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At least 19 recordsLinked to original sources
PubMed1998

Estrogen-induced hepatic toxicity and hepatic cancer: differences between two closely related hamster species.

AIMS/BACKGROUND: Estrogen is known to affect hepatobiliary function; however, it is unusual for high serum levels of estrogen to actually result in clinically detectable hyperbilirubinemia. Women affected by cholestatic jaundice during pregnancy share this genetic susceptibility with two Cricetulus hamsters, the Armenian hamster (Cricetulus migratorius) and the Chinese hamster (Cricetulus griseus). Nevertheless, the pathophysiologic process responsible for this estrogen induced icterus may be different in women and hamsters. The present study compares various facets of estrogen-induced icterus in these two closely related hamsters. METHODS: Hamsters were injected with various estrogens and the acute and chronic effects on liver were monitored by measuring changes in serum constituents and by observing changes in hepatic structure as seen grossly and by light and electron microscopy. RESULTS: In previous studies, hepatic tumors developed in most Armenian hamsters after chronic estrogen treatment, but in the present study, the livers of Chinese hamsters were remarkably free of neoplastic change under similar conditions. Also, when compared with the responses in the Armenian hamsters, signs of hepatic destruction and regeneration were less prevalent in estrogen-treated Chinese hamsters, and they were less susceptible to the effects of estrogen (because larger doses of estrogen were required to produce icterus and the bilirubin levels were lower and of shorter duration). In contrast to the findings in Armenian hamsters, bile canaliculi were severely affected in livers of estrogen-treated Chinese hamsters, and hepatic microvesicular steatosis, indicative of an unusual lipodystrophy caused by estrogen, was prominent. An additional lesion peculiar to the Chinese hamster was striking sinusoidal dilatation, which may be analogous to the oral contraceptive-induced sinusoidal dilatation in humans. CONCLUSIONS: Although these two hamster species are genetically similar, the genes activated by the estrogen receptor show remarkable heterogeneity when their respective livers are examined. Comparisons within these species may provide information about the specific gene activation responsible for particular pathologic events.

Adenoma, Liver Cell↗
PubMed1996

Flutamide-induced toxic hepatitis. Potential utility of ursodeoxycholic acid administration in toxic hepatitis.

Flutamide is a nonsteroidal antiandrogen commonly used in the treatment of prostate cancer. Hepatic toxicity associated with flutamide has been reported with an incidence from less than 1% to about 5%. Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, has been widely used in the treatment of cholesterol gallstones and of several liver diseases, but few data are now available concerning its use in the management of drug-induced hepatitis. The case of a patient who presented severe hepatitis with jaundice following use of flutamide is reported. UDCA treatment was started on admission and, contemporaneously, flutamide was withdrawn. Clinical and biochemical improvement was progressively observed, and the patient was discharged six weeks after the admission. Since fatal flutamide-related hepatitis has been reported, monitoring of serum liver tests is advocated during flutamide administration, and the effectiveness of UDCA in the treatment of drug-induced hepatotoxicity requires further study.

Adenocarcinoma↗
PubMed2004

Longitudinal effect of antiretroviral therapy on markers of hepatic toxicity: impact of hepatitis C coinfection.

To characterize longitudinal hepatic toxicity of antiretroviral therapy in HIV-infected women with and without hepatitis C virus (HCV) infection, we measured alanine and aspartate aminotransferase values among women initiating highly active antiretroviral therapy (HAART). For 312 HIV/HCV coinfected women who received HAART for a mean of 1.8 years, the prevalence of elevated aminotransferase levels >3 times and >5 times the upper limit of normal (ULN) was low (<12% and <4%, respectively), and the prevalence of elevated aminotransferase levels declined over time. When we analyzed trends in aminotransferase levels according to type of HAART received among HCV-infected and uninfected women, we found that mean aminotransferase levels declined among 539 women receiving therapy with protease inhibitors (decreases of 5.34%-4.23% of the ULN per year; P values for trend of.007-.06), but mean values among 128 women receiving therapy with nonnucleoside reverse-transcriptase inhibitors remained stable (from decreases of 1.65% to increases of 7.57% of the ULN per year; P values of.19-.71). Our findings lend support to assertions that antiretroviral therapy is safe for women with HCV infection.

Adult↗
PubMedDate not supplied

[Impact of seasons on efficacy of physiotherapeutic correction of hepatic function in toxic hepatitis in experiment].

Experiments on 172 Wistar rats modeled CCl4-hepatitis in transitory phases of about-annual cycle. In the autumn phase the animals with toxic hepatitis demonstrated poor normalization of biochemical parameters while the efficacy of physiotherapy (sapropel combined with magnetic field) was very high. In spring, normalization of the biochemical parameters was very high while the above physiotherapeutic complex was low effective.

Animals↗
PubMed2005

Antioxidant effect of Sargassum polycystum (Phaeophyceae) against acetaminophen induced changes in hepatic mitochondrial enzymes during toxic hepatitis.

The present study was aimed to examine the protective effects of Sargassum polycystum (Phaeophyceae) alcoholic extract on changes in liver mitochondrial enzymes against acetaminophen induced toxic hepatitis in experimental rats. The levels of protein, lipid peroxide, glutathione (GSH) in mitochondrial fraction, superoxide dismutase (SOD) and catalase (CAT) were also determined. The activities of tricarboxylic acid enzymes such as isocitrate dehydrogenase (ICD), alpha-ketoglutarate dehydrogenase (alpha-KGD), succinate dehydrogenase (SD), malate dehydrogenase (MD), NADH dehydrogenase, and cytochrome-c-oxidase were determined in mitochondrial fraction. The rats intoxicated with acetaminophen showed significant elevation in the levels of lipid peroxides with decreased levels of protein, GSH, SOD, CAT and impaired tricarboxylic acid cycle enzyme activities. The prior oral administration of S. polycystum alcoholic extract showed significant diminution in the severity of toxic hepatitis in acetaminophen-induced rats by maintaining the activities of tricarboxylic acid enzymes with concomitant improvement in the hepatic mitochondrial antiperoxidative status when compared with intoxicated animals. The results obtained in the present study indicate that the protective effects of S. polycystum extract may be due to the presence of some active compounds that are inhibitory against the free radicals generated during lipid peroxidation in acetaminophen induced toxic hepatitis.

Acetaminophen↗
PubMed1991

[Toxic hepatitis from cinchophen: report of 3 cases].

Three cases of hepatic toxicity due to cincophen (a uricosuric drug used for the treatment of gout) are reported. The three patients were females aged 57, 60 and 67 years, respectively, who were treated with cincophen because of renoureteral urate stones. The mean dose was 300 mg/day for a mean duration of 3-4 months before the hepatotoxic features first developed. Cincophen induces hepatic necrosis through a hypersensitivity or metabolic idiosyncrasy mechanism with histologic abnormalities similar to those due to isoniazid, anticonvulsants, halothane and methyldopa. In two patients the disease presented as acute hepatitis. One had severe hepatic failure and died. Cincophen had been widely used in Europe and severe hepatotoxicity reactions have been reported since then (with a mortality rate of about 50%). It is still commercially available in Spain in two preparations as lithium cincophenate and piperacine. The present study has the aim of recalling the severe problems associated with cincophen hepatotoxicity, so that new cases can be prevented.

Aged↗
PubMed1983

Hepatitis, toxic epidermal necrolysis and pancreatitis in association with sulindac therapy.

We report 2 patients who had serious adverse effects after taking sulindac. One of these patients developed toxic hepatitis and Stevens-Johnson/toxic epidermal necrolysis syndrome which resulted in death. Such fatal reaction to sulindac therapy has not been reported previously. There was temporal relation of ingestion of sulindac to 2 episodes of acute pancreatitis in the 2nd patient, strongly suggesting drug induction. Recent reports of similar side effects with other nonsteroidal antiinflammatory drugs suggest that these drugs may have potentially more serious toxicity than has been recognized.

Acute Disease↗
PubMed2001

Metabolic, idiosyncratic toxicity of drugs: overview of the hepatic toxicity induced by the anxiolytic, panadiplon.

Preclinical drug safety evaluation studies, typically conducted in two or more animal species, reveal and define dose-dependent toxicities and undesirable effects related to pharmacological mechanism of action. Idiosyncratic toxic responses are often not detected during this phase in development due to their relative rarity in incidence and differences in species sensitivity. This paper reviews and discusses the metabolic idiosyncratic toxicity and species differences observed for the experimental non-benzodiazepine anxiolytic, panadiplon. This compound produced evidence of hepatic toxicity in Phase 1 clinical trial volunteers that was not predicted by rat, dog or monkey preclinical studies. However, subsequent studies in Dutch-belted rabbits revealed a hepatic toxic syndrome consistent with a Reye's Syndrome-like idiosyncratic response. Investigations into the mechanism of toxicity using rabbits and cultured hepatocytes from several species, including human, provided a sketch of the complex pathway required to produce hepatic injury. This pathway includes drug metabolism to a carboxylic acid metabolite (cyclopropane carboxylic acid), inhibition of mitochondrial fatty acid beta-oxidation, and effects on intermediary metabolism including depletion of glycogen and disruption of glucose homeostasis. We also provide evidence suggesting that the carboxylic acid metabolite decreases the availability of liver CoA and carnitine secondary to the formation of unusual acyl derivatives. Hepatic toxicity could be ameliorated by administration of carnitine, and to a lesser extent by pantothenate. These hepatocellular pathway defects, though not directly resulting in cell death, rendered hepatocytes sensitive to secondary stress, which subsequently produced apoptosis and hepatocellular necrosis. Not all rabbits showed evidence of hepatic toxicity, suggesting that individual or species differences in any step along this pathway may account for idiosyncratic responses. These differences may be roughly applied to other metabolic idiosyncratic hepatotoxic responses and include variations in drug metabolism, effects on mitochondrial function, nutritional status, and health or underlying disease.

Animals↗
PubMedDate not supplied

[Effect of aevite and riboflavin on the electrolyte balance in the wall of the hepatic blood vessels in experimental toxic hepatitis].

The effects of aevite and riboflavin on electrolyte balance in the vessel wall were studied in toxic hepatitis in the cat. Significant changes in the contents of Na+, K+, Ca2+ and Mg2+ ions in the hepatic blood vessels were found in all periods of observation. The treatment of toxic hepatitis with aevite and riboflavin results in normalization of electrolyte balance of the vessel wall.

Animals↗
PubMedDate not supplied

[Effect of enterosorption effects on hepatic enzyme spectrum in experimental toxic hepatitis].

Influence of a new sorbent based on the AU-L lignin on the hepatic enzyme spectrum has been investigated in rats with experimental toxic hepatitis. The intact animals were in control group. There was a shift in lactate dehydrogenase (LDH) isoenzymic spectrum to the LDH5 side, glucose-6-phosphate dehydrogenase (G-6-PDH) activity increased to 144.7% against the control. Aspartate aminotransferase (AsT) activity reduced 2 times and alanine aminotransferase (ALT) activity enhanced 1.3 times, LDH2 activity increased 2.8 times in the liver of rats with toxic hepatitis which received sorbent for 7 days versus the untreated animals. The LDH4 and LDH5 fractions activity lowered to the level of the intact animals. G-6-PDH activity continued to increase, aminotransferase activity reduced up to the level less than control. The aerobic shifts in the LDH isoenzymic spectrum in which LDH4 and LDH5 fractions' activity completely returned to the control level evidence for glycolysis conversion to the aerobic type that apparently was promoted by positive effects of enterosorbent.

Animals↗
PubMed2005

[Effect of heptral and folic acid on the hepatic functions during toxic hepatitis].

The aim of study was to evaluate effectiveness of heptral (S-Adonosylmethionine-Adomet) and folic acid during the acute toxic damage of the liver induced by carbon tetrachloride. Experiments have been carried out on pubertal rats. The carbon tetrachloride intoxication was performed by subcutaneous injection of CCL(4) 1 ml/kg dissolved in 1 ml of olive oil. The activity of aspartat-and alaninaminotransferases, alkaline phosphatase, the content of free and total billirubine in the blood, as well as total oxidant and antioxidant activity of the blood, were measured by the spectrophotometric techniques. Oxidative stress, cytolyses of the hepatocytes and cholestasis were observed during CCL(4) intoxication. Heptral, and in less degree, folic acid improved liver function during the acute toxic damage, but complex therapy with heptral and folic acid revealed more expressive hepatoprotective effect. It is suggested that better positive effect of complex therapy with heptral and folic acid compared with monotherapy by each drug is probably associated with resynthesis of methionine from homocystein (toxic metabolite of adenosylmethionine) by folate. This combination allows reducing the side effects of heptral induced by homocysteine.

Animals↗
PubMed2005

Improved hepatic toxicity profile of portal vein adjuvant hepatic infusional chemotherapy.

PURPOSE: To determine whether floxuridine (FUDR) can be delivered with low hepatic toxicity through the portal vein (PV) as an adjuvant to surgically treated colorectal metastases. PATIENTS AND METHODS: Fifty-one patients undergoing complete resection and/or ablation for colorectal hepatic metastases were prospectively enrolled at a National Cancer Institute-designated comprehensive cancer center. Two sequential phase II trials were performed. Each trial included complete surgical treatment followed by sequential, alternating (22 patients) or concurrent (29 patients) regional PV FUDR and systemic fluorouracil (FU) with leucovorin chemotherapy. RESULTS: Fifty percent of patients were male. The mean age at diagnosis was 57 years. The mean number of lesions resected was three (range, one to 11 lesions). The stage at diagnosis was II, III, and IV in 16.9%, 52.8%, and 28.3% of patients, respectively. One- and 3-year overall survival rates were 92.7% and 41.8%, respectively. The 1- and 3-year disease-free survival rates were 64.5% and 19%, respectively. The site of first recurrence was hepatic in 35.9% of patients. Treatment was terminated early in 24 patients (17 patients progressed, two refused treatment, and five had nonhepatic toxicities). Fifty-five percent of patients received 75% to 100% of the planned FUDR courses, and 72% received greater than 50% of the planned FUDR dose. Only four patients required dose reductions of FUDR because of grade 3 hepatic toxicity. No patient required biliary stenting or had discontinuation of PV infusion because of hepatic toxicity. CONCLUSION: The delivery of PV FUDR and FU with leucovorin can be performed with a high percentage of expected drug delivery and a low drug-induced hepatic toxicity rate, while achieving acceptable overall and disease-free survival.

Adult↗
PubMed1983

Hepatic toxicity of antiepileptic drugs: a review.

Hepatic toxicity of antiepileptic drugs has been well recognized for many years. Despite the increasing awareness of chronic toxicity of antiepileptic drugs, this aspect has remained of limited importance. Since the introduction of valproate, this situation has changed fundamentally. Following a general introduction to the classification and symptomatology of drug-induced hepatic toxicity, a detailed description of hepatic toxicity caused by phenytoin, carbamazepine, and valproate is presented, including classification, symptomatology and histological features. Hepatic toxicity caused by all three drugs may be classified as idiosyncratic reactions. However, whereas toxic reactions following phenytoin and carbamazepine are characterised by a rather short duration of exposure before symptoms occur with accompanying clinical features of hypersensitivity, valproate-induced hepatic toxicity exhibits no signs of hypersensitivity and often occurs following prolonged exposure, speaking in favor of a metabolic aberration as the underlying cause. Hypotheses explaining the mechanisms involved in this phenomenon are reviewed. Guidelines for averting valproate-induced hepatic toxicity are presented.

Anticonvulsants↗
PubMed1997

Trihalomethane comparative toxicity: acute renal and hepatic toxicity of chloroform and bromodichloromethane following aqueous gavage.

Bromodichloromethane (BDCM) and chloroform (CHCl3) are by-products of drinking water chlorination and are the two most prevalent trihalomethanes (THMs) in finished drinking water. To date, no comprehensive comparison of the acute renal and hepatic effects of BDCM and CHCl3 following oral gavage in an aqueous dosing vehicle has been conducted. To characterize BDCM- and CHCl3-induced nephro- and hepatotoxicity following aqueous gavage and compare directly the responses between these THMs, 95-day-old male F-344 rats were given single oral doses of 0.0, 0.75, 1.0, 1.5, 2.0, or 3.0 mmol BDCM or CHCl3/kg body wt in an aqueous 10% Emulphor solution. Compound-related hepatic and renal damage was evaluated by quantitating clinical toxicity markers in the serum and urine, respectively. Both THMs appear to be equally hepatotoxic after 24 h, but BDCM caused significantly greater elevations in serum hepatotoxicity markers than CHCl3 at 48 h following exposure to 2.0 and 3.0 mmol/kg. In addition to causing more persistent liver toxicity than CHCl3, BDCM also appears to be slightly more toxic to the kidney at lower doses. Potency differences between the two THMs may be due to pharmacokinetic dissimilarities such as greater metabolism of BDCM to reactive metabolites or more extensive partitioning of BDCM into kidneys and fat depots, resulting in prolonged target tissue exposure.

Animals↗
PubMed1993

Toxic hepatic injury is associated with proliferation of portal nerve fibers.

Hepatic innervation is thought to play an important role in the regulation of metabolism. Regenerating liver nodules in cirrhosis have a paucity of nerve fibers. The situation in chronic necroinflammatory and cholestatic liver diseases is unclear. We have therefore evaluated hepatic innervation in toxic hepatitis and non-specific reactive hepatitis. Liver biopsies from 42 patients considered to have chronic toxic liver injury, 25 patients with chronic reactive inflammatory infiltrates and variable degree of hepatic fibrosis and the control group comprising of 23 individuals who had undergone laparotomy for non-hepatic reasons (trauma etc.) and who had entirely normal hepatic histology were studied histologically and immunohistochemically for the presence of nerve fibres. Semiquantitative analysis showed significant proliferation of portal nerve fibers in biopsies confirmatory of toxic liver injury. Assessment of hepatic neural elements may be useful in the differential diagnosis of unspecified liver injury where toxic injury may be implicated.

Adolescent↗
PubMed1992

Methionine enkephalin accumulates in plasma but not in brain or cerebrospinal fluid of rats with acute toxic hepatitis.

In order to determine whether acute toxic hepatitis in the rat is associated with an accumulation of methionine enkephalin in plasma and increased blood-to-brain transfer of methionine enkephalin, immunoreactive methionine enkephalin levels were determined by radioimmunoassay in plasma, cerebrospinal fluid and whole brain samples from rats with thioacetamide induced acute toxic hepatitis. Thioacetamide treatment was associated with an 8.7-fold increase in plasma immunoreactive methionine enkephalin levels (P less than or equal to 0.005) 24 h after treatment. However, this marked elevation in plasma immunoreactive methionine enkephalin levels was not associated with an increase in whole brain or cerebrospinal fluid immunoreactive methionine enkephalin levels. These data suggest that increased plasma-to-brain transfer of methionine enkephalin does not occur in this model of acute toxic hepatitis.

Acute Disease↗
PubMed1989

Model systems for detecting the hepatic toxicity of pyrrolizidine alkaloids and pyrrolizidine alkaloid N-oxides.

Indicine N-oxide (INO) is a pyrrolizidine alkaloid (PA) with antitumor activity in animals and humans. Prior studies showed that despite the known hepatic toxicity of the PAs, INO did not produce hepatic toxicity in animals but caused unpredictable lethal hepatic toxicity in humans. In this study we have attempted to find a model system for predicting the hepatotoxic potential of antitumor PAs. Primary cultures of rat hepatocytes showed toxicity only with the most hepatotoxic PAs such as lasiocarpine, but did not detect toxicity with other PAs. Subchronic intraperitoneal administration of PAs to weanling rats and adult mice produced, in surviving animals, hepatic megalocytosis and centrilobular necrosis with heliotrine (H) and 9-O-(R(-)-2-(4'-chlorophenyl)-2-hydroxybutyryl)retronecine N-oxide (RC1NO) but only megalocytosis with INO. Thus, despite previous reports, weanling rats offered no advantage over adult mice for detecting significant hepatic toxicity with PAs. Phenobarbital pretreatment of the mice did not increase the hepatic toxicity of any of the PAs. Subchronic oral administration of PAs to adult mice produced hepatic megalocytosis and centrilobular necrosis in surviving animals with H and RC1NO and megalocytosis with INO. Animals that died acutely following oral administration of INO showed hepatic centrilobular necrosis. Administration of several courses of INO intravenously to dogs produced histological evidence of centrilobular hemorrhagic necrosis. It is concluded that there is no single animal model that will predict hepatic toxicity of the type seen in humans with the antitumor PAs. A combination of studies using adult mice and dogs and lethal doses of the PAs offers the best way of detecting potential hepatic toxicity.

Administration, Oral↗