المؤلفون: Tatsuki Fukami, Masataka Nakano, Cheng Zhongzhe, Keigo Konishi, Miki Nakajima, Takuo Ogiso

المصدر: Toxicology. 448:152648

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Metabolite, Pharmacology, Toxicology, Superoxide dismutase, Mefenamic Acid, 03 medical and health sciences, chemistry.chemical_compound, Superoxide Dismutase-1, 0302 clinical medicine, Tolfenamic acid, Lactate dehydrogenase, medicine, Humans, Aged, biology, Superoxide, Anti-Inflammatory Agents, Non-Steroidal, Quinones, CYP1A2, Hep G2 Cells, Glutathione, Middle Aged, 030104 developmental biology, Flufenamic acid, chemistry, Microsomes, Liver, biology.protein, Female, 030217 neurology & neurosurgery, medicine.drug

الوصف: Mefenamic acid (MFA), one of the nonsteroidal anti-inflammatory drugs (NSAIDs), sometimes causes liver injury. Quinoneimines formed by cytochrome P450 (CYP)-mediated oxidation of MFA are considered to be causal metabolites of the toxicity and are detoxified by glutathione conjugation. A previous study reported that NAD(P)H:quinone oxidoreductase 1 (NQO1) can reduce the quinoneimines, but NQO1 is scarcely expressed in the human liver. The purpose is to identify enzyme(s) responsible for the decrease in MFA-quinoneimine formation in the human liver. The formation of MFA-quinoneimine by recombinant CYP1A2 and CYP2C9 was significantly decreased by the addition of human liver cytosol, and the extent of the decrease in the metabolite formed by CYP1A2 was larger than that by CYP2C9. By column chromatography, superoxide dismutase 1 (SOD1) was identified from the human liver cytosol as an enzyme decreasing MFA-quinoneimine formation. Addition of recombinant SOD1 into the reaction mixture decreased the formation of MFA-quinoneimine from MFA by recombinant CYP1A2. By a structure-activity relationship study, we found that SOD1 decreased the formation of quinoneimines from flufenamic acid and tolfenamic acid, but did not affect those produced from acetaminophen, amodiaquine, diclofenac, and lapatinib. Thus, SOD1 may selectively decrease the quinoneimine formation from fenamate-class NSAIDs. To examine whether SOD1 can attenuate cytotoxicity caused by MFA, siRNA for SOD1 was transfected into CYP1A2-overexpressed HepG2 cells. The leakage of lactate dehydrogenase caused by MFA treatment was significantly increased by knockdown of SOD1. In conclusion, we found that SOD1 can serve as a detoxification enzyme for quinoneimines to protect from drug-induced toxicity.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b87a4d480157923941c6379d49783999Test
https://doi.org/10.1016/j.tox.2020.152648Test

المؤلفون: Shao-Kuang Chang, Chian-Ren Jeng, Jiunn-Wang Liao, Jenn-Sheng Hwang, Shun-Cheng Wang, Victor Fei Pang

المصدر: Toxicology. 192:139-148

مصطلحات موضوعية: Insecticides, Diaphragm, Diaphragmatic breathing, Pharmacology, Toxicology, Median lethal dose, Lethal Dose 50, chemistry.chemical_compound, Thiocarbamates, Lactate dehydrogenase, medicine, Animals, Muscle, Skeletal, Creatine Kinase, Cartap, L-Lactate Dehydrogenase, biology, business.industry, Myocardium, Heart, Diaphragm (structural system), Phrenic Nerve, Microscopy, Electron, Instillation, Drug, Thigh, chemistry, Anesthesia, Toxicity, biology.protein, Female, Creatine kinase, Rabbits, Contracture, medicine.symptom, business, Muscle Contraction

الوصف: Cartap is extensively used to control agricultural pests. Pertinent literatures have indicated that it causes no eye irritation [D.E. Ray, Insecticides derived from plants and other organisms, in: W.J. Hayes, E.R. Laws (Eds.), Handbook of Insecticide Toxicology, Classes of Insecticides, vol. 2, Academic Press, New York, 1991, p. 611; C. Tomlin, Cartap, in: C. Tomlin (Ed.), The Insecticide Manual, 12th ed., British Crop Protection Council, Surrey, UK, 2000, p. 144]; however, the instillation of a little cartap through the eye has caused death in rabbits. The aim of this study was to determine the ocular toxicity of cartap in New Zealand White rabbits. Cartap was directly instilled into the low conjunctival sac of eyes, at doses of 0, 5, 7.5, 10 and 12.5 mg/kg body weight. The changes in the enzymes and isoenzymes of creatine kinase (CK), lactate dehydrogenase (LD), as well as pathological changes in the muscles of the heart, thigh and diaphragm were determined in the cartap-treated rabbits. Moreover, the neuromuscular effect of cartap was examined using the isolated rabbit phrenic-nerve diaphragm model. The results indicated that rabbits developed severe signs and they died within 20 min of ocular instillation. The ocular LD50 of cartap was 8.1 mg/kg body weight. Treatment with cartap increased the activities of CK and LD enzymes and their isoenzymes, CK-1, CK-2, and CK-3 in serum, and CK-3 and LD-5 in the diaphragm. Microscopically, hypercontraction bands and the rupture of myofibers of the diaphragm were observed in dead rabbits. Cartap did not affect nerve-evoked twitch but induced irreversible contracture and twitch depression on the isolated rabbit's diaphragm. These results indicate that the rabbit is susceptible to cartap toxicity; the effect of cartap caused contracture and damage to the diaphragm might play a pivotal role in respiratory paralysis and death of rabbits during intoxication.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::de03fb181a037a7ddcf14b1a9af16d90Test
https://doi.org/10.1016/s0300-483xTest(03)00268-3

المؤلفون: D.D. Venkatesh Babu, Ganesan Velmurugan, Subbiah Ramasamy

المصدر: Toxicology. 307:103-108

مصطلحات موضوعية: Blood Glucose, medicine.medical_specialty, Toxicology, medicine.disease_cause, Cardiotoxins, Lipid peroxidation, chemistry.chemical_compound, Internal medicine, Blood plasma, medicine, Animals, Pesticides, Rats, Wistar, Creatine Kinase, Cardiotoxicity, L-Lactate Dehydrogenase, Myocardium, Troponin I, Organophosphate, Heart, Glutathione, medicine.disease, Rats, Oxidative Stress, Endocrinology, Biochemistry, chemistry, Monocrotophos, Female, Cardiomyopathies, Oxidative stress, Dyslipidemia

الوصف: The morbidity and mortality rate of cardiovascular diseases are increasing massively worldwide. The environmental pollutants especially agrochemicals are the most unrecognized cardiovascular risk factors. Monocrotophos (MCP), an organophosphate pesticide with acetylcholine esterase inhibition activity is widely used in India and other parts of the world. The present study investigated the cardiotoxicity of prolonged intake of MCP. Wistar rats were administered 1/50th of LD50 dosage of MCP (0.36mg/kg body weight) orally via gavage daily for three weeks. MCP administered animals exhibited mild-hyperglycemia and dyslipidemia in blood. Cardiac oxidative stress was conferred by accumulation of protein carbonyls, lipid peroxidation and glutathione production. The cardiac markers (cTn-I, CK-MB and LDH) were showed elevated expression in blood plasma, which signals the cardiac tissue damage. The histopathology of the heart tissue authenticated the MCP induced tissue damage by showing signs of nonspecific inflammatory changes and oedema between muscle fibres. Thus the findings of this preliminary study illustrate the cardiotoxic effect of prolonged MCP intake in rats and suggest that MCP can be a possible independent and potent environmental cardiovascular risk factor.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5ec87d82e06815418d951e0f8f57e398Test
https://doi.org/10.1016/j.tox.2012.11.022Test

المؤلفون: Deborah A. Howatt, C. Gary Gairola, Sung Gu Han, Alan Daugherty

المصدر: Toxicology. 299:133-138

مصطلحات موضوعية: Apolipoprotein E, endocrine system, medicine.medical_specialty, Apolipoprotein B, Saturated fat, Interleukin-1beta, Toxicology, Lesion, Mice, Random Allocation, Apolipoproteins E, Internal medicine, medicine, Animals, Receptor, Lung, Mice, Knockout, L-Lactate Dehydrogenase, biology, Interleukin-6, Tumor Necrosis Factor-alpha, Chemistry, Surfactant protein D, Atherosclerosis, Pulmonary Surfactant-Associated Protein D, Cholesterol, Endocrinology, Receptors, LDL, LDL receptor, Immunology, biology.protein, Female, Tobacco Smoke Pollution, lipids (amino acids, peptides, and proteins), medicine.symptom, Tunica Intima, Bronchoalveolar Lavage Fluid, Lipoprotein

الوصف: Plasma lipoproteins play important roles in the development and progression of atherosclerosis. Two widely used mouse models of experimental atherosclerosis, apolipoprotein E-deficient (ApoE -/-) and LDL receptor-deficient (LDLr -/-) mice, have major differences in lipoprotein characteristics. These include differences in lipoprotein cholesterol distribution, lipoprotein compositions, apoliporoteins distribution, and susceptibility to oxidation. In the present study, we compared pulmonary and cardiovascular responses of ApoE -/- and LDLr -/- mice to sidestream cigarette smoke (SSCS) exposure to determine if strain differences influence their predisposition to SSCS-mediated promotion of atherosclerosis. Female ApoE -/- and LDLr -/- mice were maintained on a saturated fat enriched diet and exposed to SSCS in whole body exposure chambers for 15 weeks (4h/day, 5 days/week). At terminations, the levels of pulmonary injury markers in bronchoalveolar lavage (BAL) fluids from 6 mice per group and atherosclerotic lesion formation in 14 mice per group were analyzed. Total BAL cells and polymorphonuclear leukocytes were not significantly altered by SSCS exposure in both mouse models. Total protein, LDH, and cytokine concentrations in cell-free BAL fluids were also not significantly affected by chronic SSCS exposure in either mouse strain. SSCS significantly reduced surfactant protein D levels in both strains to a similar extent. However, SSCS exposure increased significantly the percent atherosclerotic lesion areas covering aortic intimal surfaces of ApoE -/- (control-25.3±1.52 vs. SSCS-31.9±2.02, p=0.012) as well as in LDLr -/- (control-30.97±1.1 vs. SSCS-36.61±1.7, p=0.028) mice. In contrast, the serum cholesterol concentrations of SSCS-exposed ApoE -/- mice were similar to that of controls (control-1255±85 vs. SSCS-1190±61mg/dl, p=0.552) but increased significantly in SSCS-exposed LDLr -/- mice (control-998±114 vs. SSCS-1577±142mg/dl, p=0.008). These results showing different effects of identical SSCS exposure on plasma cholesterol concentrations in these two mouse models suggest a role of multiple mechanisms in SSCS-induced atherosclerosis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d845f5618b1dd96d87f3664d3332d4c9Test
https://doi.org/10.1016/j.tox.2012.05.015Test

المؤلفون: Dianne K. Anestis, Sarah L. Miles, Suk K Hong, Gary O. Rankin, Lawrence H. Lash

المصدر: Toxicology. 163:73-82

مصطلحات موضوعية: Male, Kidney Cortex, Time Factors, Metabolite, Renal cortex, Succinimides, Pharmacology, Biology, Toxicology, Nephrotoxicity, chemistry.chemical_compound, Sex Factors, Sulfate conjugate, In vivo, Lactate dehydrogenase, medicine, Animals, Cells, Cultured, Kidney, Dose-Response Relationship, Drug, L-Lactate Dehydrogenase, Molecular Structure, Rats, Inbred F344, Rats, Dose–response relationship, medicine.anatomical_structure, Biochemistry, chemistry, Models, Animal, biology.protein, Female

الوصف: The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) induces nephrotoxicity in vivo that is characterized as acute polyuric renal failure and proximal tubular necrosis. However, earlier in vitro studies have failed to reproduce the in vivo nephrotoxicity seen with NDPS or its nephrotoxic metabolites N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA). The purpose of this study was to examine the nephrotoxic potential of NDPS, its known non-conjugated metabolites, the O-sulfate conjugate of NDHS (NSC), and the putative metabolite N-(3,5-dichlorophenyl)maleimide (NDPM) and its hydrolysis product N-(3,5-dichlorophenyl)maleamic acid (NDPMA) using freshly isolated renal cortical cells (IRCC). IRCC were obtained from untreated male or female Fischer 344 rats following collagenase perfusion of the kidneys. Cells (approximately 4 million per ml) (N=4) were incubated with up to 1.0 mM NDPS or an NDPS metabolite or vehicle for up to 120 min. Cytotoxicity was determined by measuring lactate dehydrogenase (LDH) release into the medium. Only NSC (>0.5 mM) and NDPM (> or =0.5 mM) exposure increased LDH release from IRCC. NSC 1.0 mM or NDPM 0.5 mM increased LDH release from IRCC within 15--30 min of exposure. NDPS or the remaining NDPS metabolites did not increase LDH release at bath concentrations of 1.0 mM for exposures of 120 min. IRCC from male and female rats responded similarly to the toxic effects of NDPS and its metabolites. These results demonstrate that sulfate conjugates of NDPS metabolites can be fast acting nephrotoxicants and could contribute to NDPS nephrotoxicity in vivo. These results also suggest that the kidney probably accumulates toxic sulfate conjugates of NDPS metabolites rather than forming the conjugates. In addition, mechanisms responsible for gender differences in nephrotoxicity seen with NDPS and NDPS metabolites in vivo either occur prior to renal accumulation of sulfate conjugates and/or represent biochemical/physiological differences between the genders.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::383edc437bc6898b6d34db659ab6dc84Test
https://doi.org/10.1016/s0300-483xTest(01)00376-6

المؤلفون: Daniel Acosta, Rosita J. Rodriguez

المصدر: Toxicology. 117:123-131

مصطلحات موضوعية: Male, Antifungal Agents, Metabolite, Tetrazolium Salts, Pharmacology, Biology, Toxicology, Rats, Sprague-Dawley, chemistry.chemical_compound, Lactate dehydrogenase, medicine, Animals, Coloring Agents, Cytotoxicity, Cells, Cultured, Unspecific monooxygenase, L-Lactate Dehydrogenase, Cell Membrane, Monooxygenase, Mitochondria, Rats, Thiazoles, Ketoconazole, Liver, Mechanism of action, chemistry, Biochemistry, Toxicity, Oxygenases, Female, medicine.symptom, Oxidation-Reduction, medicine.drug

الوصف: Ketoconazole (KT) is an azole antifungal agent that has been associated with hepatotoxicity. The mechanism of its hepatotoxicity has not yet been resolved. It has been suggested that a reactive metabolite may be the cause of toxicity because the hepatic injury does not appear to be mediated through an immunoallergic mechanism. Several metabolites of KT have been reported in the literature of which the deacetylated metabolite, N-deacetyl ketoconazole (DAK), is the major metabolite which undergoes further metabolism by the flavin-containing monooxygenases (FMO) to form a potentially toxic dialdehyde. The objective of this study was to evaluate DAK's cytotoxicity and the role of FMO in a primary culture system of rat hepatocytes. Cytotoxicity was evaluated by measuring the leakage of the cytosolic enzyme, lactate dehydrogenase (LDH), into the medium and by assessing mitochondrial reduction of 3-(4,5-dimethythiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT). The cultures were exposed to various concentrations of DAK (20-160 microM) for 0.5-4 h. There was a significant increase (P < 0.05) in LDH leakage and an immediate decrease in MTT reduction (P < 0.05) as early as 0.5 h. The MTT reduction assay appeared to be more sensitive than the LDH assay in that lower concentrations were needed to observe a 50% reduction of MTT (107, 90, 75, 58 microM DAK at 0.5, 1.0, 2.0 and 4.0 h, respectively). The concentrations to observe 50% LDH leakage from the hepatocytes were 155, 133, 100, 70 microM DAK at 0.5, 1.0, 2.0 and 4.0 h, respectively. Moreover, co-treatment with methimazole, a competitive substrate for FMO, produced a significant decrease (P < 0.05) in % LDH leakage as early as 0.5 h, when compared to cells treated solely with DAK. Also, the toxicity was significantly (P < 0.05) enhanced as early as 0.5 h by n-octylamine, a known positive effector for FMO. These results demonstrate that DAK is a more potent cytotoxicant than its parent compound, KT, as reported previously by our laboratory (Rodriguez and Acosta, Toxicology, 96: 83-92, 1995) and its toxicity was expressed in a dose- and time-dependent manner. Furthermore, DAK's cytotoxicity was enhanced with n-octylamine and suppressed with methimazole, suggesting a role for FMO in the toxicity of the metabolite.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::32362eef85ecb9e7acd30dca43c4677bTest
https://doi.org/10.1016/s0300-483xTest(96)03560-3

المؤلفون: P.V. Lakshmana Rao, Rajagopalan Vijayaraghavan, Satish C. Pant, Nidhi Gupta

المصدر: Toxicology. 188:285-296

مصطلحات موضوعية: medicine.medical_specialty, Microcystins, Globulin, Microcystin-LR, DNA Fragmentation, Microcystin, Toxicology, Peptides, Cyclic, Median lethal dose, Lethal Dose 50, Mice, chemistry.chemical_compound, Internal medicine, medicine, Animals, Aspartate Aminotransferases, Lung, chemistry.chemical_classification, L-Lactate Dehydrogenase, biology, Hepatotoxin, Albumin, Alanine Transaminase, gamma-Glutamyltransferase, Survival Rate, Endocrinology, Liver, Biochemistry, chemistry, Toxicity, biology.protein, Female, Marine Toxins, Marine toxin

الوصف: The cyclic peptide toxins microcystins and nodularins are the most common and abundant cyanotoxins present in diverse water systems. They have been the cause of human and animal health hazards and even death. Over 60 microcystin variants have been reported so far. We report here the results of our study on comparative toxicity evaluation of three most predominant microcystins, MC-LR, MC-RR and MC-YR in mice. The mice were administered one LD(50) dose of MC-LR, RR and YR (43, 235.4 and 110.6 micro g/kg body weight, respectively), and biochemical and histological variables were determined at 30 min post-treatment and mean time to death (MTD). Significant increase in liver body weight index was induced by all three variants. There was marginal increase in serum levels of hepatic enzymes viz. AST, ALT and gamma-GT at 30 min post-treatment but 3-4 fold increase was observed at MTD. In contrast, enhanced LDH leakage, DNA fragmentation and depletion of hepatic glutathione was observed at 30 min post treatment in all three variants. There was no change in levels of serum protein, albumin and albumin/globulin ratio. Liver histology showed time dependent severe pathological lesions like congestion, haemorrhage, portal mononuclear cell infiltration and obliteration of chromatin material. Lung lesions were predominantly in bronchi and parenchyma. Though qualitatively lesions were identical in all three microcystin variants, degree of liver and lung lesions varied quantitatively with the toxin. The breathing pattern and respiratory frequency of the mice after i.p. administration of the toxin showed uniform pattern for 90 min followed by abrupt change in the respiratory pattern and instantaneous death. Based on biochemical and histological studies, MC-LR was found to be the most potent toxin followed by MC-YR and MC-RR.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c31098503e3f414c50bc99d11b324587Test
https://doi.org/10.1016/s0300-483xTest(03)00112-4

المؤلفون: Jiunn-Shiow Wang, Bing-Lan Liu, Shu-Peng Ho, Yew-Min Tzeng, San-Fu Tsai, Shun-Cheng Wang, Jiunn-Wang Liao, Jenn-Sheng Hwang

المصدر: Toxicology. 186:205-216

مصطلحات موضوعية: Lung Diseases, Male, Pathology, medicine.medical_specialty, Adenosine, Pulmonary toxicity, Pulmonary Fibrosis, Lung injury, Toxicology, Rats, Sprague-Dawley, Hydroxyproline, chemistry.chemical_compound, Internal medicine, Macrophages, Alveolar, medicine, Animals, Lung, Injections, Spinal, Dose-Response Relationship, Drug, L-Lactate Dehydrogenase, medicine.diagnostic_test, Tumor Necrosis Factor-alpha, business.industry, Respiratory disease, Proteins, Sugar Acids, medicine.disease, Fibronectins, Rats, Cellular infiltration, Bronchoalveolar lavage, medicine.anatomical_structure, Endocrinology, Pulmonary Emphysema, chemistry, Toxicity, Female, business, Bronchoalveolar Lavage Fluid, Interleukin-1

الوصف: The purpose of this work is to evaluate the pulmonary toxicity of purified thuringiensin in Sprague–Dawley rats. Rats were intratracheally instillated with 0, 0.4, 0.8, 1.6, 3.2, 6.4 and 9.6 mg/kg body weight of thuringiensin. The results indicated that the acute pulmonary LD 50 of thuringiensin for rats was 4.4 mg/kg. The total number of inflammatory cells and lactate dehydrogenase (LDH) activity in the bronchoalveolar lavage (BAL) fluid increased in a dose-dependent manner after thuringiensin instillation. Furthermore, an effective dose of 1.6 mg/kg was selected for the time course study of pulmonary toxicity. The treated animals showed a significant increase in the weights of the lungs, hydroxyproline levels in the lungs and total number of cells in BAL fluid 2, 4, 7, 14, 28 and 56 days after treatment. In comparison with the control, the total protein concentrations in BAL fluid were increased by 361, 615, 116, 41, 34 and 41%, after 2, 4, 7, 14, 28 and 56 days, respectively. The LDH activity in BAL fluid showed a significant increase after 1, 2, 4, 7, 14, 28 and 56 days. The increases in fibronectin levels were 164, 552, 490, 769, 335, 257 and 61% at the corresponding times, but neither tumor necrosis factor nor interleukin-1 increased. The treated rats presented abnormal histology including distributed inflammation in the bronchioles and alveoli, bronchial cellular necrosis on days 1 and 2, and areas of septal thickening with cellular infiltration and collagen deposit in the intestinal and alveolar spaces on days 4–56. Based on these biochemical and pathological parameters, intratracheal instillation of purified thuringiensin might cause significant pulmonary toxicity in rats.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a29932e3f75932b9c759de88bf83cfdaTest
https://doi.org/10.1016/s0300-483xTest(02)00744-8

المؤلفون: J.L. Kaw, R. Bajpai, M. Waseem, G.S.D. Gupta

المصدر: Toxicology. 73:161-167

مصطلحات موضوعية: inorganic chemicals, Pathology, medicine.medical_specialty, Phospholipid, Toxicology, complex mixtures, chemistry.chemical_compound, Lactate dehydrogenase, Aluminum Oxide, medicine, Animals, Lung, Physiological saline, Phospholipids, Glucuronidase, Chromatography, L-Lactate Dehydrogenase, medicine.diagnostic_test, fungi, Proteins, Dust, Quartz, respiratory system, N-Acetylneuraminic Acid, Rats, respiratory tract diseases, Sialic acid, Coal, Bronchoalveolar lavage, chemistry, Fly ash, Toxicity, Sialic Acids, Aluminum Silicates, Female, Bronchoalveolar Lavage Fluid, N-Acetylneuraminic acid

الوصف: Female wistar rats were inoculated intratracheally with 10 mg/ml suspensions of various dusts, viz: quartz, fly ash, mica and corundum in physiological saline. Biochemical markers of bronchoalveolar lavage fluid (BALF) were analysed 8 days after the instillation of the dusts. Elevated levels of proteins, sialic acid and phospholipid contents and the activity of lactate dehydrogenase correlated well with the degree of the known fibrogenic potential of different dusts in the lungs in the following order, quartz greater than fly ash greater than mica greater than corundum. beta-glucuronidase activity, was however, only elevated in the quartz inoculated group of rats. It is suggested that biochemical constituents of BALF analysed shortly after the exposure to different dusts can be useful to mirror alterations in the tissue response to mineral dusts.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::004b94ebd465e90c22499a9554afba6bTest
https://doi.org/10.1016/0300-483xTest(92)90099-z

المؤلفون: Hirofumi Yamanaka, Ronald G. Thurman, Barbara J. Keller

المصدر: Toxicology. 71:49-61

مصطلحات موضوعية: medicine.medical_specialty, Cellular respiration, Mitochondria, Liver, Mitochondrion, Biology, Toxicology, Microbodies, Clofibric Acid, chemistry.chemical_compound, Oxygen Consumption, Lactate dehydrogenase, Internal medicine, medicine, Animals, Lobules of liver, Clofibrate, Hypolipidemic Agents, Aspirin, Dose-Response Relationship, Drug, L-Lactate Dehydrogenase, Valproic Acid, Fibric Acids, Clofibric acid, Rats, Inbred Strains, Trypan Blue, Peroxisome, Rats, Endocrinology, chemistry, Toxicity, Female, Ciprofibrate, Cell Division, medicine.drug

الوصف: The purpose of this study was to test the hypothesis that a variety of structurally dissimilar peroxisomal proliferators inhibited O2 uptake and caused O2-dependent hepatotoxicity in the perfused rat liver. Aspirin, valproate, ethylhexanol, clofibric acid, ciprofibrate and perfluorooctanoate were selected as a representative group of weak, moderate, and potent peroxisomal proliferators, respectively. All compounds studied inhibited state 3 but not state 4 rates of oxygen uptake in isolated mitochondria (perfluorooctanoate greater than ciprofibrate greater than ethylhexanol greater than clofibric acid greater than aspirin greater than valproate; half maximal inhibition occurred at concentrations ranging from 0.6 to 3.2 mM depending on the compound). Clofibric acid, ethylhexanol and aspirin inhibited oxygen uptake only in upstream, oxygen-rich periportal regions of the perfused liver lobule by 30-40%. Perfusion with the six agents studied caused release of lactate dehydrogenase into the effluent perfusate in a dose-dependent manner and caused damage predominantly in periportal regions of the lobule as reflected by trypan blue uptake. A strong correlation between the concentration of compound needed to inhibit respiration in isolated mitochondria and cause hepatotoxicity in the perfused liver was observed. We propose that peroxisomal proliferators accumulate in the liver due to their lipophilicity where they inhibit actively respiring mitochondria in periportal regions of the liver lobule and cause local toxicity.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c2ea12b277112dcd131465cbcbf2e92dTest
https://doi.org/10.1016/0300-483xTest(92)90053-h