rutin and Chemical-and-Drug-Induced-Liver-Injury

Coumarin, used in the treatment of chronic venous diseases, is mainly metabolized to non-toxic 7-hydroxy-coumarin by CYP2A6. At least, 3 variant alleles, CYP2A6*2, CYP2A6*3 and CYP2A6*4A, have been shown to encode catalytically defective proteins. Sporadic elevation of liver enzymes has been reported on the chronic administration ofcoumarin. We sought to determine if susceptibility to coumarin-associated liver dysfunction is genetically determined by polymorphism in CYP2A6 and impairment of the 7-hydroxylation ofcoumarin. Additionally, we were interested in the effect of polymorphism on smoking because of the predominant role of CYP2A6 in the metabolism of nicotine.. The investigation was performed prospectively within a randomized double-blind clinical trial of the coumarin-containing drug SB-LOT (90 mg coumarin + 540 mg troxerutin/d) vs. placebo in 231 German patients with chronic venous insufficiency. Monitoring of the hepatic status involved regular measurements of liver function during the 16-week treatment. Genotyping of CYP2A6 was carried out by means of PCR and confirmed by DNA sequencing analysis.. The allelic frequencies of the variant CYP2A6*2 and CYP2A6*3 alleles were 0.023 and 0.014, respectively. There was no significant difference in the incidence of liver dysfunction between heterozygotes with CYP2A6*2, CYP2A6*3 and wild-type homozygotes. CYP2A6 polymorphism had no significant effect on smoking behavior.. No evidence was obtained that the studied polymorphism in CYP2A6 is a determinant of the coumarin-associated liver dysfunction.

Topics: Adult; Aged; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Chemical and Drug Induced Liver Injury; Coumarins; Cytochrome P-450 CYP2A6; Double-Blind Method; Drug Combinations; Female; Gene Frequency; Genotype; Humans; Hydroxyethylrutoside; Liver Diseases; Liver Function Tests; Male; Middle Aged; Mixed Function Oxygenases; Polymorphism, Genetic; Prospective Studies; Smoking; Venous Insufficiency

Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome. Paracetamol (APAP) causes, in high doses, a hepatic injury. Alogliptin (ALO), with its 100% oral bioavailability, may be able to reverse the acute hepatic injury and memory impairments.. Forty rats were divided into four groups as follows; Normal Control Group, APAP intoxicated group, ALO and SIL groups. Behavioral tests (Morris water maze, Y-maze spontaneous alteration, and novel object recognition test) were performed together with evaluating HE score. Neurotransmitters (gamma-aminobutyric acid, glutamate, dopamine, serotonin, norepinephrine and acetylcholine), as well as acetylcholinesterase activity, were determined in the hippocampus. Also, hepatotoxicity markers (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and ammonia) were measured in blood. Additionally, transforming growth factor beta 1, tumor necrosis factor alpha, cytochrome c, granzyme B and caspase-3, coiled-coil Moesin-like BCL-interacting protein 1 "beclin-1", cellular FLICE-like inhibitory protein, protein 53, TNF-α related apoptosis-inducing ligand, Fas-ligand and alpha-smooth muscle actin were measured in liver homogenate. Moreover, the histopathological investigation was performed.. APAP was able to disturb neurotransmitters which were mirrored in the performance of rats in the behavioral test. Most hepatotoxicity, apoptosis and inflammation indicators were elevated after APAP administration, while beclin-1 (autophagy marker) was declined. The tested drugs, both, reversed most of the last mentioned parameters but ALO was more efficient in reducing TGF-β1, α-SMA, TNF-α and ALP as well as increasing % alteration.. ALO and SIL elicited anti-apoptotic, anti-inflammatory and autophagic effects on paracetamol-damaged liver cells and improved memory impairments of HE.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Anti-Inflammatory Agents; Apoptosis; Autophagy; Behavior, Animal; Biomarkers; Chemical and Drug Induced Liver Injury; Dipeptidyl-Peptidase IV Inhibitors; Hepatic Encephalopathy; Hydroxyethylrutoside; Male; Maze Learning; Memory; Memory Disorders; Piperidines; Rats; Rats, Wistar; Uracil

Nickel (Ni)-induced oxidative damage is a serious problem that leads to reproductive system failure through testicular damage. The present investigation was carried out to determine the effect of troxerutin (Txn) on testicular toxicity induced by Ni in experimental rat testes. The oral administration of Txn (100 mg/kg body weight [bw]) showed a significant (p < 0.01) increase in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), glutathione reductase (GR), glucose-6-phosphate dehydrogenase (G6PD), reduced glutathione, ascorbate, total sulphydryl groups, and testis-organ weight. Subsequently, the administration of Txn also significantly reduced the accumulation of Ni, lipid peroxidation products, and protein carbonyl levels in Txn-treated animals. Testicular protection in the experimental animals by Txn is further substantiated by a remarkable reduction of Ni, which was revealed through testicular tissue histopathology. These studies suggest that Txn could prevent oxidative damage and testicular toxicity induced by Ni in experimental animals.

Topics: Animals; Antioxidants; Cell Membrane; Chemical and Drug Induced Liver Injury; Hydroxyethylrutoside; Male; Nickel; Oxidative Stress; Random Allocation; Rats; Rats, Wistar; Testis

This study investigates the effects of troxerutin on nickel (Ni)-induced oxidative stress in rats.. Nickel as nickel sulfate (20 mg/kg body weight (b.w.)) was administered intraperitoneally for 20 days to induce toxicity in the subject rats. The levels of stress markers AST, ALT, ALP, LDH, and GGT in the hepatic tissue were significantly increased while a decrease in the levels of enzymic and non-enzymic antioxidants was observed in Ni intoxicated rats.. Oral administration of troxerutin along with Ni for 20 days in a dose-dependent manner significantly reverted the stress markers in the liver tissue to near normal level. Troxerutin exhibited significant protection at 100 mg/kg b.w. Histopathological studies also supported the above findings.. Thus, we conclude that troxerutin preserved the histo-architecture and ameliorated stress markers in the liver tissue of Ni-intoxicated rats.

Topics: Alanine Transaminase; Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Hydroxyethylrutoside; Lipid Peroxides; Liver; Male; Nickel; Oxidative Stress; Protein Carbonylation; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances

Troxerutin, a trihydroxyethylated derivative of rutin, has been well-demonstrated to exert hepatoprotective properties. In the present study, we attempted to explore whether the antioxidant and anti-inflammatory mechanisms were involved in troxerutin-mediated protection from D-gal-induced liver injury. The effects of troxerutin on liver lipid peroxidation, antioxidant enzymatic activities, and the expression of inflammatory mediator were investigated in D-gal-treated mice. The results showed that troxerutin largely attenuated the D-gal-induced TBARS content increase and also markedly renewed the activities of Cu, Zn-SOD, CAT, and GPx in the livers of D-gal-treated mice. Furthermore, troxerutin inhibited the upregulation of the expression of NF-kappaB p65, iNOS, and COX-2 induced by D-gal. D-Gal-induced tissue architecture changes and serum ALT and AST increases were effectively suppressed by troxerutin. In conclusion, these results suggested that troxerutin could protect the mouse liver from D-gal-induced injury by attenuating lipid peroxidation, renewing the activities of antioxidant enzymes and suppressing inflammatory response. This study provided novel insights into the mechanisms of troxerutin in the protection of the liver.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Antioxidants; Aspartate Aminotransferases; Body Weight; Chemical and Drug Induced Liver Injury; Galactose; Hydroxyethylrutoside; Lipid Peroxidation; Liver; Male; Mice; Oxidative Stress; Transcription Factor RelA

For more than 40 years coumarin has been successfully used in the therapy of chronic venous insufficiency (CVI). The occurrence of liver injuries is rather rare and happens predominantly when doses are administered which are significantly higher than necessary for therapeutical use. Such effects caused by high coumarin concentrations are reproducible in in vivo experiments in mice or rats and HepG2-cells. In order to characterize the mechanism of liver injuries, the isolated perfused rat liver has been chosen as model. Since liver injuries are quite rare, if coumarin is used in co-medication with troxerutin, a possible protective influence of this flavonoid has been investigated. In concentrations higher than 4 mmol/l, coumarin alone is effective in the isolated perfused rat liver. Then the release of the enzymes alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) increases and there is a measurable reduction of perfusion flow, oxygen consumption and rate of bile secretion. Additionally, the concentrations of hepatic adenosine triphosphate (ATP) and oxidized and total glutathione (GSSG/GSH) decrease. In the livers of fasting animals, coumarin doubles the concentration of hepatic malondialdehyde (MDA). This effect cannot be detected if troxerutin is added. In general, troxerutin reduces the concentration of all coumarin-metabolites in the perfusate and bile and changes the ratio of the main metabolites, coumarin: 3-hydroxycoumarin: 7-hydroxycoumarin. An analysis of the metabolic steps also shows that the amount of coumarin eliminated via faeces does not stem from absorbed coumarin, because the amount of orally applied coumarin detectable in the bile is less than 1%. The study demonstrates that troxerutin has hepatoprotective properties and thus protects the liver from a possible lipid peroxidation caused by coumarin. However, it is necessary to point out that these adverse effects caused by coumarin can be detected only in very high concentrations considerably above the regular therapeutical dosage. This allows the conclusion that troxerutin is a beneficial cofactor in coumarin preparations used for the therapy of chronic venous insufficiency.

Topics: Alanine Transaminase; Animals; Anticoagulants; Bile; Chemical and Drug Induced Liver Injury; Coumarins; Glutamate Dehydrogenase; Hydroxyethylrutoside; L-Lactate Dehydrogenase; Lipid Peroxidation; Male; Melilotus; Phytotherapy; Plant Extracts; Protective Agents; Rats; Rats, Wistar

Both male and female Wistar rats were treated with daily oral doses of a combination of the active components coumarin and troxerutin (Venalot-Depot) corresponding to 1, 8, 64 and 128 mg coumarin/kg b.w., respectively. Goal of the study was to study coumarin at the target organ liver for a longer period, after it had turned out from a fertility and teratogenicity study that liver alterations were observed in the P-generation following the elevated doses' treatment up to 10 weeks (male) and 3 weeks (female). Light and electron microscopic examinations of the livers revealed the following findings: The lesions are dose- and time-dependent. First signs of coumarin-induced hepatocellular alterations are fine granular protein-like precipitations in the region of the sER (smooth endoplasmatic reticulum) which conflux to large areas. The glycogen content decreases significantly at the same time. This is followed by an osmotically controlled water redistribution in the cytoplasm and an increased water inflow from the extracellular space (vacuolar degeneration) as well as an overload of the cytoplasm with lipids, taken in by nutrition. Doses of 64 and 128 mg/kg b.w. of the test substance produced extensive hepatic alterations, associated with hypertrophy of the liver, with a focal onset in the globular periphery, subsequently extending to peripheral and intermediate lobular areas. Since light or electron microscopic alterations were not observed following doses of 1 and 8 mg/kg b.w., the dose of 8 mg coumarin/kg b.w. can be determined as no effect dose for the rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Chemical and Drug Induced Liver Injury; Coumarins; Dose-Response Relationship, Drug; Drug Combinations; Endoplasmic Reticulum; Female; Hydroxyethylrutoside; Hypertrophy; Liver; Liver Diseases; Male; Microscopy, Electron; Rats; Rats, Inbred Strains; Rutin; Time Factors

Topics: Adult; Chemical and Drug Induced Liver Injury; Coumarins; Drug Combinations; Female; Humans; Hydroxyethylrutoside; Jaundice; Lymphedema; Rutin; Turner Syndrome