Effect of cadmium on liver regeneration after partial hepatectomy in rats.

Cadmium is a nonabundant element that is widely distributed throughout the biosphere and its toxic effects are becoming potentially more serious due to industrialization. It has been reported that cadmium might interact with nucleic acid biosynthesis. In this study we examined the effect of cadmium administration, either 24 hr before or simultaneously to partial hepatectomy, on the liver regenerative process in rats, at different time intervals. The rate of DNA synthesis was suppressed markedly in the cadmium pretreated group and the first peak of liver regeneration was delayed, compared to the simply partially hepatectomized one. The administration of cadmium simultaneously to partial hepatectomy, caused a marked decrease of the rate of DNA biosynthesis, compared to the pretreatment. The rate-determining enzyme thymidine kinase was suppressed in the liver of both cadmium-treated groups. Biochemical parameters and histological findings were also coestimated. The above data suggest that either pre- or simultaneous administration of cadmium, suppressed the liver regenerative process, probably due to the inhibition of thymidine kinase.

Induction of metallothionein in the liver of carbon tetrachloride intoxicated rats: an immunohistochemical study.

Metallothioneins (MTs), are low molecular weight proteins, mainly implicated in metal ion detoxification. In the present study, we investigated the expression of hepatic MT in a rat model of injury and regeneration, induced by carbon tetrachloride (CCl(4)) administration. A single intraperitoneal injection of 1 ml CCl(4)/kg body weight was performed in male Wistar rats, killed at different time points post-administration. The enzymatic activities of aspartate and alanine aminotransferases in serum were determined, in addition to the liver histological findings, to estimate hepatotoxicity. The rate of tritiated thymidine incorporation into hepatic DNA, the enzymatic activity of thymidine kinase in liver tissue and the assessment of the mitotic index in hepatocytes, were used as indices of regeneration. MT was detected immunohistochemically in liver tissue sections. CCl(4) administration caused severe hepatic injury, followed by regeneration. MT expression became prominent as early as 12 h after the administration of CCl(4), in the nuclei of hepatocytes, while at 24 and 36 h intense cytoplasmic staining for MT appeared in the hepatocytes in the vicinity of necrotic areas. The peak of hepatocyte proliferative capacity, occurring at 48 h post-CCl(4) administration coincides with the maximum nuclear and cytoplasmic MT expression. At further time points MT expression presented a decreasing trend. Induction of MT expression was observed in the liver after a single administration of CCl(4), being more prominent at the time of maximum hepatocellular proliferation, participating actively in the replication of hepatocytes.

Effect of cadmium pretreatment on liver regeneration after partial hepatectomy in rats.

Cadmium is a rare element that is nevertheless widely distributed throughout the biosphere and its toxic effects are becoming potentially more serious due to industrialization. Liver regeneration can be considered as a spectacular example of controlled tissue increase. In this study we examined the effect of cadmium pretreatment, administered 24 h before partial hepatectomy, on the liver regenerative process in rats, at different time intervals. The rate of 3H thymidine incorporation into hepatic DNA and the activity of the enzyme thymidine kinase were used as indices of liver proliferative capacity. Thymidine kinase, the rate-determining enzyme of DNA biosynthesis, was suppressed during the first hours following partial hepatectomy in the liver of cadmium pretreated animals. DNA biosynthesis was also strongly decreased in cadmium pretreated animals, by delaying the first peak of liver regeneration, compared with the partially hepatectomized ones. Biochemical parameters, mitotic index and proliferating cell nuclear antigen staining were also coestimated. The above data suggest that cadmium pretreatment suppressed the hepatic regenerative process, probably due to the inhibition of thymidine kinase.

Hepatic stimulator substance administration enhances regenerative capacity of hepatocytes in cadmium-pretreated partially hepatectomized rats.

The liver is of central importance in the metabolism of essential and toxic metals such as cadmium (Cd). Cd pretreatment suppressed the regenerative capacity of hepatocytes, which normally occurs 24 hr after partial hepatectomy, due to the inhibition of the activity of the enzyme thymidine kinase. The effect of hepatic stimulator substance (HSS) administration (10, 20, and 40 mg protein/kg body weight) on hepatocyte proliferation was investigated in Cd-pretreated partially hepatectomized rats. HSS administration partly restored the suppressed hepatocyte DNA biosynthesis in Cd-pretreated partially hepatectomized rats. The hepatocyte mitotic activity and the percentage of proliferating cell nuclear antigen-positive nuclei were in accordance with the liver proliferative status. The administration of HSS did not affect in a statistically significant manner the activity of the enzyme thymidine kinase in Cd-pretreated partially hepatectomized rats. It is suggested that the administration of HSS ameliorates the diminished hepatocyte regenerative response to partial hepatectomy in this model of acute liver injury, due to Cd intoxication.

Putrescine administration reverses cadmium-associated inhibition of liver regeneration.

The liver is of central importance in the metabolism of essential and toxic metals such as cadmium. Cadmium pretreatment suppressed the liver regenerative response to partial hepatectomy, due to the inhibition of the enzymatic activity of thymidine kinase. Exogenous putrescine administration has been reported to stimulate liver regeneration in animal models of acute liver failure. The purpose of this study was to document whether the administration of this polyamine enhances the impaired regenerative capacity of hepatocytes in cadmium-pretreated partially hepatectomized rats. The intraperitoneal administration of putrescine (1 or 10 mg/kg body weight), at the time of surgery and at 4 and 8 hr postoperatively partly restored the suppressed hepatocyte deoxyribonucleic acid (DNA) biosynthesis and thymidine kinase activity in cadmium-pretreated partially hepatectomized rats. Mitotic activity and the percentage of hepatocytes positive for proliferating cell nuclear antigen nuclei were in accordance with the liver proliferative status. Our results showed that exogenous putrescine administration is able to improve diminished liver regeneration after partial hepatectomy in this animal model of acute hepatic injury.

Effect of interferon-alpha2b administration on rat liver regeneration after partial hepatectomy.

The purpose of the present study was to delineate the effect of interferon-alpha2b (IFN-alpha2b) administration on the liver regenerative capacity after partial hepatectomy in rats. The administration of IFN-alpha2b simultaneously with partial hepatectomy did not affect hepatic proliferation in a statistically significant manner. When IFN-alpha2b was administered either 2 or 12 hr postoperatively, an inhibition of hepatocyte proliferation was observed 24 hr postoperatively, while at further time intervals up to 48 hr, DNA synthesis remained similar to that observed in the simply partially hepatectomized rats. The enzyme thymidine kinase (TK), has been implicated in the suppression of proliferation in interferon-treated cell cultures. In all IFN-alpha2b-treated groups of rats, alterations of TK activity were observed without being correlated to the liver regenerative status. Additionally, the administration of the polyamine putrescine in partially hepatectomized rats treated at the time of surgery with IFN strongly enhanced TK activity, but did not affect DNA biosynthesis. In the above-mentioned in vivo model of controlled cellular proliferation, the administration of IFN-alpha2b affected the rate of hepatocyte proliferation depending on the time of its administration; this effect was not correlated to the enzymatic activity of TK, as inhibited TK activity is responsible for the suppressed DNA synthesis in in vitro systems.

Hepatic stimulator substance activity in the liver of thioacetamide-intoxicated rats.

AIMS/BACKGROUND: Hepatic stimulator substance (HSS) is a known hepatic growth factor which appears to be organ-specific but species non-specific. We have recently shown that the administration of HSS enhanced hepatocyte proliferation occurring due to thioacetamide (TAA)-induced liver injury in rats (Theocharis SE, et al., Scand J Gastroenterol 1998; 33: 656-63). In the present study, we examined the activity of the endogenously produced HSS in the liver of TAA administered rats during injury and regeneration. METHODS: TAA at a dose of 300 mg/kg of body weight was injected intraperitoneally in male Wistar rats. The animals were sacrificed at 0, 12, 24, 36, 48, 60 and 72 h after TAA administration. The rate of tritiated thymidine incorporation into hepatic DNA, the enzymatic activity of liver thymidine kinase and the assessment of mitotic index in hepatocytes were used to estimate liver regeneration. HSS extract was obtained from the livers of TAA-treated rats, sacrificed at the above mentioned time points. This HSS extract was injected in 34% partially hepatectomized rats, to assess its activity. The ability of the injected HSS extract to increase hepatocellular proliferation over that normally occurring 24 h following 34% partial hepatectomy was used to express the activity of HSS by determining the above mentioned indices of liver regeneration. RESULTS: The administration of TAA caused severe hepatic injury recognized histopathologically as well as by the increased activities of serum hepatic enzymes aspartate and alanine aminotrasferases. The hepatic injury, which peaked at 24 and 36 h post-TAA treatment (p<0.001), was followed by hepatocyte proliferation, presenting peaks at 48 and 60 h (p<0.001). The activity of the endogenously produced HSS from livers of TAA-treated rats increased at 36 h after TAA administration as well as being highly expressed at 48 and 60 h thus coinciding with the peak of hepatocyte proliferation. At other time points, HSS activity was decreased. CONCLUSIONS: The observed variations of HSS activity in rat liver suggest active participation of this growth factor in hepatocyte replication which follows toxin-induced liver injury as a repair mechanism process.