Protective Effect Of Cimetidine Research Articles

Identification of Novel and Early Biomarkers for Cisplatin-induced Nephrotoxicity and the Nephroprotective Role of Cimetidine using a Pharmacometabolomic-based Approach Coupled with In Vitro Toxicodynamic Modeling and Simulation

Cisplatin is widely used for the treatment of various types of cancer. However, cisplatin-induced nephrotoxicity (CIN) is frequently observed in patients receiving cisplatin therapy which poses a challenge in its clinical utility. Currently used clinical biomarkers for CIN are not adequate for early detection of nephrotoxicity, hence there is a need to identify potential early biomarkers in predicting CIN. In the current study, a combination of in vitro toxicodynamic (TD) modeling and untargeted global metabolomics approach was used to identify novel potential metabolite biomarkers for early detection of CIN. In addition, we investigated the protective role of cimetidine (CIM), an inhibitor of the organic cation transporter 2 (OCT2), in suppressing CIN. We first characterized the time-course of nephrotoxic effects of cisplatin (CIS) and the protective effects of CIM in a human pseudo-immortalized renal proximal tubule epithelial cell line (RPTEC), SA7K cell line. Secondly, we used a mathematical cell-level, in vitro TD modeling approach to quantitatively characterize the time-course effects of CIS and CIM as single agents and combination in SA7K cells. Based on the experimental and modeling results, we selected relevant concentrations of CIS and CIM for our metabolomics study. With the help of PCA (Principal Component Analysis) and PLS-DA (Projection to Latent Structure – Discriminate Analysis) analyses, we confirmed global metabolome changes for different groups (CIS, CIM, CIS+CIM vs control) in SA7K cells. Based on the criterion of a p-value ≤ 0.05 and a fold change ≥ 2 or ≤ 0.5, we identified 20 top metabolites that were significantly changed during the early phase i.e. within first 12 h of CIS treatment. Finally, pathway analysis was conducted that revealed the key metabolic pathways that were most impacted in CIN.

Protective effect of cimetidine in carbon tetrachloride-treated rats.

Cimetidine may have hepatoprotective effects. We looked for the impact of cimetidine on the hepatic changes induced by carbon tetrachloride. Male Wistar-Bratislava albino rats were randomized into four groups. Group I, control (C) received physiologic saline solution (PSS) for 3 days. Group II (CT) received PSS but the last administration being followed by a carbon tetrachloride (CT) subcutaneous (sc) injection. Group III (CT+CM) received Cimetidine (CM); at the last dose of CM there was an injection of CT as for group II. Group IV was treated only with CM. The rats were weighted at the beginning of the treatment and at the moment of the euthanasia. Blood sampled were collected. The organs were removed and weighted. A sample of left lobe of the liver was taken for histological analysis. We have analysed morphometric characteristics of the organs, histological and biochemical changes. The acute hepatotoxicity effect of CCl4 in rats after a single dose was demonstrated after 24 hours. CCl4 (group II) increases the relative weight of the liver and histologically induces fatty dystrophy and extended centrilobular necrosis. The increase of ASAT and ALAT were massive. The preventive administered cimetidine, associated with CCl4 (group III) has partially hepatic protection. The fatty infiltration is not present and the focal centrilobular necrosis is less extended. The effect of hepatic cytolysis enzymes is remarkable. Acute administering at rats, CCL4 has a characteristic hepatotoxicity spectrum, induces fatty dystrophy, hepatic centrilobular necrosis and massive increases of transaminases. Cimetidine in subacute treatment, preventive, for 3 days has protective action relative to CCl4.

Protective Effect of Cimetidine on Tannic Acid-induced Gastric Damage in Rats

The effect of cimetidine on the acidified tannic acid-induced back diffusion of gastric acid and mucosal damage was investigated in the vagotomized rat. After intragastric irrigation for 1 to 3 h, tannic acid (20-500 mg kg-1) produced a dose-related increase in gastric volume and the loss of luminal H+. The change of mucosal permeability to the electrolyte, either the loss of H+ or the gain of Na+, K+, and Ca2+, induced by tannic acid was significantly diminished by the combination with intragastric cimetidine. However, intravenous injection of cimetidine did not protect this damage and back diffusion of acid neutralized intragastric cimetidine did not reduce the back diffusion of acid and Na+, K+, and Ca2+ output provoked by acid solution. Thus, the neutralizing action of cimetidine seems responsible.

Histological and Ultrastructural Study of the Stomach Mucosa of Adult Male Albino Rats after Horizontal Gastroplasty and Cimetidine Administration

Background: The severity of mucosal damage after horizontal gastroplasty is closely related to the high PH of the pouch. Cimetidine proved to promote healing of acute gastric erosions. Aim of the Work: This research was carried out to investigate the effect of horizontal gastroplasty on the stomach mucosa and protective effect of cimetidine. Materials and Methods: A total of 15 male adult rats were divided into three equal groups. The first one considered as control. The second group was exposed to horizontal gastroplasty. The third group was exposed to horizontal gastroplasty with immediate injection of Cimetidine in a dose of 200 mg/kg/ daily for one month. The rats were sacrificed after the last dose of the drug and the stomach was removed and different sections were prepared for light and electron microscopic investigation. Results: Examination of the gastric mucosa in the control group revealed the traditional mucosal architecture. In the second group using L/M examination, the different types of cells of gastric glands were distorted with condensation of their nuclei and disruption of the epithelium of gastric glands. There was a focal area of inflammation with marked increase of inflammatory cells and areas of congestion. The lumens of gastric glands were markedly dilated and the connective tissue between the glands was increased. By E/M examination, some nuclei appeared small and condensed .The cell membrane surrounded the cells disappeared, the Golgi apparatus was dilated, the mitochondria were swelled with distortion of their cristae and the rER were distended with shedding of their ribosomes. The microvilli disappeared and secretory granules were scanty with small clear and irregular vacuoles. In the third group, L/M and E/M examinations revealed that most affections appeared in the second group have vanished.

Effects of Cytochrome P450 Inhibition by Cimetidine on the Warm Hepatic Ischemia-Reperfusion Injury in Rats

Cimetidine is an H(2)-antagonist with cytochrome P450 (P450) inhibitory activity. Recent studies showed that cimetidine improves warm ischemia-reperfusion (IR) injury in isolated rat heart and rabbit lung and in primary cultures of rat proximal tubule epithelial cells by inhibiting P450-mediated reactive oxygen species generation. Here, we studied the effects of cimetidine on the warm IR injury in the liver. Three groups of rats were treated with a single i.p. dose (0.6 mmol/kg) of cimetidine or ranitidine (an H(2) antagonist without a significant P450 inhibitory activity) or with saline 1.5 h before surgery. Livers were then subjected to 1 h of in vivo ischemia, followed by 1 h of ex vivo reperfusion using a physiologic buffer in a recirculating manner. A fourth group of animals, receiving saline pretreatment underwent sham operation instead of ischemia. Perfusate and bile samples were collected during the reperfusion, and the liver tissue was collected at the end of reperfusion period for measurement of various biochemical markers. Warm IR resulted in a significant increase in the perfusate concentrations of liver enzymes (3- to 4.5-fold) and hepatic concentrations of lipid hydroperoxides (2-fold). Whereas the glutathione concentrations in the liver tissue were not affected by IR injury, the injury caused a significant decrease ( approximately 40%) in the biliary glutathione excretion. Cimetidine treatment completely or partially reversed all the IR-mediated changes, while ranitidine was ineffective. The protective effects of cimetidine were associated with a 60% decline in the microsomal CYP2C11 activity. Whereas cimetidine, an H(2) blocker with substantial P450 inhibitory activity, is protective in warm IR injury, ranitidine, a similar drug with no significant P450 inhibitory activity, is devoid of any protective effects. Therefore, P450 inhibition appears to be the underlying mechanism in the protective effects of cimetidine in this model of IR injury.

Protective Effects of Cimetidine on Radiation-induced Micronuclei and Apoptosis in Human Peripheral Blood Lymphocytes

The radioprotective effects of cimetidine, which has been used clinically as an antagonist of H 2 receptor, on radiation-induced micronuclei and apoptosis in human peripheral blood lymphocytes (PBL) prepared from healthy donors were studied. Cells were treated with cimetidine before or after X-irradiation, and then cytokinesis-blocked micronucleus assay and flow cytometry for measurement of phosphatidylserine externalization were utilized to evaluate the radiation-induced cytogenetic damage and apoptosis. The protective effect of pre-irradiation treatment of cimetidine on radiation-induced micronuclei was dependent on the concentration. The maximum protection rates of cimetidine (1 mM) on frequencies of micronuclei were 38.8 and 30.2% for cells treated before and after X-irradiation (5 Gy), respectively. Protective effects of pre- and post-irradiation treatment with cimetidine on radiation-induced early apoptosis and decreased activity of caspase-3 were observed. A study of electron paramagnetic resonance-spin trapping with 5,5'-dimethyl-1- N -oxide revealed that the rate constant of cimetidine with radiation-induced OH radicals is about 4.5 2 10 9 l/mol/s. Cimetidine did not significantly increase the intracellular concentration of glutathione. These results suggest that cimetidine suppresses radiation-induced micronuclei and apoptosis via OH radical scavenging and an intracellular antioxidation mechanism. Cimetidine appears to be a useful candidate for the future development of post-irradiation radioprotectors.

Role of cytochrome P-450 in hydrogen peroxide-induced cytotoxicity to LLC-PK1 cells

The current study was designed to test the role of cytochrome P-450 in hydrogen peroxide-induced cytotoxicity, and to determine whether it may serve as a source of catalytic iron. Hydrogen peroxide led to iron release (as measured by iron/bathophenanthroline complex) from the microsomes prepared from LLC-PK1 cells. Cimetidine, which inhibits cytochrome P-450 by interacting with the heme iron, significantly blocked iron release, whereas ranitidine, which has a similar structure as cimetidine but is a weak inhibitor of P-450, did not have an effect (H2O2, 0.42 +/- 0.04; H2O2 + cimetidine, 0.23 +/- 0.02 nmol/mg protein; N = 4, P < 0.01). Exposure of LLC-PK1 cells to hydrogen peroxide (2.5 mM) resulted in a significant increase in the bleomycin-detectable iron (iron capable of catalyzing free radical reactions) content that was prevented by cimetidine, but not ranitidine. We then examined the effect of the inhibitors of cytochrome P-450 on cell death (as measured by Trypan blue exclusion) after exposure of LLC-PK1 cells to 2.5 mM hydrogen peroxide for 120 minutes. Inhibition of cytochrome P-450 by cimetidine significantly reduced the cell death; the effect was observed with 0.05 mM and was concentration dependent with 1 mM affording almost complete protection (H2O2, 59 +/- 1.3% vs. H2O2 + cimetidine, 11 +/- 0.7%; N = 5, P < 0.01). In contrast, ranitidine did not show any protection. We confirmed that the protective effect of cimetidine was not related to scavenging hydrogen peroxide or hydroxyl radicals or chelating iron. A second inhibitor of cytochrome P-450, piperonyl butoxide, had a similar dose-dependent beneficial effect against hydrogen peroxide-induced cell injury. Our data thus indicate an important role of cytochrome P-450 in hydrogen peroxide-induced cytotoxicity to LLC-PK1 cells and suggest that cytochrome P-450 may serve as a source of catalytic iron.

ROLE OF CYTOCHROME P-450 IN HYDROGEN PEROXIDE-INDUCED CYTOTOXICITY IN LLC-PK1 CELLS. † 2131

The current study was designed to test the role of cytochrome P-450 in hydrogen peroxide-induced cytotoxicity to LLC-PK1 cells, and to determine whether it may serve as a source of catalytic iron. Hydrogen peroxide led to iron release as measured by Fe2+-(BPS)3 from the microsomes prepared from LLC-PK1 cells. Cimetidine, which inhibits cytochrome P-450 by interacting with the heme iron, significantly blocked iron release, whereas ranitidine which has a similar structure as cimetidine but is a weak inhibitor of P-450, did not have an effect (H2O2: 0.42± 0.04, H2O2 + cimetidine: 0.23 ± 0.02 nmol/mg protein, n=4, p < 0.01). Exposure of LLC-PK1 cells to hydrogen peroxide (2.5 mM) resulted in a significant increase in the bleomycin-detectable iron (iron capable of catalyzing free radical reactions) content which was prevented by cimetidine, but not ranitidine. We then examined the effect of the inhibitors of cytochrome P-450 on cell death (as measured by trypan blue exclusion) after exposure of LLC-PK1 cells to 2.5 mM hydrogen peroxide for 120 min. Inhibition of cytochrome P-450 by cimetidine significantly reduced the cell death. The effect was observed with 0.05 mM and was concentration dependent with 1 mM affording almost complete protection (H2O2: 58.5 ± 1.3 vs H2O2 + cimetidine: 10.9 ± 0.7, n=5, p < 0.01). In contrast, ranitidine did not show any protection. We confirmed that the protective effect of cimetidine was not related to scavenging hydrogen peroxide or hydroxyl radicals or chelating iron. A second inhibitor of cytochrome P-450, piperonyl butoxide, had a similar dose-dependent beneficial effect against hydrogen peroxide-induced cell injury. Our data thus indicate an important role of cytochrome P-450 in hydrogen peroxide-induced cytotoxicity to LLC-PK1 cells suggesting that cytochrome P-450 may serve as a source of catalytic iron.

Cimetidine prevents and partially reverses CCl4-induced liver cirrhosis.

Liver injury produced by CCl4 depends on its metabolism by the liver cytochrome P450 enzyme system to a highly reactive intermediate (CCl3.). Cimetidine impairs cytochrome P450 and stimulates regenerative processes acting on DNA synthesis. This work was performed to investigate whether cimetidine may prevent CCl4-induced liver cirrhosis. Male Wistar rats were used: animals in group 1 received CCl4 (0.04 g per 100 g, i.p.) three times a week for 8 weeks; group 2 was treated with CCl4 plus cimetidine (120 mg kg-1, p.o.) three times a week for 8 weeks; group 3 received CCl4 for 8 weeks and then cimetidine for 4 weeks. Alkaline phosphatase, gamma-glutamyl transpeptidase (gamma-GTP) and alanine aminotransferase (ALT) activities, as well as protein and bilirubin, were measured in serum; collagen and lipoperoxidation were quantified in liver. Intoxication with CCl4 increased (P < 0.05) serum activities of alkaline phosphatase, gamma-GTP and ALT, and bilirubin concentration; liver collagen and lipoperoxidation were also increased. Cimetidine treatment prevented or reverted the increases in the three enzyme activities and in bilirubin content and the fall in proteins. It is worth noting that cimetidine co-treatment completely prevented both the increase in collagen content and the lipid peroxidation. The protective effect of cimetidine can be attributed to a reduction in cytochrome P450. However, it could also stimulate regenerative processes.

Effect of cimetidine on experimental atherogenesis in rabbits

It was shown that cimetidine (10 mg/kg, 12 weeks) reduces the frequency and the degree of affection of rabbit's aortas during experimental cholesterol atherosclerosis. The protective effect of cimetidine on the liver where the contents of lipids, especially cholesterol esters reduced considerably, was noted. The nature of the fatty dystrophy changes from the large-drop to the small-drop one which should be considered as a favourable phenomenon. The anti-atherogenic and hepatoprotective effects of cimetidine can be explained by slowing-down of lipoperoxidation processes which is proved in respect of blood and aorta walls.

Use of a metabolic inhibitor to reduce dapsone‐dependent haematological toxicity

AbstractAside from its established use as an antileprotic and anti‐inflammatory drug, dapsone is also effective in the therapy of Pneurnocystis carinii pneumonia. Unfortunately, its use is often limited by its dose‐dependent toxicity, such as methaemoglobinaemia and haemolysis; the latter condition occurs most frequently in gIucose‐6‐dehydrogenase deficient individuals. It is also responsible for occasional life‐threatening disorders such as agranulocytosis. Dapsone may undergo acetylation, but its toxicity is due to the product of its oxidative metabolism, dapsone hydroxylamine. This is generated in man by the constitutive hepatic cytochrome P450 enzyme IIIA4. Studies in the rat revealed that dapsone‐dependent methaemoglobinaemia could be greatly diminished by the co‐administration of metabolic inhibitors. In the isolated perfused rat liver, dapsone hydroxylamine levels and hence methaemoglobin formation fell significantly in the presence of cimetidine. In addition, the clearance of the parent drug was retarded, and perfusate concentrations of monoacetyl dapsone increased. The protective effect of cimetidine also reduced methaemoglobin formation in the whole rat during the chronic administration of dapsone. Incubation of dapsone in a two‐compartment in vitro system using human tissues in the presence of cimetidine or ketoconazole resulted in a decrease in methaemoglobin formation in all the human livers tested. Although cimetidine was only effective if incubated with microsomes and NADPH prior to the addition of dapsone. Administration of cimetidine (3 × 400 mg daily) to volunteers 3 days prior to and 4 days post administration of a single dose of 100 mg dapsone caused drug concentrations to increase by almost 30%. There was a marked fall in peak methaemoglobin levels and the percentage of the dose excreted in urine as dapsone hydroxylamine N‐glucuronide was reduced by almost one third. During high dose dapsone therapy it may be possible that the co‐administration of cimetidine might reduce toxicity while maintaining drug efficacy.

Protective Effects of Cimetidine Against Ps aer Infection in an Experimental Burned Mouse Model

Protective Effects of Cimetidine Against Ps aer Infection in an Experimental Burned Mouse Model

Effect of cimetidine, histamine H2 receptor antagonist, in the prevention of experimental stress ulcer in the rat.

The protective effect of cimetidine on gastric mucosal lesions in the rat was investigated. Through prophylactic administration of 3x 25 7g/kh body weight for 24 just prior to the test period, the incidence rate of lesions, as well as upper gastro-intestinal haemorrhage was highly significantly reduced.