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PubMed1993

Early use of cisplatin is safe after partial hepatectomy.

Although cisplatin is widely used in the treatment of liver tumors, little information is available concerning its effect on liver regeneration. This report evaluates the effect of cisplatin on liver regeneration after hepatectomy (HPx). One hundred sixty male Sprague-Dawley rats were placed into five experimental groups following 70% hepatectomy. Group I (untreated controls, n = 32) received 0.9% saline intraperitoneally (IP); group II (n = 31), cisplatin 4 mg/kg IP; group III (n = 36), cisplatin 10 mg/kg IP; group IV (n = 34), cisplatin 20 mg/kg IP; and group V (n = 27), doxorubicin 6 mg/kg intravenously (IV). Five additional sham groups underwent celiotomy without hepatectomy (n = 106) followed by the above treatment protocols. Liver regeneration was evaluated by liver weight, DNA incorporation measured by tritiated thymidine (3H-TdR), and quantitative image analysis (QIA) of hepatic nuclei at 18, 24, 36, 48, and 72 hours, and 5 days postoperatively. 3H-TdR incorporation peaked at 36 hours and was similar in hepatectomized controls group I (404 +/- 110 counts per minute [CPM]/mg liver weight) and cisplatin-treated rats (groups II to IV) (P > .05, ANOVA). All sham groups were similar to controls. QIA of feulgen-stained touch preps identified polyploid, stem line, and proliferating nuclei in both controls and treated groups. At 36 hours, QIA showed differences in mitotic status of sham, control, and adriamycin-treated HPx rats, consistent with 3H-TdR incorporation. In contrast, although cisplatin-treated rats receiving 4 mg/kg showed proliferating nuclei, QIA demonstrated decreasing hepatocyte proliferation with higher doses of cisplatin (10 mg/kg, and 20 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Partial hepatectomy and liver regeneration in pigs--the response to different resection sizes.

Liver regeneration has been extensively studied in the rat and dog models but pigs have seldom been used. They resemble man closely in their omnivorous diet and their gastroenterological and endocrinological responses. This paper describes techniques of 15, 50, 65, and 70% partial hepatectomy in the pig. Thymidine kinase activity and mitotic index were used as indices of liver regeneration. The timing and events of the regenerative response in the pig compared favorably with other animal models and the maximum regenerative response occurred on the third postoperative day, irrespective of the size of the partial hepatectomy. The 15% partial hepatectomy, which shows a minimal response to resection, provides a suitable "primed" model for the study of stimulatory substances.

Animals↗

PubMed1988

Effects of 2'-deoxy-5-fluorouridine on regenerating liver following partial hepatectomy in the rat.

UNLABELLED: This study evaluated the effect of 2'-deoxy-5-fluorouridine (FUDR) on the regeneration of the liver following partial (68%) hepatectomy in the rat. Male Sprague-Dawley rats weighing between 190 and 240 g underwent partial hepatectomy under ether anesthesia. Twelve hours postoperatively rats received intraperitoneal injections of 2'-deoxy-5-fluorouridine or 0.9% NaCl solution as follows: Group I, 0.9% NaCl solution (n = 49); Group II, 89 mg 2'-deoxy-5-fluorouridine/kg of body weight (n = 25); and Group III, 178 mg 2'-deoxy-5-fluorouridine/kg of body weight (n = 24). Sham groups underwent celiotomy and liver palpation followed by 0.9% NaCl solution injections (n = 5) or low dose 2'-deoxy-5-fluorouridine (n = 5) and high dose 2'-deoxy-5-fluorouridine (n = 5). The regenerative ability of the liver was evaluated by weight and deoxyribonucleic acid synthesis in the liver remnant. RESULT: Both low and high dose 2'-deoxy-5-fluorouridine delayed the peak of deoxyribonucleic acid synthesis from 36 to 72 hr as compared to control animals which had maximal synthesis at 25 to 36 hr postoperatively (P less than 0.01). Weight of the liver remnants demonstrated a similar pattern. CONCLUSION: High doses of 2'-deoxy-5-fluorouridine administered intraperitoneally delay, but do not inhibit, liver regeneration following partial (68%) hepatectomy as reflected by DNA synthesis and weight of the remnant.

Analysis of Variance↗

PubMed1991

Depression of liver-specific gene expression in regenerating rat liver: a putative cause for liver dysfunction after hepatectomy.

We carried out studies on the expression of liver-specific genes during regeneration of the liver and searched for changes in the expression of oncogenes and housekeeping genes. Albumin and ornithine transcarbamylase genes were the liver-specific genes examined by Northern blot analysis, using total RNAs isolated from residual livers of Sprague-Dawley rats subjected to a 68% partial hepatectomy. The mRNA levels of both genes began to decrease 8 hr after hepatectomy, both reaching the lowest levels at 24 hr, and then recovered to some extent at 48 hr. In contrast, these levels in the housekeeping and growth-related genes were augmented during this period. This would suggest that there is a selective expression of growth-related and housekeeping genes, in preference to liver-specific genes during liver regeneration. The expression of these genes in the regenerating liver was simulated in primary cultured hepatocytes during the dedifferentiation processes. It would appear that the first step in regeneration of the residual liver is dedifferentiation, in which the depression of liver-specific genes may be linked to liver dysfunction following hepatectomy.

Animals↗

PubMed1992

Intraoperative liver radiation after partial hepatectomy in a rat model.

Hepatic resection of metastatic tumor is a treatment option in selected patients. Resection margin is a prognostic factor of hepatic recurrence and survival. Although intraoperative radiation therapy (IORT) has been clinically useful in some gastrointestinal cancers, there is little information regarding its use following hepatic metastasectomy. In this study, a rat model was employed to evaluate histological changes and DNA synthesis as an indication of hepatic regenerative capacity following hepatectomy and liver IORT. All rats (N = 40) had a partial hepatectomy and were divided into four random groups: a nonradiated group and three groups of 1000, 2000, and 3000 cGy given by IORT. The only deaths occurred in the 3000 cGy group. Routine H and E staining of liver sections after 3, 6, and 10 days suggested progressive hepatocyte damage notably in the 3000 cGy group. Comparison of the final average liver weights at 10 days confirmed a diminished liver mass in the 2000 and 3000 cGy animals. DNA synthesis in hepatocytes measured by [3H]-thymidine label incorporation 3, 6, and 10 days after hepatectomy and IORT indicated a comparative and overall decrease in Day 6 peak activity between the three IORT groups. This study demonstrated delayed but substantial hepatic regeneration in the post-resected liver within the clinically useful IORT dose range (1000-2000 cGy) needed to control minimal residual tumor. This model has importance concerning the feasibility of IORT to the hepatic resection bed for patients where resection margins are inadequate.

Animals↗

PubMed1987

Hepatic protein kinase C: translocation stimulated by prolactin and partial hepatectomy.

Prolactin stimulates a hepatotrophic response similar to that caused by phorbol esters or partial hepatectomy in rats. Since phorbol esters, which activate protein kinase C, mimic prolactin action in liver, the relationship between prolactin administration and subsequent hepatic protein kinase C translocation was assessed. Prolactin administration rapidly stimulated a 4-fold elevation of membrane protein kinase C activity. The effect of prolactin on hepatic protein kinase C was specific for lactogenic hormones but could be duplicated by phorbol esters. Further, an increase in serum prolactin was demonstrated subsequent to partial hepatectomy and preceding hepatic protein kinase C translocation. Therefore, translocation of hepatic protein kinase C appears important for hepatic proliferation in response to prolactin administration and to partial hepatectomy.

Animals↗

PubMed1992

The effect of partial hepatectomy on the metabolism, distribution, and nephrotoxicity of para-methylthiobenzamide in the rat.

Para-Methylthiobenzamide (PMTB) produces injury to the liver and kidney. Toxicity is mediated via its biotransformation to a reactive S,S-dioxide metabolite. The objective of this study was to examine the role of hepatic metabolism in the production of PMTB-induced renal toxicity. Renal injury was assessed in partially hepatectomized and sham-operated rats and the effect of this procedure on the distribution and metabolism of PMTB was examined. The in vitro oxidation of PMTB and [14C]thiobenzamide by rat kidney microsomes was also examined. Plasma urea levels and renal cortical slice uptake of organic ions were used to monitor renal function. Partial hepatectomy alone did not alter renal function nor raise blood urea nitrogen levels. Nephrotoxicity resulted when a nonnephrotoxic dose of PMTB (1.2 mmol/kg) was given to partially hepatectomized rats. An HPLC method was used for measurement of PMTB and its metabolites para-methylthiobenzamide S-oxide (PMTBSO) and para-methylbenzamide (PMBA) in plasma and kidney. Hepatectomy delayed the removal of this dose of PMTB from plasma and allowed greater concentrations of PMTB and PMTBSO to accumulate in plasma and kidney at 6 and 15 hr. The level of PMBA was similar in both groups at 6 hr, but was increased in plasma and kidney of the hepatectomized group at 15 hr. Kidney microsomes rapidly converted PMTB to PMTBSO and small amounts of PMBA. [14C]TB was oxidized by microsomes to thiobenzamide S-oxide, benzamide, and covalently bound metabolites. The results indicate that partial hepatectomy lowered the threshold for the expression of nephrotoxicity by PMTB. This procedure is associated with an increased renal accumulation of PMTB and PMTBSO, which are both sequentially transformed to the toxic metabolite.

Animals↗

PubMed1987

Effects of partial hepatectomy on the immune responses in mice.

Experiments were performed to investigate the immune responses occurring as a result of partial hepatectomy (HEP) in mice. On Day 12 mice subjected to HEP showed a twofold rise in serum levels of IgG when compared with sham-operated (ShO) controls. The effects of HEP on specific antibody production following a single immunization with sheep red blood cells (SRBCs) were investigated. An early appearance of direct (IgM) splenic plaque-forming cells (PFCs) and significantly elevated indirect (IgG) PFCs were found in HEP mice. Elevated, early-appearing mercaptoethanol-resistant (IgG) hemagglutinating antibodies were also demonstrated in the sera of HEP mice. In addition to these findings our study showed that humoral and cell-mediated responses are affected by HEP in opposing fashion. Partial hepatectomy performed immediately after skin grafting suppressed a first set allograft rejection in mice. Furthermore, inhibited delayed-type hypersensitivity (DTH) response against SRBCs, as evaluated by a footpad weight assay, was demonstrated in HEP mice compared with the ShO controls. When SRBC-primed mice were partially hepatectomized 15 days later, they responded in a manner typical of the secondary immune response, showing an increased production of indirect (IgG) splenic PFCs. A similar anamnestic response was observed in mice sensitized with leptospiral antigen 50 days prior to HEP or exposed to carbon tetrachloride (CCl4) hepatotoxin. The mice responded by elevated serum IgG-specific antibodies as measured by solid-phase enzyme-linked immunosorbent assay (ELISA). Since HEP induced in mice immunological disturbances similar to those associated with liver disease, it is suggested that partial hepatectomy creating liver deficiency followed by regeneration may be a useful experimental model to study the immune status of various forms of hepatic damage.

Animals↗

PubMed1992

Alteration in sympathetic nerve activity during liver regeneration in rats after partial hepatectomy.

To determine if the sympathetic nerve has a role in liver regeneration, the alterations of tissue norepinephrine (NE) content and its turnover were measured in rats after partial hepatectomy. NE content per unit liver mass decreased progressively to about one-fourth of controls by the ninth day after partial hepatectomy. Since the total amount of NE in the whole liver did not change during nine days of liver regeneration, it was supposed that sympathetic innervation could make slower progress than proliferation of hepatocytes. Fractional turnover rate of NE was reduced transiently in regenerating liver 24-48 h after partial hepatectomy and recovered to normal 8-9 days after the operation. Such a transient reduction of NE turnover was observed specifically in the liver. These results suggest that sympathetic nerve activity of the liver is suppressed at the early stage of regeneration.

Animals↗

PubMed1994

Alterations in the stimulatory G protein of the rat liver after partial hepatectomy.

In adult male rat livers, cAMP generation in response to beta-adrenergic agonists was dramatically stimulated after partial hepatectomy. Quantitation of the alpha subunits of the stimulatory G protein (Gs alpha) using ADP-ribosylation catalyzed by cholera toxin revealed the increment in the amounts of two forms of Gs alpha, Gs alpha-S and Gs alpha-L, during liver regeneration. These increases in the amounts of both Gs alpha proteins were associated with the stimulation in their mRNA levels. In addition, partial hepatectomy gave rise to a shift in the proportion of beta-adrenergic receptor (beta-AR) in the high affinity state produced by beta-AR-Gs complex. The susceptibility of Gs alpha to trypsin was used as a probe for beta-AR-Gs coupling. The GTP-bound forms of both Gs alpha-S and Gs alpha-L were more trypsin-sensitive than their GDP-bound forms. Preincubation of liver plasma membranes prepared from partially hepatectomized rats with the agonist isoproterenol resulted in an enhancement of trypsin-sensitivity of Gs alpha-L, but not Gs alpha-S. This effect was retarded by the addition of the antagonist propranolol. We conclude that the increase in the amount of Gs alpha can be contributed to the rise in beta-response after partial hepatectomy, and suggest that beta-AR is preferentially coupled with Gs alpha-L rather than Gs alpha-S.

Adenylyl Cyclases↗

PubMed1991

Twenty-one percent partial hepatectomy. In vivo rat model for the study of liver regeneration.

We describe a new model of submaximal stimulation of liver regeneration in the rat. Removal of the right lateral lobes in the rat produced a 21% hepatectomy. The measurement accuracy of the incorporation rate of [14C]thymidine into DNA 24 h after 21% hepatectomy (n = 32) was less than that after the standard 34% hepatectomy (n = 32), with S.D./mean being 35% and 130%, respectively (F-test, p less than 0.025). This model was able to detect regeneration-stimulation activity present in liver cytosol extract and serum of 68% hepatectomized rats. Using this model we identified a subfraction of rat serum achieved after treatment of serum with ethanol and ion-exchange column, which had a highly stimulatory effect. Stimulation obtained with serum from hepatectomized pigs showed that these factors are not species specific.

Animals↗

PubMed1995

The immuno-stimulant OK-432 enhances liver regeneration after 70% hepatectomy.

The effect of reticuloendothelial system activation on hepatic regeneration after 70% hepatectomy was investigated. OK-432, a killed streptococcal preparation which increases reticuloendothelial system function, was administered to rats prior to 70% hepatectomy. Hepatic incorporation of 3H-thymidine 24 h after 70% hepatectomy was enhanced by OK-432 pretreatment. DNA synthesis was greater in pretreated than in control rats and correlated highly with reticuloendothelial system phagocytic activity prior to surgery. Methyl palmitate, which decreases reticuloendothelial system function, was administered to rats prior to 70% hepatectemy. Hepatic incorporation of 3H-thymidine 24 h after 70% hepatoctomy was significantly depressed by methylpalmitate-pretreatment. These data suggest that reticuloendothelial system plays a role in liver regeneration and that hepatocyte proliferation might be enhanced by protection from surgical stress and endotoxins with reticuloendothelial system stimulation by OK-432.

Adjuvants, Immunologic↗

PubMed1986

Biliary secretion in the rat after partial hepatectomy.

The secretory efficiency of the liver increased in rats at 12 hr after partial hepatectomy. The secretory efficiency was seen to decrease at 24 hr after partial hepatectomy and increased again at 2-4 days following liver resection. These changes would correspond to the evolution of the hepatocyte proliferative process. The secretion of bile acids expressed per 100 g of body weight had returned to normal at 16 days after partial hepatectomy, although choleresis and the secretion of inorganic electrolytes remained lowered.

Animals↗

PubMed1994

An earlier proliferative response of hepatocytes in gamma-glutamyl transferase positive foci to partial hepatectomy.

One of the hallmarks of initiated hepatocytes is their resistance to several hepatotoxins. This property forms the basis for their selective growth under conditions which are inhibitory to the non-initiated hepatocytes. Selective growth of initiated hepatocytes also occurs, albeit at a low level, in initiated rat liver without exposure to any known promoting regimen and/or in the absence of any known selective pressure to which initiated hepatocytes can possibly be resistant. This latter phenotypic property of initiated hepatocytes was further characterized by comparing the kinetics of response of hepatocytes in gamma-glutamyl transferase positive foci and in the surrounding liver to 2/3 partial hepatectomy both in the presence and in the absence of a promoting regimen. Male Fischer 344 rats (130-150 g) were initiated with a single dose of diethylnitrosamine and 1 week later they were placed on either a semi-synthetic basal diet or a promoting diet containing 1% orotic acid. Partial hepatectomy was performed 15 weeks after initiation and animals from both groups were killed at 12, 16, 20, 24, 30, 36, 48, 72 or 96 h after operation. Each animal received a pulse of 3H-labelled thymidine 1 h prior to killing. Autoradiographic studies revealed that hepatocytes in gamma-glutamyl transferase positive foci in the livers of rats fed the basal diet were significantly labelled at 16 h post-partial hepatectomy while surrounding hepatocytes were still virtually quiescent (LI 12.7 +/- 4.7 versus 1.2 +/- 0.5%, respectively). Higher labelling index in foci compared to the surrounding liver was also seen at 20 h post-PH (36.9 +/- 2.6 versus 21.5 +/- 2.4). Similar earlier response of hepatocytes in gamma-glutamyl transferase positive foci was also seen in initiated rats exposed to dietary orotic acid. In addition, orotic acid treatment appears to have imposed a slight delay on the entry of hepatocytes in the surrounding liver into 'S' phase and thereby enhancing the differential of growth response between these two populations.

Animals↗

PubMed1983

The effects of vitamin B-6 deficiency and hepatectomy on the synthesis of oxalate from glycolate in the rat.

The interrelationship between vitamin B-6 deficiency, liver and extrahepatic tissues with respect to oxalate biosynthesis from [14C1]glycolate in the rat has been investigated. Separate groups of vitamin B-6 deficient and control rats were subjected to total hepatectomy and the metabolism of injected [14C1]glycolate was followed by measuring the respired 14CO2 and analyzing the urine and blood for radioactive metabolites. Vitamin B-6 deficient and control rats were subjected to sham hepatectomies and used as controls. Vitamin B-6 deficient rats showed elevated urinary oxalate compared to controls. Hepatectomy reduced [14C]oxalate excretion and eliminated the B-6 effect. Respiratory 14CO2 was significantly lowered in hepatectomized rats and vitamin B-6 deficiency enhanced the reduction. A difference in oxalate metabolism between normal and vitamin B-6 deficient rat kidneys and possibly other tissues is indicated. The results suggest that the influence of vitamin B-6 on oxalate metabolism is mediated mainly through the liver and supports earlier observations that liver, which contains two oxalate synthesizing enzymes, glycolic acid oxidase and glycolic acid dehydrogenase, is a primary site for the synthesis of oxalate from glycolate.

Animals↗

PubMed1995

Effects of partial hepatectomy, phenobarbital and 3-methylcholanthrene on kinetic parameters of glucose-6-phosphate and phosphogluconate dehydrogenase in situ in periportal, intermediate and pericentral zones of rat liver lobules.

Glucose-6-phosphate dehydrogenase (G6PDH) and phosphogluconate dehydrogenase (PGDH) are heterogeneously distributed in liver lobules of female rats. The maximum activity of both enzymes is approximately twice higher in intermediate and pericentral zones than in periportal zones. Enzyme activities and their distribution patterns were manipulated by partial hepatectomy and treatment with phenobarbital (PB) or 3-methylcholanthrene (3-MC). Vmax values of G6PDH for glucose-6-phosphate decreased mainly in intermediate and pericentral zones after partial hepatectomy, whereas they increased after PB treatment. Vmax values of PGDH for phosphogluconate decreased after partial hepatectomy in both zones, whereas other treatments did not have any effect. The affinity of G6PDH for glucose-6-phosphate was similar in all zones and it was decreased 2-3 fold by PB and 3-MC treatment. The affinity of PGDH for phosphogluconate was 1.4-2.3 times lower in intermediate and pericentral zones than in periportal zones of all livers tested and was not affected by treatment. From these data it can be concluded that not only the maximum activity of enzymes may differ in periportal, intermediate and pericentral zones of the liver lobule but also the affinity of enzymes for their substrates. The implication of these findings is that metabolic flux rates as they occur in vivo in these different metabolic compartments may be significantly different from predictions on the basis of maximum enzyme activities as detected immunohistochemically, microchemically or cytophotometrically.

Animals↗

PubMed1996

Control of thymidine kinase during liver regeneration after partial hepatectomy.

To elucidate the molecular basis for the periodic change of thymidine kinase (TK) activity, the expressions of TK protein and TK mRNA were examined during liver regeneration. TK protein level, quantified by immunoblotting assay using the polyclonal antiserum against rat TK polypeptide produced in Escherichia coli, increased 13-fold compared with the normal at 24 h after partial hepatectomy. This was closely correlated with a 11-fold increase in TK activity. Northern blot analysis showed that the partial hepatectomy caused 12- and 8-fold increase in 2.6 kb and 1.1 kb TK mRNA at 24 h after surgery, respectively. During next 12 h the levels of both TK mRNA species reduced to 5-fold of the normal base level. This reduction was coupled with a similar decrease in the activity as well as in the amount of TK protein. The TK mRNA levels were strictly proportional to the levels of TK activity and TK protein at 48 h and 72 h after partial hepatectomy. These results demonstrate that the change in TK activity is controlled at the mRNA level during liver regeneration. The injection of alpha-adrenoceptor antagonist, phenoxybenzamine, calcium channel blocker, nifedipine or calmodulin inhibitor, trifluoperazine was also found to inhibit TK activity by the repression of its mRNA level.

Adrenergic alpha-Antagonists↗

PubMed2005

[Major hepatectomy for metastasis of colorectal cancer improves survival in the elderly].

OBJECTIVE: Assessing impact of major liver resection (LR) for hepatic metastasis of colorectal cancer (HMCC) on post operative courses and long term survival in the elderly. PATIENTS AND METHOD: Thirty-three consecutive patients aged over 70 years-old were treated in our institution for up to 3 resectable metachronous HMCC. Fifteen patients had major LR (9 right hepatectomy, 3 extended right hepatectomy, 3 left hepatectomy) without pre or postoperative chemotherapy (group 1) and 18 patients were exclusively treated by chemotherapy (group 2) because of high ASA score (ASA 3) or patients refusal. RESULTS: No patients died of another cause that colorectal cancer disease during observation time. All patients of group 2 died during observation time. Post operative mortality and morbidity of group 1 were respectively 0% and 33%. Survival at 1 and 2 years of group 1-2 were respectively 73-50% (P=0,04) and 47-15% (P=0,05). Median survival of group 1 and 2 were respectively 22 and 12 months (P=0,03). CONCLUSIONS: Major LR for HMCC could be proposed regardless the age. High ASA score, multiple (more than 4) metastasis location, evolutive disease could justify an exclusive medical approach.

Age Factors↗