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At least 199 records · Page 11Linked to original sources
PubMed2005

Mechanisms of benzarone and benzbromarone-induced hepatic toxicity.

Treatment with benzarone or benzbromarone can be associated with hepatic injury. Both drugs share structural similarities with amiodarone, a well-known mitochondrial toxin. Therefore, we investigated the hepatotoxicity of benzarone and benzbromarone as well as the analogues benzofuran and 2-butylbenzofuran. In isolated rat hepatocytes, amiodarone, benzarone, and benzbromarone (20 micromol/L) decreased mitochondrial membrane potential by 23%, 54% or 81%, respectively. Benzofuran and 2-butylbenzofuran had no effect up to 100 micromol/L. In isolated rat liver mitochondria, amiodarone, benzarone, and benzbromarone, but not benzofuran, decreased state 3 oxidation and respiratory control ratios for L-glutamate (50% decrease of respiratory control ratio at [micromol/L]: amiodarone, 12.9; benzarone, 10.8; benzbromarone, <1). Amiodarone, benzarone, and benzbromarone, but not benzofuran, also uncoupled oxidative phosphorylation. Mitochondrial beta-oxidation was decreased by 71%, 87%, and 58% with 100 micromol/L amiodarone or benzarone and 50 micromol/L benzbromarone, respectively, but was unaffected by benzofuran, whereas ketogenesis was not affected. 2-Butylbenzofuran weakly inhibited state 3 oxidation and beta-oxidation only at 100 micromol/L. In the presence of 100 micromol/L amiodarone, benzarone or benzbromarone, reactive oxygen species production was increased, mitochondrial leakage of cytochrome c was induced in HepG2 cells, and permeability transition was induced in isolated rat liver mitochondria. At the same concentrations, amiodarone, benzarone, and benzbromarone induced apoptosis and necrosis of isolated rat hepatocytes. In conclusion, hepatotoxicity associated with amiodarone, benzarone, and benzbromarone can at least in part be explained by their mitochondrial toxicity and the subsequent induction of apoptosis and necrosis. Side chains attached to the furan moiety are necessary for rendering benzofuran hepatotoxic.

Amiodarone↗
PubMed1995

Hepatic toxicity resulting from cancer treatment.

Radiation-induced liver disease (RILD), often called radiation hepatitis, is a syndrome characterized by the development of anicteric ascites approximately 2 weeks to 4 months after hepatic irradiation. There has been a renewed interest in hepatic irradiation because of two significant advances in cancer treatment: three dimensional radiation therapy treatment planning and bone marrow transplantation using total body irradiation. RILD resulting from liver radiation can usually be distinguished clinically from that resulting from the preparative regime associated with bone marrow transplantation. However, both syndromes demonstrate the same pathological lesion: veno-occlusive disease. Recent evidence suggests that elevated transforming growth factor beta levels may play a role in the development of veno-occlusive disease. Three dimensional treatment planning offers the potential to determine the radiation dose and volume dependence of RILD, permitting the safe delivery of high doses of radiation to parts of the liver. The chief therapy for RILD is diuretics, although some advocate steroids for severe cases. The characteristics of RILD permit the development of a grading system modeled after the NCI Acute Common Toxicity Criteria, which incorporates standard criteria of hepatic dysfunction.

Dose-Response Relationship, Radiation↗
PubMedDate not supplied

[Colestasic toxic hepatitis caused by terbinafine: case report].

Trichophytic onychomycosis of the feet represents an important and serious medical problem. Until recent years, there was not cure for this unpleasant pathology. It is only at the beginning of the 50s, especially at the onset of the antimycotic systemic therapy that a cure is available offering high rate of clinical and mycological therapy. The purpose of this report is to better inform on the undesirable side-effects of antimycotic agents which are currently so largely disseminated. The case of a young patient is presented who was enjoying good health and who after 6 weeks of starting therapy with terbinafine on a doses of 1 pill of 250 mg a day, to treat a trichophytic onychomycosis in both feet, developed severe symptoms of toxic colostatic hepatitis duly corroborated after pertinent testing. Patient had a full recovery after a few months of having interrupted her therapy, apparently without any sequel. The literature in this regard has been revised and a close monitoring of the hepatic function is recommended prior and during treatment with this drug. The need to continue research to find an ideal antimycotic still not found is also recommended.

Adult↗
PubMed2005

[Mitochondrial hepatic toxicity associated with antiretroviral treatment].

Highly active antiretroviral therapy (HAART) has become the gold standard treatment of HIV/AIDS infection. NRTI-related mitochondrial toxicity has been recognized as a serious adverse effect of HAART. The mechanisms underlying NRTI-induced mitochondriopathy involve the inhibition of the human DNA polymerase gamma mtDNA mutations and oxidative stress. The clinical spectrum of NRTI-related toxicity ranges from a subclinical disease e.g. mild hepatic abnormalities, to a rare life-threatening condition with lactic acidosis and hepatic insufficiency. In the latter, liver histology shows massive steatosis. Ultrastructural assessment of mitochondrial abnormalities may be of help to address the NRTI toxicity in poorly symptomatic patients. Efforts have been recently made to assess the clinical relevance of non-invasive tests including the evaluation of mtDNA or mitochondrial functions in peripheral blood mononuclear cells for the diagnosis of NRTI-associated toxicity.

Acquired Immunodeficiency Syndrome↗
PubMed1984

On the mechanism of butylated hydroxytoluene-induced hepatic toxicity in rats.

The relations between serum transaminase activity and the hepatic contents of glutathione and lipid peroxide were examined following oral administration to rats of butylated hydroxytoluene (BHT; 500 or 1000 mg/kg). The glutathione level rapidly diminished and reached a minimum at 6 hr after BHT administration. The period of depletion was dependent on dose: restoration of the glutathione level took longer in high-dose rats than in low-dose rats. The content of hepatic lipid peroxide was not markedly changed by BHT throughout the experimental period. The activity of glutathione S-transferase was not affected until 12 hr after BHT administration but, thereafter, it increased with time and was accompanied by elevation of the glutathione level. Though the activities of serum glutamate-oxaloacetate transaminase and glutamate-pyruvate transaminase were not affected by low-dose BHT, they increased rapidly in the high-dose rates after a lag period of about 6 hr and reached a maximum at 24 hr after administration; at that time, the livers of the high-dose rats showed centrilobular necrosis. The results indicate that acute hepatic injury was induced by the high-dose BHT. Pretreatment with cobaltous chloride inhibited the increase in the activities of the serum transaminases produced by the high-dose of BHT accompanying the depletion of microsomal cytochrome P-450 content and the induction of glutathione content. These observations suggest that hepatic damage was associated with prolonged depletion of glutathione rather than with lipid peroxidation in the liver, and that the activated metabolites of BHT rather than the parent compound induced the tissue damage.

Alanine Transaminase↗
PubMed1985

Halothane hepatitis: toxicity or hypersensitivity?

A 32 year old female developed a severe hepatitis (serum bilirubin 544 mumol/l) one week after a halothane anaesthetic. Six months later a general anaesthetic was administered via a halothane free circuit without incident. A year later a further non halothane anaesthetic was administered this time utilising the routine circuit after briefly flushing the rubber tubing with oxygen. That evening she became febrile and the following day abnormal liver function tests were documented. She remained asymptomatic.

Adult↗
PubMedDate not supplied

[Hepatic toxicity of drugs].

This review deals in its first part with the hepatic mechanisms of drug detoxification and toxification as well as with the physiopathological mechanisms of drug-induced liver diseases. In the second part, the clinical and biological pictures of drug-induced pathological lesions are reviewed. Any liver abnormality should alert the clinician towards a possible toxic aetiology so that the risk of fulminant, eventually lethal, or of severe chronic liver disease can be avoided.

Chemical and Drug Induced Liver Injury↗
PubMed1977

Toxic hepatitis in black patients in natal.

The clinical and pathological features of toxic centrilobular zonal necrosis in Natal Blacks are described. It is suggested that this condition may be caused by the toxic action of Callilepis laureola (known to the Zulu as 'impila'). This plant and other herbs are used by many Blacks for self-medication or are prescribed by herbalists and witchdoctors.

Adolescent↗
PubMed2006

Role of the Kupffer cell in mediating hepatic toxicity and carcinogenesis.

Kupffer cells are resident macrophages of the liver and play an important role in its normal physiology and homeostasis as well as participating in the acute and chronic responses of the liver to toxic compounds. Activation of Kupffer cells directly or indirectly by toxic agents results in the release of an array of inflammatory mediators, growth factors, and reactive oxygen species. This activation appears to modulate acute hepatocyte injury as well as chronic liver responses including hepatic cancer. Understanding the role Kupffer cells play in these diverse responses is key to understanding mechanisms of liver injury. Idiosyncratic drug-induced liver disease results in morbidity and mortality, impacting severely on the development of new pharmacological agents. Modulation of the response of Kupffer cells by drugs has been suggested as a cause for the idiosyncratic response. Similarly, liver damage seen in chronic ethanol consumption appears to be modulated by Kupffer cell activation. More recent evidence has noted a contributory role of Kupffer cell activation in the process of hepatic carcinogenesis. Several nongenotoxic carcinogens, for example, activate Kupffer cells resulting in the release of cytokines and/or reactive oxygen species that induce hepatocyte cell proliferation and may enhance clonal expansion of preneoplastic cells leading to neoplasia. Kupffer cells therefore appear to play a central role in the hepatic response to toxic and carcinogenic agents. Taken together, the data presented in this symposium illustrate to the toxicologist the central role played by Kupffer cells in mediating hepatotoxicity.

Acute Disease↗
PubMedDate not supplied

[Effect of stimulation and depression of macrophages on development of paracetamol-induced acute toxic hepatitis in rats].

The role of macrophage (Kupffer cell) stimulation and suppression in the development of a toxic liver damage was studied in rats with acute hepatitis induced by paracetamol (acetaminophen, 1000 mg/kg). Pretreatment with carboxymethylated (1-->3)-beta-D-glucan (25 mg/kg, i.p., 48 h before paracetamol) for the macrophage stimulation or with gadolinium chloride (GdCl3, 7.5 mg/kg, i.v., 24 h before paracetamol) for the macrophage suppression has a protective effect manifested by normalization of the liver function test parameters and by a decrease in the degree of morphological changes in the liver cells. A relation between these positive effects and the TNF-alpha secretion by macrophages is discussed.

Acetaminophen↗
PubMed1990

Severe chemotherapy-related hepatic toxicity associated with MZ protease inhibitor phenotype.

We describe a 10 1/2-month-old boy in whom fulminant hepatic failure following chemotherapy for Wilms' tumor developed. He then received an orthotopic liver transplant. An unexpected finding was the accumulation of alpha 1-antitrypsin (AAT) in periportal hepatocytes. A pretransplant serum sample showed a Pi MZ phenotype. The rarity of hepatic failure following treatment for Wilms' tumor raises the possibility of an increased susceptibility to toxic injury in the presence of AAT accumulation. Determination of the frequency of protease inhibitor MZ phenotype in patients who have chemotherapy-related hepatotoxicity could be used to initiate a prospective study aimed at identifying an at-risk population for chemoradiotherapy-related hepatoxicity.

Alleles↗
PubMed2000

[Evaluation of hepatic toxicity following high-dose 5-FU arterial infusion chemotherapy: analysis of 42 cases of colorectal liver metastases].

The regional toxicity of an anticancer agent for normal liver tissue following hepatic arterial infusion chemotherapy (HAI) was evaluated in terms of morphology, function, and histopathology. Forty-two patients(M:F = 30:12; mean age, 59.9 years) with liver metastases from colorectal cancer were treated with HAI using a totally implantable vascular access port system from July 1994 to March 1999. The regimen used here was so-called weekly high-dose 5-fluorouracil(5-FU) infusion(5-FU, 1,000 mg/m2/week). Volume measurement of the liver demonstrated not only whole liver atrophy including the tumor but also volume reduction of the non-tumorous lobe. Atrophic change of the liver was seen in patients who were administered over 20 g/m2 of 5-FU(p < 0.01). The CT attenuation values of the liver were examined, and fatty infiltration was seen in six patients. Histologic examination of liver biopsies from the non-tumorous part revealed steatosis and infiltration of inflammatory cells in the portal triad, which were not seen in specimens prior to HAI. On clinical laboratory findings, enzymes representing bile duct, including alkaline phosphatase, leucine amino peptidase, and gamma-glutamyltranspeptidase, were increased in 22 patients. In terms of regional toxicity for long-term HAI, 20 g/m2 of 5-FU, is the key dose at which to consider temporary cessation or dose reduction.

Adult↗
PubMedDate not supplied

Inhibition of hepatic toxicities from polybrominated biphenyls and aflatoxin B in rats fed cauliflower.

Feeding diets containing cauliflower to rats inhibited hepatic residues of polybrominated biphenyls (PBB) with a reduction of fatty livers produced by 50 ppm of dietary PBB. Cauliflower diets also reduced the toxic effects of aflatoxin in Fischer rats, i.e. prevented mortality and internal hemorrhaging, and reduced liver pathology. These diets enhanced hepatic aminopyrine N-demethylase and p-nitroanisole O-demethylase activities. A kinetic study of aryl hydrocarbon hydroxylase reaction rates showed that apparent Km was lower in liver, kidney, and intestine, with a higher Vmax in the intestine. These data, combined with earlier studies, suggest that microsomal enzyme induction, especially in liver and intestine, affords a detoxication mechanism of two widespread food contaminants when animals are under a cauliflower dietary regimen.

Aflatoxins↗
PubMed1993

[Hepatic toxicity of antitubercular agents. Role of different drugs. 199 cases].

One hundred and ninety-nine cases of hepatic injury related to antituberculous treatment were analysed in order to assess the role played by each drug and to look for predisposing factors. This is a retrospective study of 169 cases reported in the literature and 30 cases reported to the regional pharmacovigilance centre of Paris Saint-Antoine. The mortality rate was related to the dose of isoniazid: it was 43 percent with a daily dose higher than 300 mg, and 9 percent with a daily dose of 300 mg or less (P < 0.001). Hepatic injury appeared significantly earlier in the case of rifampicin combination: 11 weeks without rifampicin and 2 weeks with rifampicin (P < 0.01). The role of pyrazinamide was difficult to determine because isoniazid and pyrazinamide were always used in combination. The influence of a preexisting liver disease could not be evaluated because of the small number of cases reported (8 cases). Alcoholism did not increase the mortality rate. Our results confirm the dose-dependent toxicity of isoniazid. Because of the short time elapsed before the apparent onset of hepatitis observed with the rifampicin combination, a close supervision of the patients should be exerted during the first weeks of treatment.

Adolescent↗
PubMedDate not supplied

[Effect of mellaril on the liver lysosomes of rats with acute toxic hepatitis].

In 24 hours after a single administration of melleril (30 mg/kg) an elevated injuriousness of "heavy" and "light" liver lysosomes of rats subjected to "in vitro" treatment with a pH 5.0 solution at 37 degrees was recorded. Introduction of melleril to rats with toxic CCl4-induced hepatitis (CCl4 dosage of 0.15 ml per 100 g body weight) depresses free activity of acid phosphatase, this fall, however, failing to reach the corresponding values in intact animals. An elevated injuriousness of "heavy" and "light" lysosomas undergoing treatment at pH 5.0 and 37degrees, revealed in all variants of the tests, is related to activation of lysosomal phospholipases with subsequent liberation of surfactant lipids and volumetric changes of the particles.

Acid Phosphatase↗
PubMed1994

Hepatic arterial infusion of verapamil and doxorubicin with complete hepatic venous isolation and extracorporeal chemofiltration: pharmacological evaluation of reduction in systemic drug exposure and assessment of hepatic toxicity.

Tumour resistance to chemotherapeutic drugs through expression of the multidrug resistance phenotype is a major impediment in the treatment of hepatic malignancies. We performed hepatic arterial infusion of verapamil (at a dose known to block P-glycoprotein activity) and doxorubicin combined with complete hepatic venous isolation and extracorporeal chemofiltration in non-tumour-bearing pigs with normal livers to evaluate the pharmacology and toxicology of this drug combination. The complete hepatic venous isolation-chemofiltration system significantly reduced system exposure to both verapamil and doxorubicin (P < 0.01). Hepatic arterial infusion of verapamil (2 mg/kg) alone did not result in hepatocellular toxicity. However, the combination of verapamil and doxorubicin (3 mg/kg or 5 mg/kg) produced significant elevations in liver enzymes (P < 0.01), and gross histological evidence of liver damage in 90% of the treated animals. The results of this study indicate that hepatic arterial infusion of verapamil and doxorubicin, in an attempt to improve treatment response in unresectable liver tumours expressing the multidrug resistance phenotype, may not be tolerated by patients with limited hepatic reserve.

Animals↗