Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In rats, 3 days treatment with paracetamol (1 oral dose of 1 g/kg daily) produced a complete protection against the hepatotoxic actions of a further dose of paracetamol as documented by determination of serum enzyme activities (glutamic-oxaloacetic transaminase, (GOT), glutamic-pyruvic transaminase (GPT), sorbitol dehydrogenase (SDH), bromsulphthalein retention and histological investigations. Subacute paracetamol treatment decreased liver glutathione levels by 46%, liver microsomal cytochrome P-450 content by 23%, hepatic hydroxylation of aniline by 29% and hepatic demethylation of aminopyrine by 46%. It afforded also some protection against the hepatotoxic actions of carbon tetrachloride, bromobenzene and thioacetamide, but did not influence the antiphlogistic activity of paracetamol (carrageenan paw edema test). Plasma and liver concentrations of free paracetamol after oral administration of 1 g/kg paracetamol were somewhat higher in the subacutely paracetamol-pretreated rats than in the non-pretreated control animals whereas no differences in the concentrations of conjugated paracetamol were found between the 2 groups. Pretreatment with paracetamol did not influence the urinary excretion of free paracetamol but caused some shift in the urinary excretion of paracetamol conjugates: pretreated rats excreted 23% less of the paracetamol glucuronide and sulfate and 33% more of the paracetamol mercapturate than the control animals. A depression of the microsomal mixed-function oxidase activity is presumed to be the main cause of the paracetamol-induced protection against paracetamol hepatotoxicity.
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PMID:Studies on the mechanism of paracetamol-induced protection against paracetamol hepatotoxicity. 47 30

Lipid peroxidation may contribute to the nephrotoxicity of cephaloridine, a beta-lactam antibiotic. Copper and Se may protect against free radical damage, and dietary Se deficiency potentiates cephaloridine nephrotoxicity. The objectives of this study were to further investigate potentiation of cephaloridine toxicity by Se deficiency and to determine whether Cu deficiency increases cephaloridine-induced injury. Weanling male Sprague-Dawley rats were fed adequate, Cu-deficient, Se-deficient, and Se and Cu-deficient diets for 4 wk and subsequently injected i.p. with cephaloridine (1200 mg/kg body wt) or saline. Nephrotoxic response to cephaloridine occurred, with increased plasma urea, kidney weight, excretion of urinary enzymes, and kidney lesions. Cephaloridine also increased plasma sorbitol dehydrogenase activity. Selenium deficiency depressed kidney glutathione peroxidase activity (78%) and potentiated cephaloridine nephrotoxicity. Copper deficiency did not increase cephaloridine nephrotoxicity; the small depression (13%) in kidney Cu,Zn-superoxide dismutase activity may not have been sufficient to impair antioxidant status. However, the marked depression in kidney glutathione peroxidase activity during Se deficiency may have impaired antioxidant status and enhanced cephaloridine-induced injury. In contrast to results in the kidney, neither Se deficiency nor Cu deficiency potentiated cephaloridine hepatotoxicity, as assessed by plasma SDH activity.
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PMID:Cephaloridine nephrotoxicity is potentiated by selenium deficiency but not copper deficiency in rats. 158 39

The synergistic hepatotoxicity of dietary disulfiram (DSF) with 1,2-dichloroethane (DCE) subchronically administered by inhalation at three concentration levels (150, 300, and 450 ppm) was studied. The criteria for hepatotoxicity were treatment-related increases in serum activities of sorbitol dehydrogenase, 5'-nucleotidase, and alkaline phosphatase, and in liver-to-body weight ratios. DSF alone did not elicit these responses while DCE at the highest concentration level increased liver-to-body weight ratios and the activity of 5'-nucleotidase. Exposure to DSF alone decreased cytochrome P450 levels, but in combination with DCE, the decrement of cytochrome P450 was additive in a DCE concentration-dependent manner. However, depression of cytochrome P450 by DCE alone was not concentration dependent. Although DSF and DSF/DCE combination increased the activity of glutathione S-transferases (GSTs), both DSF and DCE singly and in combination increased the tissue levels of reduced glutathione (GSH). Evidence is presented showing that the potentiation of the hepatotoxicity of DCE observed in the presence of DSF may be due to an inhibition of microsomal mixed-function oxidase-mediated metabolism of DCE and to a compensatory increase in DCE metabolism to reactive metabolites generated by GST-mediated conjugation of DCE with GSH.
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PMID:Interaction between 1,2-dichloroethane and tetraethylthiuram disulfide (disulfiram). II. Hepatotoxic manifestations with possible mechanism of action. 378 26

Serum activities of sorbitol dehydrogenase (SDH), lactate dehydrogenase (LDH), gamma-glutamyltranspeptidase (gamma-GT), and alkaline phosphatase (ALP) were measured before, during, and after milk fat depression in 9 cows fed a high-concentrate ration during 2 experiments. In 7 of the 9 cows, increases in serum SDH and LDH activities were observed during milk fat depression. The gamma-GT activity showed only moderate changes, whereas the ALP activity remained unchanged. During recovery from milk fat depression, decreases of SDH, LDH, and gamma-GT activities were found in nearly all cows. Association of this phenomenon with changes found in beef cattle, such as ruminal lesions and liver abscesses, are discussed.
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PMID:Changes of serum enzyme activities in cows with milk fat depression. 613 78

The effects of polychlorinated biphenyls (PCBs) on the development of several intestinal and serum marker enzymes have been studied. The three congeners 4-monochloro (1-CB), 3, 4, 3',4'-tetrachloro (4-CB), and 2, 4, 5, 2', 4, 5'-hexachloro (6-CB) biphenyl were administered orally to pregnant rats on d 8, 11, 13, 15, and 18 or gestation. 1-CB and 6-CB were intubated at doses of 30 mg/kg.d (total dose, 150, mg/kg) and 4-CB was administered at 3 mg/kg-d (total dose, 15 mg/kg). Levels of intestinal alkaline phosphatase, monoamine oxidase, and Na+, K+-adenosin-5'-etriphosphatase and levels of serum alkaline phosphatase, sorbitol dehydrogenase, and beta-hydroxybutyrate dehydrogenase were measured in the dams after weaning and in their offspring at -1, 6, 20, and 55 d of age. Intestinal alkaline phosphatase activity was elevated at the later postnatal stages in the 1-CB group and depressed at 55 d in the 4-CB group, whereas serum alkaline phosphatase levels were markedly depressed prenatally and postnatally in the 4-CB and 6-CB groups, respectively, Intestinal monoamine oxidase levels were markedly increased in the 6-CB group at -1, 6, and 20 d of age and significantly depressed in the 4-CB animals at -1 and 55 d of age. There was an increase in monoamine oxidase activity in the 4-CB group at 6 d. The 1-CB group exhibited depression of monoamine oxidase levels at 6 and elevation at 20 and 55 d. Intestinal Na+, K+-ATPase levels were elevated throughout development in the 1-CB animals and at -1 and 6 d in the 4-CB group. The 6-CB animals showed elevated levels of Na+, K+-ATPase only at 6 d. Serum beta-hydroxybutyrate dehydrogenase and sorbitol dehydrogenase were induced prenatally in the 4-CB animals but enzyme activities decreased to normal by 55 d of age. Significant depression of activity was evident in the 1-CB and 6-CB groups at -1 d in both enzymes. Dams in the 1-CB group showed significant changes in intestinal monoamine oxidase, serum sorbitol dehydrogenase, and serum alkaline phosphatase. Serum levels were elevated in the 4-CB group. Activities of intestinal enzymes remained unchanged in the 4-CB group. All maternal enzyme levels monitored were not significantly changed in the 6-CB group.
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PMID:Effects of polychlorinated biphenyls on the development of intestinal and serum marker enzymes. 627 53

Eight foals, 2 to 5 days of age, with similar clinical signs and laboratory and pathologic findings, died from hepatic failure. The predominant clinical signs were depression and icterus. Abnormally high values were found for plasma ammonia content, aromatic-to-branch-chain amino acid ratio, total serum bilirubin content, gamma glutamyl transferase activity, alkaline phosphatase activity, and PCV; partial thromboplastin time and prothrombin time were prolonged. Some foals had high sorbitol dehydrogenase activity. These laboratory findings were suggestive of subacute hepatic disease and failure. Predominant pathologic findings were limited to the liver and brain. The livers were less than half the expected size for 2- to 5-day-old foals, had prominent bile ductule proliferation, hepatic cell necrosis, and mild periportal fibrosis. These findings suggested both prenatal and postnatal diseases caused by exposure to a hepatoxin. The predominant lesion in the brain was the presence of Alzheimer type II astrocytes, which are characteristic of hepatoencephalopathy. Although the periportal fibrosis was suggestive of in utero exposure to a toxin, epidemiologic information suggested that the hepatic failure more likely resulted from oral inoculation of a microorganism culture product at birth. The same disease was reproduced in 2 newborn foals by feeding this product.
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PMID:Toxic hepatic failure in newborn foals. 665 19

In a chronic toxicity study in the rat, bidisomide administered as a dietary admixture produced a dose-related lowering of reticulocytes and leucocytes. Plasma alanine aminotransferase activity was increased at 300 mg/kg and decreased at 900 mg/kg. The potential mechanisms of these effects were investigated by comparing the responses in groups of male Sprague-Dawley rats receiving a control diet, or 300 or 1200 mg/kg/day bidisomide. Subsets of these groups were co-treated subcutaneously with folinic acid or with a vitamin B1, B6, B12 complex. Subsets of control and 300 mg/kg groups were maintained on a 20-25% feed restriction regimen for 3 months, to mimic the depression in body weight gain observed in animals receiving 1200 mg/kg. Body weight gains were significantly reduced at 1200 mg/kg and in all feed-restricted animals. Plasma and liver alanine aminotransferase (ALT) and plasma aspartate aminotransferase (AST) levels were also reduced at this dose level. At 300 mg/kg, plasma transaminases, glutamate dehydrogenase (GLDH) and sorbitol dehydrogenase (SDH) activities were increased. These changes were prevented in animals receiving folinic acid supplementation. Plasma glucose, triglycerides, and unsaturated and total iron binding capacities were decreased, while plasma iron levels tended to increase, mainly at the high dose. Vitamin supplementation prevented a decrease in reticulocyte counts at 300 mg/kg. Bidisomide increased urinary formimino-glutamic acid (FIGLU) excretion but did not affect methylmalonic acid (MMA) or taurine excretion. The effect on FIGLU at 1200 mg/kg was prevented by folinic acid co-treatment. Absolute liver weight was lowered at both dose levels and in feed-restricted animals. However, the relative liver weights were unaffected. Thymidine kinase and thymidylate synthase activity of the bone marrow cells were not altered by the bidisomide treatment. Except for the increase in plasma transaminase, GLDH and SDH levels at 300 mg/kg, changes in clinical chemistry parameters are considered to result mainly from nutritional restrictions. Changes in hematologic parameters appear to be related to the combination of decreased feed consumption (leukocytes) and decreased availability or utilization of folates (reticulocytes). This alteration, however, did not affect DNA synthesis in bone marrow. The prevention by folinic acid, but not by feed restriction, of the elevation of liver enzymes at 300 mg/kg is an intriguing, yet unexplained finding. There was no evidence that bidisomide affected B6 and B12 availability.
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PMID:Effect of folate supplementation on clinical chemistry and hematologic changes related to bidisomide administration in the rat. 858 20

Riddelliine is a naturally occurring pyrrolizidine alkaloid, a class of compounds occurring in rangeland plants of the genera Crotalaria, Amsinckia, and Senecio. Two-week and 13-week rodent toxicity studies of riddelliine were conducted because riddelliine can be a contaminant of foodstuffs, such as meat, grains, seeds, milk, herbal tea, and honey. In addition to histopathology, evaluations included clinical pathology and reproductive toxicity. In vitro genetic toxicity studies included assessments of mutagenicity in Salmonella typhimurium and of the induction of chromosomal aberrations and sister chromatid exchanges in Chinese hamster ovary cells. Riddelliine was also evaluated in vivo for the induction of micronuclei in mouse bone marrow and in peripheral blood and for the induction of S-phase synthesis and unscheduled DNA synthesis in the liver of rats and mice. In the 2-week studies, groups of five male and five female F344/N rats and B6C3F1 mice were administered riddelliine in 0.1 M phosphate buffer by gavage at dose levels of 0, 0. 33, 1.0, 3.3, 10, or 25 mg/kg body weight five times per week, for a total of 12 doses. Four of five male rats in the 25 mg/kg group died or were killed moribund before the end of the study. Mean body weight gains of male rats in the 10 and 25 mg/kg groups were depressed. No deaths or body weight effects were observed in female rats. Male rats had dose-related hemorrhagic centrilobular hepatic necrosis, hepatocytic karyomegaly and cytologic alterations, pulmonary hemorrhage and/or edema, splenic extramedullary hematopoiesis, and pancreatic edema. Female rats exhibited fewer and less severe lesions than identically treated male rats. Heart weights of treated male and female rats were lower than those of the controls. No deaths or effects on body weight were observed in treated mice. Dose-related increases in absolute and relative liver weights and increased incidences of hepatic cytomegaly were the only treatment-related findings in male and female mice administered riddelliine. In the 13-week studies, groups of 20 male and 20 female F344/N rats and B6C3FI mice were administered riddelliine in 0.1 M phosphate buffer by gavage five times per week for 13 weeks. Rats received 0, 0.1, 0.33, 1.0, 3.3, or 10 mg/kg and mice received 0, 0.33, 1.0, 3.3, 10, or 25 mg/kg. Ten animals from each dose group were killed after 13 weeks of treatment. The remaining 10 animals in each dose group were observed without further treatment for up to 14 weeks; five animals from each dose group were killed after 7 weeks of recovery, and the remaining five animals per dose group were killed at the end of the 14-week recovery period. During the 13-week treatment period, 19 of 20 male rats in the high-dose group died; all others survived. Body weight gains were decreased with increasing dose at Week 13. During the 14-week recovery period, all male rats survived, but five high-dose females died. Mean body weight gains of dosed and control male rats were similar throughout the 1 4-week recovery period; the final mean body weights of the treated males approached the final mean body weight of the controls. Similarly, mean body weight gains among the treated female rats were similar to the control value at the end of the 14- week recovery period. However, the final mean body weight of female rats given 1.0 or 3.3 mg/kg remained lower than that of controls at the end of the 14-week recovery period. In the 13-week study, the most significant treatment-related histopathologic lesions in rats occurred in the liver and included hepatocyte cytomegaly and karyomegaly, cytoplasmic vacuolization, centrilobular necrosis, mixed inflammatory cell infiltration, and bile duct hyperplasia. Vascular lesions in the kidneys and lungs were observed in most high- dose rats after 13 weeks of riddelliine administration. Additional lesions were found in the heart, spleen, kidneys, and pancreas at 13 weeks. At the end of the 14-week recovery period, hepatocyte karyomegaly, cytomegaly, and cytoplasmic vacuolization persisted. In addition, the incidence of bile duct hyperplasia was markedly increased in dosed female rats, and foci of cytologic alteration or hyperplastic hepatocytes were observed in dosed rats that were allowed to recover for up to 14 weeks. Adenomas of the liver occurred in 2 of 10 females in the 10 mg/kg group at 13 weeks and in one of five females in this group after the 14-week recovery period; no adenomas were found in the livers of control females. Serum activities of alkaline phosphatase in male rats and sorbitol dehydrogenase in female rats increased with increasing dose. Reticulocyte counts consistently increased and platelet counts consistently decreased with increasing dose in treated male and female rats. The clinical pathology findings were indicative of liver damage and erythrocyte and platelet sequestration. In mice in the 13-week study, no deaths related to riddelliine treatment occurred. Body weight gains were depressed at the two highest dose levels (10 and 25 mg/kg); the depression in body weight persisted throughout the 14- week recovery period. Dose-related increases in erythrocyte counts in male mice and in reticulocyte counts in female mice were observed. Dose-related decreases in platelet counts were also observed in both males and females. Centrilobular cytomegaly in the liver was noted at 13 weeks in males and females administered 25 mg/kg riddelliine; this lesion persisted through the recovery period in females. At the end of the 14-week recovery period, bile duct hyperplasia was seen in the liver in high-dose female mice. Epithelial hyperplasia of the forestomach was noted in male and female mice in the 10 and 25 mg/kg groups after 13 weeks of treatment, but this lesion became less severe during the recovery period. In male rats administered up to 3.3 mg/kg and in male mice administered up to 25 mg/kg for 13 weeks, riddelliine did not adversely affect any of the reproductive end points evaluated. In female rats given 10 mg/kg and in female mice given 25 mg/kg, the length of the estrous cycle was increased. However, no unequivocal adverse effects were noted on fertility, pup growth and survival, or weight gain of dams during pregnancy during the mating trial in rats, although mean body weights of dams given 0.1 or 1.0 mg/kg were significantly lower than the mean body weight of the controls throughout gestation and lactation. In contrast, riddelliine administered at a dose of 25 mg/kg was toxic to the dams in the mouse mating trial, resulting in lower body weights at the beginning of gestation and throughout lactation. Administration of 25 mg/kg riddelliine to mouse dams also affected fetal growth and survival; the average live litter size was significantly reduced, the number of pups born dead was increased, and the average pup weight was reduced throughout the 21-day postpartum period. Riddelliine was mutagenic in Salmonella typhimurium strain TA100 with, but not without, S9 activation; results of mutagenicity testing were negative in strains TA97, TA98, and TA1535. Riddelliine induced sister chromatid exchanges in Chinese hamster ovary (CHO) cells with and without S9. Chromosomal aberrations were induced in CHO cells only in the presence of S9. The frequency of micronucleated erythrocytes in mouse peripheral blood samples was not elevated after 4 or 13 weeks of daily gavage treatments; however, a weakly positive response was noted in the peripheral blood and bone marrow of male mice administered a single, high dose of riddelliine by gavage. Unscheduled DNA synthesis was detected in cultured hepatocytes from male and female rats and mice following 5 or 30 days of riddelliine treatment by gavage. In addition, an increase in S-phase DNA synthesis was observed in cultured hepatocytes of male and female rats treated for either time period. In summary, the administration of riddelliine to rodents by gavage for up to 13 weeks resulted in a spectrum of neoplastic and nonneoplastic effects similar to those previously described for other pyrrolizidine alkaloids. Rats were found to be somewhat more sensitive than mice, and males more sensitive than females, to the toxic effects of riddelliine. The no-observed-adverse-effect level (NOAEL) for histopathologic changes in the 13-week studies was 3.3 mg/kg body weight for mice and 0.1 mg/kg body weight for rats. The liver was the primary target of riddelliine-induced injury that resulted in lesions characterized by cytomegaly and cytologic alteration in rats and mice and also by marked necrotic and proliferative changes in rats. Riddelliine is carcinogenic to female F344/N rats, based on the occurrence of hepatocellular adenomas. Synonyms: 13,19-didehydro-12,18-dihydroxy senecionan-11,16- dione; trans-15-ethylidine-12b-hydroxy-12a-hydroxymethyl-13-methylenesenec-1-enine; 3-ethylidine-3,4,5,6,9,11,13,14,14a,14b-decahydro-6-hydroxy-6-(hydroxymethyl)-5-methylene (1,6)di-oxacyclododecino(2,3,4-gh)-pyrrolizidine-2,7-dione.
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PMID:NTP technical report on the toxicity studies of Riddelliine (CAS No. 23246-96-0) Administered by Gavage to F344 Rats and B6C3F1 Mice. 1220 79

Male and female F-344 rats and B6C3F1 mice (10/sex/group) were exposed to N,N-dimethylformamide (DMF) by whole body inhalation exposure at 0, 50, 100, 200, 400, or 800 ppm, 6 h/day, 5 days/week, for 13 weeks. A concentration-dependent depression in body weight occurred in rats of both sexes at 400 (6-11%) and 800 ppm (20-22%). In contrast, all weight changes in both sexes of mice were within 10% of controls. No rats died, while 5 mice died from nonexposure-related causes. Relative liver weights were significantly increased at all DMF concentrations in both sexes and both species. Activities of serum sorbitol dehydrogenase (SDH) were statistically increased in male and female rats (200 to 800 ppm) on study days 4, 24, and 91 (13 weeks). Activities of alanine aminotransferase (ALT) and isocitrate dehydrogenase (ICD) were statistically increased in both sexes of rats exposed to 800 ppm DMF at all time points. Cholesterol (CHOL) levels were statistically increased in male and female rats (50-800 ppm) at all sampling time points. Levels of total bile acids (TBA) were statistically increased in both sexes of rats (400-800 ppm) on days 24 and 91. Centrilobular hepatocellular necrosis (minimal to moderate) was seen in rats of both sexes exposed at 400 and 800 ppm, with the lesions more severe in females. Centrilobular hepatocellular hypertrophy (minimal to mild) was found in all groups of DMF-exposed male mice, and in female mice exposed at 100-800 ppm. For male and female rats the no-observed-adverse-effect concentration (NOAEC) for microscopic liver injury was 200 ppm. The NOAEC was 50 ppm for female mice, but an NOAEC based upon the absence of microscopic liver injury was not determined in male mice.
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PMID:Thirteen-week inhalation toxicity of N,N-dimethylformamide in F344/N rats and B6C3F1 mice. 1265 34

The medical records of 19 horses with acute hemoperitoneum were reviewed. The causes for the hemoperitoneum were idiopathic (8 horses), splenic hematoma with capsular tear (7), bleeding from the reproductive tract (3), multicentric hemangiosarcoma (1), and systemic amyloidosis (1). The affected horses were between 4 and 32 years of age (median 11.5 years). The most consistent findings on initial examination were depression, tachycardia, tachypnea, pale mucous membranes, prolonged capillary refill time, colic, and abdominal discomfort. Less common clinical signs included abdominal distention, profuse sweating, ataxia, and broad ligament mass palpated on rectal examination. Clinicopathologic abnormalities commonly detected were anemia, neutrophilia, lymphopenia, thrombocytopenia, hypoproteinemia, hypocalcemia, azotemia, increased creatinine kinase, and sorbitol dehydrogenase activity. Hemoperitoneum was diagnosed on the basis of abdominocentesis, transabdominal ultrasonography, and postmortem examination. Sixteen horses were treated, and 3 horses were euthanized at owners' request because of severe clinical signs. The treatment consisted of the administration of intravenous fluids, plasma or blood transfusion, nonsteroidal drugs, antimicrobial drugs, and antifibrinolytic and procoagulant agents. Rapid clinical deterioration was observed in 2 horses, necessitating euthanasia. The remaining 14 horses survived the abdominal bleeding (survival rate 74%) and were discharged 3-15 days (median 7.0 days) after presentation. Postmortem examination of the 6 nonsurvivors showed massive abdominal hemorrhage from splenic hematoma with capsular tear (2 horses), multicentric hemangiosarcoma with liver rupture (1), systemic amyloidosis with splenic hematoma and capsular tear (1), and bilateral ruptured ovarian hematomas (1). In one horse, no origin of the bleeding could be determined during postmortem examination.
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PMID:Acute hemoperitoneum in horses: a review of 19 cases (1992-2003). 1595 49


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