Altered membrane lipid dynamics and chemoprevention by non-steroidal anti inflammatory drugs during colon carcinogenesis.

The present work focuses on the anti-neoplastic role of non steroidal anti-inflammatory drugs (NSAIDs) in modulating the biophysical parameters of the colonic membranes in 1,2-dimethylhydrazine dihydrochloride (DMH) induced carcinogenesis. The steady-state fluorescence polarization technique was applied to assess membrane fluidity, membrane polarity and lipid phase states. The decline in cholesterol content, biosynthesis and cholesterol: phospholipids ratio with DMH treatment indicates more fluidity associated with carcinogenesis. The DMH group had shown lower order parameter indicating more fluidity whereas NSAIDs resulted in increasing the membrane lipid order. The converging effects of these changes were more in membrane phase separations and membrane phase state. In DMH treatment membrane shows lesser phase separation or high polarity, and more liquid crystalline state while for NSAID groups membranes have higher phase separations or low polarity, and more of the gel phase. Further, NSAIDs induced anti-proliferative effects were evidently observed by apoptosis in the colonocytes by using acridine orange-ethidium bromide fluorescent staining and Terminal de-oxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The results suggest that NSAIDs induced alteration in the membrane biophysical parameters may be an important initiating event for the chemopreventive action.

Evaluation of chemopreventive response of two cycloxygenase-2 inhibitors, etoricoxib and diclofenac in rat colon cancer using FTIR and NMR spectroscopic techniques.

Non steroidal anti inflammatory drugs (NSAIDs) are efficacious in chemoprevention of colorectal cancer. Therefore, the potential ability of Etoricoxib, a selective cycloxygenase-2(COX-2) inhibitor and Diclofenac, a preferential COX-2 inhibitor are considered in the chemoprevention of 1, 2-dimethylhydrazine (DMH) induced colon carcinogenesis in rat model. DMH was injected s.c. for six weeks while Etoricoxib and Diclofenac were fed daily orally alone and also in combination with an weekly subcutaneous injection of 1,2-dimethylhydrazine dihydrochloride (DMH) to the rats. After the treatment period of 6 weeks the animals were sacrificed by an overdose of ether anesthesia and the colonic tissues were removed and studied by the FTIR and NMR Spectroscopic techniques to evaluate the changes occurring in the lipid bilayer of colonic membrane lipids. The alterations in wave number of FTIR spectra as well as the chemical shifts of NMR spectra were recorded which signify the modulation of membrane lipids during colon carcinogenesis and possible cancer prevention by the oral administration of NSAIDs in an experimental model of chemical induced colon carcinogenesis.

Evaluation of chemopreventive response of two cycloxygenase-2 inhibitors, etoricoxib and diclofenac in rat colon cancer using FTIR and NMR spectroscopic techniques / Evaluación de la respuesta quimiopreventiva de dos inhibidores de la ciclooxigenasa 2, etoricoxib y diclofenaco en el cáncer de colon murino empleando las técnicas espectroscópicas FTIR Y NMR

Non steroidal anti inflammatory drugs (NSAIDs) are efficacious in chemoprevention of colorectal cancer. Therefore, the potential ability of Etoricoxib, a selective cycloxygenase-2(COX-2) inhibitor and Diclofenac, a preferential COX-2 inhibitor are considered in the chemoprevention of 1, 2-dimethylhydrazine (DMH) induced colon carcinogenesis in rat model. DMH was injected s.c. for six weeks while Etoricoxib and Diclofenac were fed daily orally alone and also in combination with an weekly subcutaneous injection of 1,2-dimethylhydrazine dihydrochloride (DMH) to the rats. After the treatment period of 6 weeks the animals were sacrificed by an overdose of ether anesthesia and the colonic tissues were removed and studied by the FTIR and NMR Spectroscopic techniques to evaluate the changes occurring in the lipid bilayer of colonic membrane lipids. The alterations in wave number of FTIR spectra as well as the chemical shifts of NMR spectra were recorded which signify the modulation of membrane lipids during colon carcinogenesis and possible cancer prevention by the oral administration of NSAIDs in an experimental model of chemical induced colon carcinogenesis (AU)

Los fármacos antiinflamatorios no esteroideos (AINE) son eficaces en la prevención del cáncer colorrectal. Por lo tanto, la capacidad potencial de Etoricoxib, un inhibidor selectivo de la ciclooxigenasa-2(COX-2), y de Diclofenaco, un inhibidor preferencial de la COX-2, se considera en la quimioprevención de la carcinogénesis de colon inducida por 1, 2-dimetilhidracina (DMH) en el modelo murino. Se inyectó s.c. DMH durante 6 semanas a la vez que se administraban diariamente por vía oral Etoricoxib y Diclofenaco solos y en combinación con una inyección s.c. semanal de dihidrocloruro de 1,2-dimetilhidracina (DMH) a las ratas. Después del período de tratamiento de 6 semanas, se sacrificó a los animales mediante una sobredosis de anestesia con éter y se extirpó el tejido colónico para estudio con las técnicas espectroscópicas FTIR y NMR para evaluar los cambios que ocurrieron en la bicapa lipídica de las membranas lipídicas colónicas. Se registraron las alteraciones en el número de onda del espectro FTIR así como las desviaciones químicas del espectro NMR, lo que significa la modulación de los lípidos de membrana durante la carcinogénesis colónica y la posible prevención del cáncer mediante la administración de AINE por vía oral en un modelo experimental de carcinogénesis colónica inducida por un agente químico (AU)

The effect of prostaglandin synthase inhibitor, aspirin on the rat intestinal membrane structure and function.

Aspirin at a dose of 50 mg/kg body weight was found to decrease the activity of the rat intestinal brush border membrane (BBM) - associated enzymes such as the sucrase, lactase, maltase and alkaline phosphatase. Aspirin treatment also led to a decrease in the microviscosity in the native as well as the benzyl alcohol treated membrane which might be due to the lipid peroxidative damage in the membrane. Physical correlation of the membrane oxidative damage was evident as the Fourier Transformation Infra Red (FTIR) study of the Aspirin treated membrane, which include an increased proportion of gauche to trans conformer, shift in the methylene C-H asymmetric and symmetric stretching frequencies, C = O double bond stretching, NH bending, antisymmetric (N)-CH3 bending, C-N stretching and antisymmetric CNC stretching while there was no change in the CH2 wagging and twisting as well as in NH-bending amide bond I and II. Aspirin treatment also caused an alteration in the glucose and histidine transport, as evident by a decreased Vmax value while the apparent Km remaining unchanged in the control and Aspirin-treated animals confirming that there was no change in the substrate affinity constant of the membrane transport proteins for the glucose and the basic amino acid, although the rate of transport decreased considerably. There was a decrease noted in the energy of activation of glucose and histidine transport when studied at different temperature but no change in the temperature of phase transition in the BBM with Aspirin treatment, thus implying that perhaps the thermotropic phase transition in the membrane may have relatively little effect on the transport processes. The result suggests an underlying molecular mechanism indicating the implied membrane damage by Aspirin, an important member of the non-steroidal antiinflammatory drug (NSAID) family which could possibly through an oxidative damage may lead to an altered molecular structure, physical state and biological functions of the intestinal membrane.

The effect of prostaglandin synthase inhibitor, aspirin on the rat intestinal membrane structure and function / El efecto del inhibidor de la sintasa de prostaglandina, aspirina, sobre la estructura y función de la membrana intestinal de la rata

Aspirin at a dose of 50 mg/kg body weight was found to decrease the activity of the rat intestinal brush border membrane (BBM) - associated enzymes such as the sucrase, lactase, maltase and alkaline phosphatase. Aspirin treatment also led to a decrease in the microviscosity in the native as well as the benzyl alcohol treated membrane which might be due to the lipid peroxidative damage in the membrane. Physical correlation of the membrane oxidative damage was evident as the Fourier Transformation Infra Red (FTIR) study of the Aspirin treated membrane, which include an increased proportion of gauche to trans conformer, shift in the methylene C-H asymmetric and symmetric stretching frequencies, C = O double bond stretching, NH bending, antisymmetric (N)-CH3 bending, C-N stretching and antisymmetric CNC stretching while there was no change in the CH2 wagging and twisting as well as in NH-bending amide bond I and II. Aspirin treatment also caused an alteration in the glucose and histidine transport, as evident by a decreased Vmax value while the apparent Km remaining unchanged in the control and Aspirin-treated animals confirming that there was no change in the substrate affinity constant of the membrane transport proteins for the glucose and the basic amino acid, although the rate of transport decreased considerably. There was a decrease noted in the energy of activation of glucose and histidine transport when studied at different temperature but no change in the temperature of phase transition in the BBM with Aspirin treatment, thus implying that perhaps the thermotropic phase transition in the membrane may have relatively little effect on the transport processes. The result suggests an underlying molecular mechanism indicating the implied membrane damage by Aspirin, an important member of the non-steroidal antiinflammatory drug (NSAID) family which could possibly through an oxidative damage may lead to an altered molecular structure, physical state and biological functions of the intestinal membrane (AU)

Se encontró que la aspirina a una dosis de 50 mg/kg de peso corporal disminuye la actividad de las enzimas asociadas a la membrana con borde en cepillo (MBC) del intestino de la rata como la sucrasa, lactasa, maltasa y fosfata alcalina. El tratamiento con aspirina también produjo una disminución de la microviscosidad en la membrana nativa así como en la membrana tratada con alcohol bencílico, lo que podría deberse a la lesión de peroxidación lipídica de la membrana. La correlación física de la lesión oxidativa de la membrana fue evidente como mostró el estudio Fourier Transformation Infra Red (FTIR) de la membrana tratada con aspirina, que incluía un aumento en la proporción de la conformación levo a trans, un cambio en las frecuencias de estiramiento metileno C-H asimétrico y simétrico, el estiramiento de los dobles enlaces C = O, la curvatura NH, la curvatura anti-simétrica (N)-CH3, el estiramiento C-N y el estiramiento anti-simétrico CNC, mientras que no hubo cambios en el movimiento y retorcimiento CH2 ni en la curvatura NH del enlace amida I y II. El tratamiento con aspirina también produjo una alteración en el transporte de glucosa e histidina, como se evidenció por una disminución del valor de la Vmax mientras que la Km aparente permaneció inalterada en los animales control y tratados con aspirina, lo que confirma que no hubo cambios en la constante de afinidad por el sustrato de las proteínas transportadoras de membrana para la glucosa y el aminoácido básico, si bien la tasa de transporte disminuyó considerablemente. Se apreció un descenso en la energía de activación del transporte de glucosa e histidina cuando se estudiaron a temperaturas distintas, pero no hubo cambios en la temperatura de la fase de transición de la MBC con el tratamiento con aspirina, lo que implica que quizás la fase de transición termotrópica en la membrana pudiera tener un efecto relativamente pequeño sobre los procesos de transporte. El resultado sugiere un mecanismo molecular subyacente lo que indica el daño implícito de la membrana por la aspirina, un miembro importante de la familia de fármacos antiinflamatorios no esteroideos (AINE), que posiblemente a través de un daño oxidativo podría producir una alteración de la estructura molecular, del estado físico y de las funcionesbiológicas de la membrana intestinal (AU)

Chemopreventive response of diclofenac, a non-steroidal anti-inflammatory drug in experimental carcinogenesis / Respuesta quimiopreventiva del diclofenaco, un fármaco antiinflamatorio no esteroideo en la carcinogénesis de colon experimental

The chemopreventive response was evaluated of nonsteroidal anti-inflammatory drug, Diclofenac, a preferential cyclooxygenase-2 (COX-2) inhibitor in 1,2-dimethyhydrazine (DMH)-induced colon cancer in rat model. The signs of neoplasm were evident in the animals receiving 30mg of DMH per kg body weight in a weekly s.c injection for six weeks. The putative biomarker of carcinogenesis was visible in the form of multiple plaque lesions in DMH treatment and then regression seen in those animals which also received an oral dose of Diclofenac, 8 mg/kg body weight whereas no such macroscopic neoplastic lesions were seen in the animals receiving Diclofenac only or the control animals receiving the vehicle of the drug. Histopathological results showed the presence of early aberrant changes in the form of severe dysplasia and also numerous crypt fissions in the apical surface of the colonic mucosa. A very high expression of COX-2 was seen in the colonic epithelium of DMH-treated rats, as analyzed by immunohistochemistry. Also, the apoptotic events were assessed by terminal deoxynucleotidyl dUTP nick end labeling (TUNEL) assay, where the DMH group shows few number of TUNEL positive cells which dramatically increased in the Diclofenac treatment. The results suggest that Diclofenac could be an effective chemopreventive agent in colon cancer, where perhaps apoptosis plays a very dominant end effect in cancer cell killings (AU)

Se evaluó la respuesta quimiopreventiva del fármaco antiinflamatorio no esteroideo, diclofenaco, un inhibidor preferente de la ciclooxigenasa-2 (Cox-2), en el cáncer de colon inducido por 1,2-dimetilhidracina (DMH) en un modelo de rata. Los signos de neoplasia fueron evidentes en los animales que recibieron 30 mg de DMH por kg de peso corporal mediante inyecciones s.c. semanales durante 6 semanas. El biomarcador putativo de la carcinogénesis fue visible en la forma de múltiples lesiones en placas con el tratamiento de DMH y la posterior regresión apreciada en los animales que también recibieron una dosis oral de diclofenaco, 8 mg/kg de peso corporal, mientras que no se vieron tales lesiones neoplásicas macroscópicas en los animales que recibieron solamente el diclofenaco o en los animales control que recibieron el vehículo del fármaco. Los resultados histopatológicos mostraron la presencia de cambios aberrantes precoces en la forma de una displasia intensa y también numerosas fisiones de las criptas en la superficie apical de la mucosa colónica. Se vio una expresión muy elevada de Cox-2 en el epitelio colónico de las ratas tratadas con DMH, al analizarlo por inmunohistoquímica. También se evaluaron los eventos apoptóticos mediante el ensayo terminal deoxynucleotidyl dutp nick end labeling (TUNEL), en el que el grupo DMH mostró un pequeño número de células TUNEL positivas, que se incrementó notablemente en el grupo de tratamiento con diclofenaco. Estos resultados sugieren que podría existir un agente quimiopreventivo eficaz para el cáncer de colon en el que, quizás, la apoptosis desempeñe un efecto terminal muy dominante en la muerte de las células cancerosas (AU)

Chemopreventive response of diclofenac, a non-steroidal anti-inflammatory drug in experimental carcinogenesis.

The chemopreventive response was evaluated of nonsteroidal anti-inflammatory drug, Diclofenac, a preferential cyclooxygenase-2 (COX-2) inhibitor in 1,2-dimethyhydrazine (DMH)-induced colon cancer in rat model. The signs of neoplasm were evident in the animals receiving 30mg of DMH per kg body weight in a weekly s.c injection for six weeks. The putative biomarker of carcinogenesis was visible in the form of multiple plaque lesions in DMH treatment and then regression seen in those animals which also received an oral dose of Diclofenac, 8 mg/kg body weight whereas no such macroscopic neoplastic lesions were seen in the animals receiving Diclofenac only or the control animals receiving the vehicle of the drug. Histopathological results showed the presence of early aberrant changes in the form of severe dysplasia and also numerous crypt fissions in the apical surface of the colonic mucosa. A very high expression of COX-2 was seen in the colonic epithelium of DMH-treated rats, as analyzed by immunohistochemistry. Also, the apoptotic events were assessed by terminal deoxynucleotidyl dUTP nick end labeling (TUNEL) assay, where the DMH group shows few number of TUNEL positive cells which dramatically increased in the Diclofenac treatment. The results suggest that Diclofenac could be an effective chemopreventive agent in colon cancer, where perhaps apoptosis plays a very dominant end effect in cancer cell killings.

Effect of non-steroidal anti-inflammatory drugs and the pro-carcinogen 1, 2 dimethylhydrazine on the rat intestinal membrane structure and function / Efecto de los fármacos antiinflmatorios no esteroideos y del procarcinógeno 1,2-dimetilhidracina sobre la estructura y función de la membrana intestinal de la rata

The present study was designed to evaluate the effects of three non-steroidal anti-inflammatory drugs (NSAIDs) with varying cycloxygenase selectivities on the small intestinal biochemical composition, function and histology during 1, 2-dimethylhydrazine (DMH) administration. Sprague Dawley male rats were divided into five different groups viz: Group 1 (control, vehicle treated), Group 2 (DMH-treated, 30 mg/kg body weight/week in 1 mM EDTA-saline, subcutaneously), Group 3 (DMH + aspirin-60 mg/kg body weight), Group 4 (DMH + celecoxib-6 mg/kg body weight), Group 5 (DMH + etoricoxib-0.64 mg/kg body weight). After six weeks of treatment, brush border membrane was isolated from the jejunum segment of all the groups and changes in the associated enzymes such as sucrase, lactase, maltase, alkaline phosphatase, membrane lipid composition, fluorescence polarizations of diphenylhexatriene, pyrene excimer formation, histological changes and surface characteristics were studied. The results indicated a significant alteration in the enzyme activity as well as changes in the structure and function of the intestine in the presence of the pro-carcinogen, DMH, which suggests the possible chemopreventive efficacy of NSAIDs against the intestinal cancer (AU)

El presente estudio se diseñó para evaluar los efectos de tres fármacos antiinflamatorios no esteroideos (AINE) con diferente selectividad por la ciclooxigenasa sobre la composición bioquímica, la función y la histología del intestino delgado durante la administración de 1,2-dimetilhidracina (DMH). Se distribuyó a ratas macho Sprague Dawley en grupos distintos: Grupo 1 (control, tratado con vehículo), Grupo 2 (tratado con DMH, 30 mg/kg de peso /semana en 1 mM de EDTA-salino, subcutáneo), Grupo 3 (DMH + aspirina-60 mg/kg de peso), Grupo 4 (DMH + celecoxib-6 mg/kg de peso), Grupo 5 (DMH + etoricoxib-0,64 mg/kg de peso). Tras seis semanas de tratamiento, se aisló la membrana en cepillo de un segmento del yeyuno en todos los grupos y se estudiaron los cambios en las enzimas asociadas tales como sucrasa, lactasa, maltasa, fosfatasa alcalina, en la composición lipídica de la membrana, las polarizaciones de fluorescencia del difenilhexatrieno, la formación del excímero pireno, los cambios histológicos y las características de la superficie. Los resultados indican una alteración significativa de la actividad enzimática así como cambios en la estructura y función del intestino en presencia del procarcinógeno DMH, lo que sugiere la posible eficacia quimio-preventiva de los AINE frente al cáncer de intestino (AU)

Intestinal toxicity of non-steroideal anti-inflammatory drugs with differential cyclooxigenase inhibition selectivity / Toxicidad intestinal de los fármacos antiinflamatorios no esteroideos con una selectividad diferenciada en la inhibición de la ciclooxigenasa

The present study was designed to investigate the gastrointestinal side effects of cycloxygenase (COX) inhibitor with varying selectivity, called the non-steroidal antiinflammatory drugs (NSAIDs) viz., non-selective COX-1 & 2 inhibitor —aspirin, prefentially selective COX-2 inhibitor— nimesulide and highly selective COX-2 inhibitor- celecoxib. Treatment with NSAIDs exhibited a decrease in the activity of rat intestinal brush border membrane associated enzymes such as sucrase, lactase, maltase and alkaline phosphatase as compared to the control in the duodenum, jejunum and ileum. The uptake of D-glucose and L-histidine in the everted intestinal sac was found to be decreased. Also the decease of glucose and histidine uptake was found to be dependent on the substrate concentration, temperature and the time interval of incubation. The physical state and composition of brush border membrane was found to be altered as evident in the FTIR spectrum, by appearance of new peaks while disappearance of certain peaks occurred which were characteristics of the control membrane. The changes in wave number as well as peaks height were also noticed. Alterations in protein profile of the membrane were demonstrated using SDS-PAGE analysis where disappearance of few bands and change in the relative intensities of the bands were noticed and correlated with the alterations that have taken place at the molecular level. Histological studies have depicted a marked decrease in the absorption surface area such as the villi height of the intestinal segment. In addition, crypt number also deceased in the treated animals, an indication that such changes also correlate well with the changes in the transport of the end product nutrients

Se diseñó este estudio para investigar los efectos adversos gastrointestinales de los inhibidores de la ciclooxigenasa (COX) con selectividad variable, denominados fármacos antiinflamatorios no esteroideos (AINE), inhibidores no selectivos de la COX-1 y la COX-2 —aspirina, los inhibidores predominantemente selectivos de la COX-2— nimesulida, y los inhibidores muy selectivos de la COX-2 —celecoxib. El tratamiento con AINE mostró un descenso de la actividad de las enzimas asociadas a la membrana en cepillo intestinal de la rata, tales como sucrasa, lactasa, maltasa y fosfatasa alcalina, en comparación con el control, en el duodeno, yeyuno e íleon. Se halló que la captación de D-glucosa y L-histidina en el saco intestinal revertido estaba disminuida. También se encontró que la captación de glucosa e histidina dependía de la concentración de sustrato, la temperatura y el intervalo de tiempo de incubación. El estado físico y la composición de la membrana en borde en cepillo estaban alterados como se evidenció en el espectro FTIR, con aparición de nuevas picos y desaparición de ciertos picos característicos de la membrana control. También se apreciaron cambios en el número de ondas así como la altura de los picos. Se demostraron cambios en el perfil de proteínas de membrana mediante el análisis SDSPAGE, apreciándose desaparición de algunas pocas bandas y cambio en las intensidades relativas de las bandas, correlacionándose con las alteraciones que ocurrían a nivel molecular. Los estudios histológicos han mostrado un descenso marcado de la superficie de absorción, como por ejemplo la altura de las vellosidades del segmento intestinal. Además, el número de criptas también disminuyó en los animales tratados, un indicador de que tales cambios también se correlacionan bien con los cambios en el transporte de los nutrientes finales

Effects of non steroidal anti-inflammatory drugs on the antioxidant defense system and the membrane functions in the rat intestine / Efectos de los fármacos aniinflamatorios no esteroideos sobre el sistema de defensa antioxidante y las funciones de membrana en el intestino de rata

In the present study the effects of two cycloxygenase-2 (COX-2) selective inhibitors, celecoxib and nimesulide as compared to a non-selective COX inhibitor, aspirin was studied in the rat intestine. Female Wistar rats weighing between 150-175 g were divided into four groups having 8 animals each as follows: Group 1(Control), Group 2- Aspirin (40 mg/kg), Group 3- Nimesulide (10 mg/kg) and Group 4- Celecoxib (10 mg/kg). After 35 days of treatment the animals were sacrificed, intestine removed and the effects on the antioxidant defense system, membrane composition and functions along with the membrane specific enzymes were studied in different regions of the intestine. The study showed a significant increase in the lipid peroxide levels as TBA-reactive substance as well as the conjugated dienes, except for celecoxib treated group which showed a decrease. Significant decrease was also observed in the level of reduced glutathione (GSH), superoxide dismutase (SOD), glutathione-s-transferase and catalase activities for aspirin and nimesulide group while Celecoxib caused an increase in glutathione reductase (GR). Aspirin and nimesulide exhibited an increase in the brush border membrane (BBM) bound enzyme activities like sucrase, lactase, maltase and alkaline phosphatase in the small intestine while celecoxib showed decrease in lactase, maltase and alkaline phosphatase. The phospholipid content increased only for aspirin treated group while cholesterol decreased in all the treatment groups. Also celecoxib treatment brought about an increase in glycolipid content. The membrane fluidity was studied by the rotational diffusion of 1, 6, diphenyl, 1, 3, 5 hexatriene (DPH) incorporated in the membrane and the fluorescence polarization (p), fluorescence anisotropy(r), anisotropy parameter [r0/r -1]-1 and order parameter [S2 = (4/3r – 0.1)/ r0] were recorded. No significant change in the fluorescence parameters were observed in the BBM and the liposomes made from the BBM lipids for the treatment groups. These results indicate that celecoxib may be accepted as a safer drug in terms of overall gastro-intestinal toxicity as compared to the aspirin and nimesulide (AU)

En el presente estudio se comparaban los efectos de dos inhibidores selectivos de la ciclo-oxigenasa-2 (COX-2), celecoxib y nimesulide, con los de un inhibidor no selectivo de la COX, la aspirina, en el intestino de la rata. Se escogieron ratas Wistar hembra, con un peso de 150-175 g, y se las dividió en 4 grupos, con 8 animales cada uno, como sigue: Grupo 1 (Control), Grupo 2 – Aspirina (40 mg/kg), Grupo 3 – Nimesulide (10 mg/kg), y Grupo 4 – Celecoxib (10 mg/kg). Tras 35 días de tratamiento, se sacrificó a los animales, se extirpó el intestino, y se estudiaron los efectos sobre el sistema de defensa antioxidante, la composición de la membrana y sus funciones, además de las enzimas de membrana específicas, en diferentes regiones del intestino. El estudio mostró un aumento significativo de las concentraciones de peróxido lipídico como sustancia TBA reactiva así como de dienos conjugados, excepto para el grupo tratado con celecoxib que mostró un descenso. También se observó un descenso significativo en las actividades de glutatión reducido (GSH), de superóxido dismutasa (SOD), de glutatión-s-transferasa y de catalasa en los grupos tratados con aspirina y con nimesulide, mientras que el grupo tratado con celecoxib tuvo un aumento de la glutatión reductasa (GR). La aspirina y el nimesulide mostraron un aumento de las actividades de las enzimas ligadas a la membrana de borde en cepillo (BBM) como la sucrasa, lactasa, maltasa y fosfatasa alcalina. El contenido en fosfolípidos aumentó sólo en el grupo tratado con aspirina mientras que el colesterol disminuyó en todos los grupos de tratamiento. En el grupo de celecoxib también se objetivó un aumento en el contenido en glucolípidos. Se estudió la fluidez de la membrana mediante difusión rotacional del 1,6-difenil-1,3,5-hexatrieno (DPH) incorporado a la membrana y se registraron la polarización de fluorescencia (p), la anisotropía de fluorescencia (r), el parámetro de anisotropía [r0/r -1]-1 y el parámetro de orden [S2 =(4/3 r – 0,1)/ r0]. No se observaron cambios significativos en los parámetros de fluorescencia en la BBM ni de los liposomas formados a partir de los lípidos de la BBM en ninguno de los grupos tratados. Estos resultados indican que se puede considerar al celecoxib como un fármaco más seguro en cuanto a toxicidad gastrointestinal general en comparación con el nimesulide y la aspirina (AU)