaicin-sensitive sensory neurons (CSN), on intestinal lesions produced by loxoprofen administration in rats. METHODS: Animals were given loxoprofen (10-100 mg/kg p.o.) and killed 24 h later. Lafutidine (10 and 30 mg/kg), cimetidine (100 mg/kg) or famotidine (30 mg/kg) was given twice p.o. at 0.5 h before and 6 h after loxoprofen. Omeprazole (100 mg/kg) was given p.o. once 0.5 h before. Ampicillin (800 mg/kg) was given p.o. twice at 24 h and 0.5 h before loxoprofen, while 16,16-dimethyl prostaglandin E(2) (dmPGE(2); 0.01 mg/kg) was given i.v. twice at 5 min before and 6 h after. RESULTS: Loxoprofen dose-dependently produced hemorrhagic lesions in the small intestine, accompanied by invasion of enterobacteria and increased inducible nitric oxide synthase (iNOS) expression as well as myeloperoxidase activity in the mucosa. The ulcerogenic response to loxoprofen (60 mg/kg) was significantly prevented by lafutidine (30 mg/kg), similar to dmPGE(2) and ampicillin, and the effect of lafutidine was totally attenuated by ablation of CSN. Neither cimetidine, famotidine nor omeprazole had a significant effect against these lesions. Lafutidine alone increased mucus secretion and reverted the decreased mucus response to loxoprofen, resulting in suppression of bacterial invasion and iNOS expression. In addition, loxoprofen downregulated Muc2 expression, and this response was totally reversed by lafutidine mediated by CSN. CONCLUSION: Lafutidine protects the small intestine against loxoprofen-induced lesions, essentially mediated by the CSN, and this effect may be functionally associated with increased Muc2 expression/mucus secretion, an important factor in the suppression of bacterial invasion.
Subject(s)
Acetamides/pharmacology , Anti-Ulcer Agents/pharmacology , Histamine H2 Antagonists/pharmacology , Intestinal Mucosa/drug effects , Intestine, Small/drug effects , Peptic Ulcer/prevention & control , Phenylpropionates , Piperidines/pharmacology , Pyridines/pharmacology , 16,16-Dimethylprostaglandin E2/pharmacology , Ampicillin/pharmacology , Animals , Anti-Bacterial Agents/pharmacology , Capsaicin/pharmacology , Cimetidine/pharmacology , Disease Models, Animal , Enterobacteriaceae/pathogenicity , Famotidine/pharmacology , Intestinal Mucosa/metabolism , Intestinal Mucosa/microbiology , Intestinal Mucosa/pathology , Intestine, Small/metabolism , Intestine, Small/microbiology , Intestine, Small/pathology , Male , Mucin-2/genetics , Nitric Oxide Synthase Type II/genetics , Omeprazole/pharmacology , Peptic Ulcer/chemically induced , Peptic Ulcer/metabolism , Peptic Ulcer/microbiology , Peptic Ulcer/pathology , Peroxidase/metabolism , Proton Pump Inhibitors/pharmacology , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Sensory Receptor Cells/drug effectsABSTRACT
BACKGROUND AND AIMS: The effects of an EP4 agonist/antagonist on the healing of lesions produced by indomethacin in the small intestine were examined in rats, especially in relation to the expression of vascular endothelial growth factor (VEGF) and angiogenesis. METHODS: Animals were given indomethacin (10 mg/kg s.c.) and killed at various time points. To impair the healing of these lesions, a small dose of indomethacin (2 mg/kg p.o.) or AE3-208 (EP4 antagonist: 3 mg/kg i.p.) was given once daily for 6 days after the ulceration was induced, with or without the co-administration of AE1-329 (EP4 agonist: 0.1 mg/kg i.p.). RESULTS: Indomethacin (10 mg/kg) caused severe damage in the small intestine, but the lesions healed rapidly decreasing to approximately one-fifth of their initial size within 7 days. The healing process was significantly impaired by indomethacin (2 mg/kg) given once daily for 6 days after the ulceration. This effect of indomethacin was mimicked by the EP4 antagonist and reversed by co-administration of the EP4 agonist. Mucosal VEGF expression was upregulated after the ulceration, reaching a peak on day 3 followed by a decrease. The changes in VEGF expression paralleled those in mucosal cyclooxygenase-2 expression, as well as prostaglandin E(2) (PGE(2)) content. Indomethacin (2 mg/kg) downregulated both VEGF expression and angiogenesis in the mucosa during the healing process, and these effects were significantly reversed by co-treatment with the EP4 agonist. CONCLUSION: The results suggest that endogenous PGE(2) promotes the healing of small intestinal lesions by stimulating angiogenesis through the upregulation of VEGF expression mediated by the activation of EP4 receptors.
