Lyso-phosphatidylcholine is implicated in thioacetamide-induced liver necrosis

Thioacetamide is a weak hepatocarcinogen. To determine whether alterations in lysophosphatidylcholine are implicated in thioacetamide-induced hepatic necrosis, rats were injected i.p. with this agent (50 mg/Kg body weight per day) or diluent for 1, 3, 8 and 30 days. Serum catalytic activities of aminotransferases were determined. Incorporation of (32P)-orthophosphate into hepatic lysophosphatidylcholine was also evaluated in animals killed 75 minutes or 13 hours after isotope administration. Results demonstrate that: A significant increase in hepatic lysolecithin concentration occurs when a maximum level of serum aminotransferases is present. An increase of (32P)-orthophosphate radioactive incorporation in lysolecithin was observed at the two assayed labelling periods, which suggest an activation of phospholipase A. The radioactivity present in lysolecithin after 13 h isotope injection showed a close correlation with serum level of aminotransferases. From these results it can be deduced that lysolecithin is implicated in TAA-induced necrosis and may be generated by increase in either phospholipase A activity and/or synthesis.     

Regulation of rat liver phosphofructokinase levels in Morris hepatomas.

The levels of the major liver phosphofructokinase isozyme (PFK-L₂) and the PFK regulatory factor were measured in adult and fetal liver as well as Morris hepatomas of different differentiation states. The results indicate that both the PFK-L₂ activity and the PFK regulatory factor levels in well and highly differentiated hepatomas are not statistically different from the amounts found in adult liver. In the poorly differentiated hepatomas and fetal liver, the levels of both PFK-L₂ and PFK regulatory factor are approximately 2 and 3 fold greater, respectively, than what was found in adult liver.     

Tumor necrosis factor in solid tumors: increased blood levels in the metastatic disease.

TNF, a cytokine produced by macrophages, is able either to exert an antitumor activity, or to determine severe clinical complications, such as cachexia and septic shock. Increased blood levels of TNF have been described in cancer patients. The present study was performed to better define TNF secretion in patients with solid tumors. The study included 48 cancer patients (lung cancer: 22; colon cancer: 11; breast cancer: 10; renal cancer: 5), and among them 27 showed distant organ metastases. TNF serum levels were measured by IRMA method. The control group comprised 40 healthy subjects. TNF levels were also evaluated in relation to those of SIL-2R, whose increase seems to be associated with an unfavorable prognosis in cancer. High levels of TNF were seen in 27/48 (56%) patients. Mean levels of TNF were significantly higher in cancer patients than in controls. Moreover, within the cancer group, TNF mean values were significantly higher in metastatic patients than in those without metastases; the highest levels were observed in patients with visceral lesions as dominant metastasis sites. Finally, patients with high TNF concentrations showed significantly higher mean levels of SIL-2R than those with normal values. This study shows that the neoplastic metastatic disease is associated with an exaggerated TNF secretion.     

Regulation of some nitrogen catabolizing enzyme levels in chick liver.

Xanthine dehydrogenase, purine nucleoside phosphorylase, and tyrosine aminotransferase are all increased sharply in liver of chicks by dietary protein. Results in this paper show that most amino acids have this effect, with methionine and tryptophan being more effective than the remainder. This suggested that any source of amino nitrogen could cause a build-up of a nitrogenous intermedate(s) necessary for enzyme accumulation. The above hypothesis was tested by blocking the breakdown of amino acids using various antimetabolites. Results were uniformly successful in raising enzyme levels, and furthermore it was found that antimetabolites and amino acids are not additive, suggesting that they act by a similar mechanism.     

Serum glutamate dehydrogenase as a marker of hepatocyte necrosis in alcoholic liver disease.

Serum glutamate dehydrogenase concentration was assessed as a marker of the degree of hepatocyte necrosis found at liver biopsy in 95 patients suspected of having alcoholic liver disease. Although the serum concentration was raised in 54 patients, no relation between it and the severity of hepatocyte necrosis could be established. Glutamate dehydrogenase was therefore not confirmed to be a useful indicator of hepatocyte necrosis in patients with chronic alcoholism.     

Glutamate dehydrogenase: a reliable marker of liver cell necrosis in the alcoholic.

The usefulness of blood enzyme determinations as markers of liver necrosis was tested in 100 alcoholics who underwent biopsy during clinical investigation. Mean values of glutamate dehydrogenase (GDH), serum aspartate and alanine transferase (SGOT and SGPT), ornithine carbamoyltransferase (OCT), and gamma-glutamyltranspeptidase (gamma-GTP) tended to rise with increasing liver cell necrosis, though values of SGOT, SGPT, OCT, and gamma-GTP showed considerable overlap between the 32 patients with histologically proved hepatitis and the 68 without. By contrast, GDH values showed virtually no overlap between patients with and without hepatitis, and a value of two and a half times the normal value discriminated between the two groups. Because of its easy determination and its reliable reflection of liver cell necrosis the GDH concentration should be estimated routinely in alcoholic patients.     

Lycopene inhibits DNA damage and liver necrosis in rats treated with ferric nitrilotriacetate.

Experimental and epidemiological evidence suggests that lycopene, a carotenoid present in tomatoes, tomato products, and several fruits and vegetables, may play a role in preventing certain cancers in humans. We have investigated the effect of lycopene pretreatment on lipid peroxidation, oxidative damage to DNA, and histopathological changes in liver of animals subjected to intraperitoneal (ip) ferric nitrilotriacetate (Fe-NTA) administration. Compared with control rats, liver of Fe-NTA-treated animals showed a significant increase in the 8-oxo-7,8-dihydro-2'-deoxyguanosine level and a 75% increase in malondialdehyde accumulation concomitant with histopathological changes. Five days of lycopene pretreatment (10 mg/kg body weight, ip) almost completely prevented liver biomolecule oxidative damage and protected the tissue against the observed histological alterations.     

Hepcidin mRNA levels in mouse liver respond to inhibition of erythropoiesis

Hepcidin, a key regulator of iron metabolism, decreases intestinal absorption of iron and its release from macrophages. Iron, anemia, hypoxia, and inflammation were reported to influence hepcidin expression. To investigate regulation of the expression of hepcidin and other iron-related genes, we manipulated erythropoietic activity in mice. Erythropoiesis was inhibited by irradiation or posttransfusion polycythemia and stimulated by phenylhydrazine administration and erythropoietin. Gene expression of hepcidin and other iron-related genes (hemojuvelin, DMT1, ferroportin, transferrin receptors, ferritin) in the liver was measured by the real-time polymerase chain reaction. Hepcidin expression increased despite severe anemia when hematopoiesis was inhibited by irradiation. Suppression of erythropoiesis by posttransfusion polycythemia or irradiation also increased hepcidin mRNA levels. Compensated hemolysis induced by repeated phenylhydrazine administration did not change hepcidin expression. The decrease caused by exogenous erythropoeitin was blocked by postirradiation bone marrow suppression. The hemolysis and anemia decrease hepcidin expression only when erythropoiesis is functional; on the other hand, if erythropoiesis is blocked, even severe anemia does not lead to a decrease of hepcidin expression, which is indeed increased. We propose that hepcidin is exclusively sensitive to iron utilization for erythropoiesis and hepatocyte iron balance, and these changes are not sensed by other genes involved in the control of iron metabolism in the liver.     

Changes in polyphosphoinositide levels in rat liver nuclei in response to prolactin, a known hepatic mitogen.

The effect of prolactin action on nuclear polyphosphoinositide synthesis was investigated in isolated rat liver nuclei. An increased uptake of phosphate from [gamma 32P] adenosinetriphosphate was observed in both phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate with a maximum response at 10(-12) M concentration of hormone. Pulse-chase experiments in isolated nuclei following prolactin treatment indicate that the observed increase in accumulation of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate is mainly due to a decrease in their rate of turnover possibly induced by a change in activity of polyphosphoinositide-specific monoesterases. In vitro prolactin also reduces the activity of nuclear phospholipase C specific for phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate. Moreover, this feature is strongly supported by the concomitant decrease in nuclear diacylglycerol mass. Thus these data suggest that once prolactin reaches the nucleus an intranuclear signalling is evoked through inositol lipid metabolism.     

Serum neopterin levels in liver cirrhosis

Neopterin is a pyrazino-pyrimidine compound which is biosynthesized by macrophages. Increased concentrations of neopterin have been reported in conditions causing a stimulation of cellular immunity, such as viral and other infections, graft versus host disease, autoimmune disease and different malignancies. Recently, urinary neopterin levels have been found increased in patients with acute viral hepatitis and NANB chronic hepatitis. In the present study, neopterin serum levels have been measured in 23 cirrhotic patients (6 HBV related, and 17 cryptogenetic cirrhosis, 7 of them occurring in alcoholic subjects) and in 24 normal subjects. Mean values of serum neopterin were significantly increased in cirrhotics (3.92 +/- 3.28 ng/ml versus 1.24 +/- 0.51 ng/ml in controls, p less than 0.01). Serum neopterin values were not found to be significantly different in cirrhotics assessed in three different clinical classes according to Child's classification and in cirrhotics with and without serological findings of active disease. In fact, in cirrhotic patients, serum neopterin levels did not correlate with the values of serum AST, ALT, ALP, GGT and gamma-globulin. These data show that increased levels of serum neopterin occur in cirrhotic patients, but there is no relation between serum neopterin values and the activity or the clinical severity of the disease. The results are consistent with the hypothesis that activated macrophages are involved in all stages of liver cirrhosis irrespective of its aetiology.