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At least 181 records · Page 10Linked to original sources
PubMed2006

Sinusoidal endothelial cells as an early target for hepatic toxicants.

Recent studies demonstrate that the hepatic sinusoidal endothelial cells (SEC) are a sensitive direct target for early toxicity to acetaminophen (paracetamol, APAP) and this toxicity is exacerbated following a single and multiple week-end type alcoholic binge(s). SEC become swollen and begin to lose the ability to endocytose FITC-FSA, a ligand for the scavenger receptor, as early as 30 minutes after the administration of APAP. Gaps through the SEC appear to be formed by the destruction and/or coalescence of fenestrae and are seen as early as 2 hrs after the administration of APAP which is prior to any evidence of injury to parenchymal cells. The gaps permit red blood cells to penetrate into the Space of Disse. Subsequently, the sinusoid may collapse or disintegrate reducing blood flow. The gaps are larger and more frequent in ethanol binged animals subsequently treated with APAP. Similar gaps are seen in the early stages of hepatic venoocclusive disease. Administration of a NO donor or a MMP-2 and MMP-9 inhibitor minimizes endothelial injury and red blood cell penetration into the Space of Disse. The injury is exacerbated when an inhibitor of eNOS is administered and minimized when iNOS is inhibited suggesting a protective role for constitutive NO derived from SEC. Both NO and MMPs are known to affect the cytoskeleton of SEC which in turn affects the formation and maintenance of the fenestrae.

Acetaminophen↗
PubMed1995

[Hair analysis in the diagnosis of toxic hepatitis after Ecstasy abuse].

HISTORY AND CLINICAL FINDINGS: A young man, aged 18 years, was admitted to hospital for suspected hepatitis, having developed increasing jaundice without any pain. His urine was light brown in colour and the stools often liquid and pale. Every 14 days for the last 4 months he had been taking 2 tablets of "ecstasy" (methylenedioxyamphetamine; MDMA). Physical examination was unremarkable and the patient was in good general condition. TESTS: The activities of GOT, GPT and alkaline phosphatase were raised (to 903, 744 and 270 U/l, respectively) as was the bilirubin concentration (16.8 mg/dl). Tests were negative for: leptospira and the viruses of mumps, HI, varicella zoster, picornavirus, cytomegaly, Coxsackie and hepatitis, A, B and C. Ultrasound revealed hepatomegaly, with a normal echo pattern. Hair analysis demonstrated, in two different hair segments (0-2 cm and 2-4 cm, respectively) both MDMA (6.4 and 4.3 micrograms/g hair) and its metabolite MDA (0.7 and 5.0 micrograms/g hair). TREATMENT AND COURSE: No specific treatment was required. After intake of the drug had been stopped the transferase activities and bilirubin concentration became essentially normal. CONCLUSION: Hair analysis can be valuable in confirming "ecstasy" abuse, especially when it is denied, and thus contribute to clarifying the cause of toxic hepatitis.

Adolescent↗
PubMed2001

The preventive role of deferoxamine against acute doxorubicin-induced cardiac, renal and hepatic toxicity in rats.

The iron chelating activity of deferoxamine (DFO) has been exploited to obtain protection against the peroxidative damage in rat heart which was induced by the administration of an acute dose of doxorubicin (DXR, 25 mg x kg(-1), i.v.). The peroxidative lesions were evaluated both biochemically and histopathologically, 48 h after DXR administration. Abnormal biochemical changes including a marked increase in the levels of serum creatine kinase isoenzyme (CK-MB), and lactate dehydrogenase (LDH), as well as elevated serum creatinine, blood urea nitrogen and transaminases (ALT and AST) levels were observed. Myocardial tissue from DXR treated rats showed a marked increase in malondialdehyde (MDA) production and depletion of reduced glutathione (GSH) contents. Similar results were also observed in both kidney and liver tissues. Pretreatment of rats with DFO, given i.p. 30 min prior to DXR injection, substantially reduced the peroxidative damage in the myocardium, hepatic and renal tissues and markedly lowered the serum CK-MB, LDH and the other biochemical variables. The protective effects obtained by DFO administration, however, were not complete and did not reach those of the control group. The significant protection against DXR-induced cardiomyopathy by DFO was evident from the histopathological findings observed by light microscopy. DFO at a dosing level equivalent to 10-fold of that of DXR was useful to obtain protective effects. Higher DFO dosing levels did not, however, show more improvement in the DXR-induced cardiotoxicity and at the same time exhibited hepatoxicity which was confirmed by microscopical examination. These results strongly suggest that DFO protects against acute DXR-induced cardiotoxicity in a dose-dependent manner with recognizing the presence of mild DFO-related biochemical and cytological hepatic toxicity.

Analysis of Variance↗
PubMedDate not supplied

[Influence of qualitatively different diets on the reproductive capacity and function of the adrenal cortex in rats with experimental toxic hepatitis].

The effect of a diet rich in protein and the group B vitamins on the function of the ovaries and adrenal cortex, as well as on the reproductive capacity of animals with experimental affection of the liver produced by administration of carbon tetrachloride was studied on 115 mongrel albino female-rats. A high-standard semisynthetic diet devised at the Institute of nutrition of the AMS of the USSR and three isocaloric experimental diets calorifically enriched by 20, 50 and 100 per cent and containing a double amount of the group B vitamins were used in tests. The protein and vitamins enrichment of the diet, although failing to normalize the estrual cycle, neveretheless contributed to a significant reduction of the embryos' death in pregnant animals, the restoration of the reproductive capacity of the rats being directly proportional to the degree of the protein enrichment of the diet. The use of experimental diets helped normalize the adrenal cortex function in pregnant rats with toxic hepatitis, this manifesting itself in the falling amount of corticosterone in the blood serum outflowing from the suprarenals down to the control level.

Adrenal Cortex↗
PubMed1978

Selective modification of the renal and the hepatic toxicities of chloroform by induction of drug-metabolizing enzyme systems in kidney and liver.

Renal and hepatic microsomal enzyme activities were measured in ICR male mice treated with phenobarbital (PB), 3-methylcholanthrene (3MC), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or polychlorinated biphenyls (PCB). The effect of these agents on subsequently administered single doses of chloroform (CHCI3) were also determined. 3MC, TCDD and PCB increased renal as well as hepatic microsomal enzyme activities. PB increased hepatic but not renal microsomal enzyme activities. The hepatotoxicity of CHCI3 was increased by pretreatment with PB but decreased by pretreatment with TCDD. 3MC and PCB were without effect on CHCI3-induced liver damage. Pretreatment with 3MC, TCDD or PCB reduced the renal toxicity of CHCI3, but PB had no effect on CHCI3-induced kidney damage. Since at least one product of enzymatic metabolism of CHCI3 is believed to be a toxic, reactive intermediate the differential effects of inducers of microsomal drug-metabolizing enzyme activities on the renal and hepatic toxicities of CHCI3 strongly suggest that the CHCI3 metabolite(s) ultimately responsible for renal and hepatic damage are not generated at a common site. That is the metabolite responsible for hepatic is probably generated in the liver and the metabolite responsible for renal damage is probably generated in the kidney.

Animals↗
PubMed1992

[Combined chemotherapy of toxic hepatitis in patients with pulmonary tuberculosis].

The follow-up involved patients with infiltrative pulmonary tuberculosis who developed toxic medicamentous hepatitis associated with antituberculosis drugs. They were treated by the method of combined pharmacotherapy which comprised sodium nucleinate (0.5 g 4 times daily), splenin (2 ml twice a day) and quercetin. The given combination of drugs rapidly improved clinical parameters and normalized immunologic tests.

Adult↗
PubMed1977

[Effect of triton WR 1339 on the ultrastructure of liver parenchymal and stromal cells in rats with chronic toxic hepatitis].

A preliminary injection of triton WR 1339 protectively influenced the chronic toxic CCl4-hepatitis. The ultrastructural peculiarities were close to the normal ones in hepatocytes, in addition to the increased triglyceride rejection from cells by means of autophagy. The revealed stimulation signs of pinocytosis in hepatocytes and the Kupfer cells are accompanied by the activation of the Golgi complex and, probably, by the increased protein catabolism in lysosomes. The signs of phagocytosis increase in the Kupfer cells were determined. It is supposed that the marked ultrastructural peculiarities of liver cells reflect a more effective restoration or a lesser injury under the influence of triton WR 1339.

Animals↗
PubMed1994

Renal and hepatic toxicity after high-dose 7-hydroxymethotrexate in the rat.

To examine directly the hepatic and renal toxicity of 7-hydroxymethotrexate (7-OH-MTX) without interference of the parent compound methotrexate (MTX), we purified and gave 100 mg/kg 7-OH-MTX to rats, a dose resulting in serum levels of 7-OH-MTX comparable with those achieved in the clinic after the administration of high-dose MTX (HD-MTX). After only 5 h, the 7-OH-MTX-treated rats demonstrated 2.6-fold increases in serum creatinine values and 2-fold elevations in serum aspartate aminotransferase (ASAT) levels as compared with the controls. Morphologic evidence of toxicity, however, was apparent only in the kidneys. Intraluminal cellular debris containing membranous material and deteriorated organelles was seen, but no precipitate of the delivered drug. The peak serum concentration of 7-OH was up to 939 microM, and concentrations of 7-OH-MTX declined triphasically, showing a t1/2 alpha value of 2.45 min, a t1/2 beta value of 30.5 min, and a terminal half-life (t1/2 gamma) of 240 min. The total clearance value was 14.5 ml min-1 kg, and the postdistributional volume of distribution (V beta) was 5070 ml/kg. Our results may indicate a direct toxic effect of 7-OH-MTX on kidney and liver cells.

Animals↗
PubMed1995

Hepatic toxicity associated with 2'-3' dideoxyinosine in children with AIDS.

Among 34 children with AIDS enrolled in a trial with 2'-3' dideoxyinosine (ddI), six (aged 1-6 years) developed liver abnormalities within 2-18 months after institution of ddI. Two children died of fulminant hepatic failure (one had also an adenovirus infection), and four had a striking elevation of alkaline phosphatases (AP: 1120-7000 IU/L). All of them received sulfa drugs and antifungic treatment with ketoconazole or fluconazole. Three had a serology positive for hepatitis C virus. The evolution of liver enzymes following withdrawal and rechallenge with ddI in the children with elevated AP was an indication of drug-induced toxicity in two patients. In both of the others, readministration of ddI did not cause any subsequent problems. Liver histology in the patients with fulminant hepatitis showed an extensive hepatic necrosis. Liver biopsy done in two other patients revealed a mild granulomatous hepatitis in one and nonspecific changes (i.e., steatosis and a mild inflammation) in the other. Hepatic toxicity has been described with ddI and other nucleoside analogs in adult patients. These six children had many potential causes of liver disease. It may be that ddI is not hepatotoxic per se but that it precipitates liver disease in predisposed patients. We recommend that liver functions be carefully monitored when using this drug.

Acquired Immunodeficiency Syndrome↗
PubMed2004

The canals of hering might represent a target of methotrexate hepatic toxicity.

Methotrexate treatment for psoriasis is known to cause hepatic fibrosis in some patients, which might progress to cirrhosis. The fine, radiating, fibrous septa developing in this setting have a distribution that is reminiscent of the location of the canals of Hering (coH). To assess the possibility of fibrous obliteration of the coH in patients receiving methotrexate, we developed a staining technique by combining an immunohistochemical stain for cytokeratin 7 with a modified Masson trichrome. Sixteen biopsy specimens from 7 patients were evaluated. The biopsies had a variety of histologic changes, including steatosis, anisonucleosis, multinucleation, chronic inflammation, bile duct damage, and ductular reaction. Fibrosis was present in 13 biopsy specimens (81%) and was mild in 7, moderate in 3, and severe in 3 specimens. Compared with normal (control) liver specimens, biopsy specimensfrom patients receiving methotrexate had decreased numbers of coH (1.9 +/- 0.8 vs 5.2 +/- 1.7; P < .025). In specimens with moderate or severe fibrosis, fibrous septa sometimes extended along the coH. These findings suggest that scarring of the coH might be a consequence of the toxic effects of methotrexate.

Adult↗