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Indomethacin-induced mitochondrial dysfunction and oxidative stress in villus enterocytes
Jayasree Basivireddy1, Anju Vasudevan, Molly Jacob
1Department of Gastrointestinal Sciences, The Wellcome Trust Research Laboratory, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India.
Abstract:
Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to cause small intestinal damage but the pathogenesis of this toxicity is not well established. Intestinal epithelial cells are thought to be affected by these drugs in the course of their absorption. These cells are of different types, viz. villus, middle and crypt cells. There is little information on which of these cells, if any, are particularly vulnerable to the effects of NSAIDs. This paper aimed to study the effects of indomethacin, an NSAID commonly used in toxicity studies, on different populations of enterocytes. Effects of the drug were assessed in terms of oxidative damage, mitotic activity, mitochondrial function and lipid composition in enterocytes isolated from the small intestine of rats that had been orally administered indomethacin. In addition, the effects of arginine and zinc in protecting against such changes were assessed. Cell viability, tetrazolium dye (MTT) reduction and oxygen uptake were significantly reduced in villus tip cells from rats dosed with the drug. Thymidine uptake was higher in the crypt cell fraction from these rats. Similarly, products of lipid peroxidation were elevated in the villus tip cells with a corresponding decrease in the level of the anti-oxidant, alpha-tocopherol. In isolated mitochondrial preparations from various enterocyte fractions, significant functional impairment and altered lipid composition were seen mainly in mitochondria from villus cells. Arginine and zinc pre-treatment were found to protect against these effects. These results suggest for the first time that the villus tip cells are more vulnerable to the damaging effects of indomethacin and that oxidative stress is possibly involved in this damage.
Insights
Nonsteroidal anti-inflammatory drugs (NSAIDs) cause small intestinal damage. Villus tip cells are most vulnerable to NSAID toxicity, with oxidative stress potentially playing a key role in this damage.
Area of Science:
- Gastroenterology
- Toxicology
- Cell Biology
Background:
- Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to induce small intestinal damage.
- The precise mechanisms underlying NSAID-induced enteropathy remain incompletely understood.
- Specific intestinal epithelial cell populations vulnerable to NSAIDs have not been clearly identified.
Purpose of the Study:
- To investigate the differential effects of indomethacin, a common NSAID, on various enterocyte populations in the rat small intestine.
- To assess the roles of oxidative damage, mitochondrial function, and lipid composition in NSAID-induced enterocyte toxicity.
- To evaluate the protective potential of arginine and zinc against indomethacin-induced intestinal damage.
Main Methods:
- Oral administration of indomethacin to rats, followed by isolation of enterocytes from different small intestinal regions (villus tip, middle, crypt).
- Assessment of cell viability, mitochondrial function (MTT reduction, oxygen uptake), mitotic activity (thymidine uptake), oxidative damage (lipid peroxidation, alpha-tocopherol levels), and mitochondrial lipid composition.
- Evaluation of protective effects of arginine and zinc pre-treatment.
Main Results:
- Villus tip enterocytes exhibited significantly reduced cell viability, MTT reduction, and oxygen uptake following indomethacin administration.
- Increased thymidine uptake was observed in crypt cells, suggesting altered cell proliferation.
- Elevated lipid peroxidation products and decreased alpha-tocopherol levels were prominent in villus tip cells, indicating oxidative stress.
- Mitochondria isolated from villus cells showed impaired function and altered lipid composition.
- Arginine and zinc pre-treatment demonstrated protective effects against these indomethacin-induced changes.
Conclusions:
- Villus tip enterocytes are particularly susceptible to the toxic effects of indomethacin.
- Oxidative stress is implicated as a significant factor in NSAID-induced damage to intestinal villus cells.
- Arginine and zinc may offer protective benefits against NSAID enteropathy.