Heme Oxygenase-1 Protects Gastric Mucosal Cells against Non-steroidal Anti-inflammatory Drugs

Aburaya, Mayuko; Tanaka, Ken Ichiro; Hoshino, Tatsuya; Tsutsumi, Shinji; Suzuki, Keitarou; Makise, Masaki; Akagi, Reiko; Mizushima, Tohru

doi:10.1074/jbc.m602074200

Cited by 83 publications

(68 citation statements)

References 70 publications

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“…Local production of CO will be beneficial since the disturbance of gastric microcirculation is deeply implicated in the pathogenesis of AGML (16). Several lines of studies suggest that HO-1 prevents gastric and colonic damages (14,15). Metabolites of HO-1 also show protective effects against the gastro-intestinal lesions.…”

Section: Discussionmentioning

confidence: 99%

Polaprezinc (Zinc L-Carnosine) Is a Potent Inducer of Anti-oxidative Stress Enzyme, Heme Oxygenase (HO)-1 — a New Mechanism of Gastric Mucosal Protection

et al. 2009

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Abstract. Heme oxygenase (HO)-1 is implicated in cytoprotection in various organs. We tested a possibility that polaprezinc (PZ), an anti-ulcer drug, could induce HO-1 in the gastric mucosa. Male 6-week-old Wistar rats were intragastrically administered PZ. Gastric expression of HO-1 was assessed by real time RT-PCR and western blotting, and localization of HO-1 was observed by in situ hybridization and immunohistochemistry. The levels of HO-1 mRNA were increased in a dose-dependent manner. The levels of HO-1 mRNA were increased 4-fold by PZ at the dose of 200 mg/ kg at 3 h as compared with control levels. The levels of immunoreactive HO-1 were increased 3-fold at 6 h. Signals for HO-1 mRNA and immunoreactivity were detected strongly in the surface gastric mucosal cells and moderately in the gastric macrophages. Treatment with an HO-1 inhibitor, stannous mesoporphyrin (SnMP) significantly worsened the HCl-induced acute gastric mucosal lesions and increased the apoptosis of mucosal cells. Mucosal lesions were decreased by pretreatment with PZ, while they were increased by co-administration with SnMP. These data indicate for the first time that PZ is an effective inducer of HO-1 in the stomach. PZinduced HO-1 functions as a part of the mucosal protective effects of PZ.

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Section: Discussionmentioning

confidence: 99%

Polaprezinc (Zinc L-Carnosine) Is a Potent Inducer of Anti-oxidative Stress Enzyme, Heme Oxygenase (HO)-1 — a New Mechanism of Gastric Mucosal Protection

et al. 2009

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“…[30][31][32] However, it has been reported that NSAIDs induce necrosis and apoptosis in cultured gastric mucosal cells and in the gastric mucosa in a manner independent of COX inhibition, [33][34][35][36][37] and that the total inhibition of PG production in the stomach causes very little gastric damage in rats. 38) Therefore it is now believed that the inhibition of COX by NSAIDs is not the sole explanation for the gastrointestinal side effects of NSAIDs, 39) and it is assumed that other mechanisms in addition to PG deficiency are involved in the gastric ulcerogenicity of NSAIDs.…”

Section: Discussionmentioning

confidence: 99%

Co-administration of Water Containing Magnesium Ion Prevents Loxoprofen-Induced Lesions in Gastric Mucosa of Adjuvant-Induced Arthritis Rat

Nagai

Takeda

Itanami

et al. 2012

Biological & Pharmaceutical Bulletin

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Non-steroidal anti-inflammatory drugs (NSAIDs) comprise one of the most frequently used classes of medicines in the world; however, NSAIDs have significant side effects, such as gastroenteropathy, and rheumatoid arthritis patients taking NSAIDs are more susceptible to NSAID-induced gastric lesions as compared to patients with other diseases. In Asian countries, loxoprofen has been used clinically for many years as a standard NSAID. We demonstrate the preventive effect of the co-administration of water containing magnesium ion (magnesium water, 1-200 µg/kg) on the ulcerogenic response to loxoprofen in adjuvant-induced arthritis (AA) rats. Oral administration of loxoprofen (100 mg/kg) caused hemorrhagic lesions in the gastric mucosa of AA rats 14 d after adjuvant injection, and, following loxoprofen administration, the lesion score of AA rats was significantly higher than that of normal rats. The expression of inducible nitric oxide synthase (iNOS) mRNA and nitric oxide (NO) production in the gastric mucosa of AA rats were also increased by the administration of loxoprofen, and the increase in lesions and NO were prevented by the administration of aminoguanidine, an iNOS inhibitor. The co-administration of magnesium water decreased the ulcerogenic response to loxoprofen in AA rats. In addition, the co-administration of magnesium water attenuated the increase in iNOS mRNA expression and NO production in AA rats receiving loxoprofen. These results suggest that the oral co-administration of magnesium water to AA rats has a potent preventive effect on the ulcerogenic response to loxoprofen, probably by inhibiting the rise in iNOS and NO levels in the gastric mucosa.

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“…To test this hypothesis, we compared the gastrointestinal toxicity of indomethacin and 1 in C57BL6 mice. COX inhibition is believed to be a component of this undesired side effect of NSAIDs, but other possible mechanisms, including injury due to direct physical contact with the lining of the stomach, have been suggested (25). Thus, controversy surrounds the role of COX inhibition in the gastrointestinal toxicity of NSAIDs in general and indomethacin in particular.…”

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confidence: 99%

Desmethyl Derivatives of Indomethacin and Sulindac as Probes for Cyclooxygenase-Dependent Biology

Felts¹,

Ji²,

Stafford³

et al. 2007

ACS Chem. Biol.

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Cyclooxygenases (COX) have been implicated in the etiology of a number of diseases, but defining the precise contribution of COXs to these diseases is challenging. Potent COX inhibitors exist, but they display off-target effects. 2′-Desmethyl derivatives of indomethacin and sulindac sulfide were synthesized that demonstrated reduced COX inhibitory activity but were inducers of peroxisome proliferator-activated receptor γ-dependent transcription, adipocyte differentiation, or apoptosis of colon cancer cell lines. 2′-Desmethylindomethacin demonstrated gastrointestinal toxicity lower than that of indomethacin in C57BL6 mice, highlighting the importance of COX activity in maintaining gastrointestinal homeostasis and establishing that COX inhibition contributes to gastrointestinal toxicity by nonsteroidal antiinflammatory drugs. These compounds serve as useful probes of COX-dependent biology and may represent leads for antidiabetic and anticancer drugs.

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Heme Oxygenase-1 Protects Gastric Mucosal Cells against Non-steroidal Anti-inflammatory Drugs

Cited by 83 publications

References 70 publications

Polaprezinc (Zinc L-Carnosine) Is a Potent Inducer of Anti-oxidative Stress Enzyme, Heme Oxygenase (HO)-1 — a New Mechanism of Gastric Mucosal Protection

Polaprezinc (Zinc L-Carnosine) Is a Potent Inducer of Anti-oxidative Stress Enzyme, Heme Oxygenase (HO)-1 — a New Mechanism of Gastric Mucosal Protection

Co-administration of Water Containing Magnesium Ion Prevents Loxoprofen-Induced Lesions in Gastric Mucosa of Adjuvant-Induced Arthritis Rat

Desmethyl Derivatives of Indomethacin and Sulindac as Probes for Cyclooxygenase-Dependent Biology

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