Relationship between expression of cyclin D1 and impaired liver regeneration observed in fibrotic or cirrhotic rats

BACKGROUND AND AIM: The mechanisms responsible for impaired regenerative ability after hepatic resection observed in chronic liver disease are not fully understood. We have examined the relationships between an altered expression of cell cycle-related proteins in regenerating liver after partial hepatectomy and the impaired regenerative process observed in fibrotic and cirrhotic rats. METHODS: We performed 70% partial hepatectomy in both control and porcine serum-induced fibrotic rats, and 45% partial hepatectomy in thioacetamide-induced cirrhotic rats because of the high mortality associated with 70% partial hepatectomy. Liver regeneration was monitored by proliferating cell nuclear antigen labeling index and the expression of G1 regulatory cell cycle-related proteins was determined by immunoblot analysis. RESULTS: Compared with controls, hepatocyte DNA synthesis, and induction of cyclin D1 and p21(CIP1) proteins were delayed but not suppressed in porcine serum-induced fibrotic rats and markedly inhibited in thioacetamide-induced cirrhotic rats. p27(KIP1) protein levels were unaffected by partial hepatectomy and did not differ among all three groups. CONCLUSION: Two distinct rat models of liver fibrosis and cirrhosis showed markedly different proliferative responses after partial hepatectomy. The delay or failure of cyclin D1 induction, but not the increase of p21(CIP1) or p27(KIP1) might be responsible for their impaired liver regeneration.     

Effect of Vitamin E Deficiency on Inhibition of Liver Regeneration by Long-Term Administration of Alcohol

The effects of vitamin E (VE) deficiency on liver regeneration suppressed by long-term administration of alcohol were studied. Male rats were divided into two groups: the alcohol group and the control group. In addition, each group was subdivided into two groups according to the presence or not of VE. Altogether, four groups were provided: a group maintained on the VE-deficient alcohol diet (group EA), a group maintained on the VE-deficient control diet (group EC), a group maintained on the ordinary alcohol diet (group A), and a group maintained on the ordinary control diet (group C). After pair-feeding for 6 weeks, partial hepatectomy was performed to determine the ornithine decarboxylase (ODC) activity, polyamine levels, lipid peroxide levels, and DNA synthesis. DNA synthesis at 24 hr after partial hepatectomy was suppressed significantly in the alcohol administration group, regardless of the presence or not of VE. DNA synthesis at 48 hr after partial hepatectomy tended to show low values in group EA, compared with group A. As for the hepatic ODC activity, group EA showed the lowest value at 4 hr after partial hepatectomy. Of polyamines, the putrescine level in group EA at 4 hr after partial hepatectomy was significantly low, compared with the other three groups. The levels of spermidine and spermine decreased by long-term administration of alcohol, but the effect of VE deficiency was not found. The lipid peroxide level increased significantly in the VE-deficient diet administration group, but the effect of alcohol administration was not found. These results suggested that the decrease in putrescine after ODC suppression by VE deficiency in addition to the decrease in spermidine and spermine caused by long-term alcohol administration were concerned with suppression of DNA synthesis later.     

The effect of chronic ethanol feeding on ornithine decarboxylase activity and liver regeneration

The effects of ethanol on liver regeneration are poorly understood. Acute and chronic exposure to ethanol have been found to exert opposite effects on the induction of ornithine decarboxylase, the rate-limiting enzyme for polyamine biosynthesis. Polyamines are necessary for DNA synthesis and liver regeneration after chemical or surgical liver injury. Short-term exposure to ethanol, which inhibits ornithine decarboxylase has been shown to inhibit DNA synthesis and liver regeneration, whereas more chronic exposure to ethanol increases ornithine decarboxylase activity and therefore could conceivably stimulate DNA synthesis and regeneration. To explore this later possibility, the effects of chronic ethanol consumption on ornithine decarboxylase activity, DNA synthesis and liver regeneration were studied in rats after sham laparotomy and partial hepatectomy. Chronic ethanol feeding failed to inhibit the induction of ornithine decarboxylase that occurred after partial hepatectomy and yet significantly inhibited posthepatectomy DNA synthesis and restitution of liver mass. These data suggest that the induction of hepatic polyamine biosynthesis is dissociated from DNA synthesis and liver regeneration after chronic consumption of ethanol.     

Opposite responses of nuclear spermidine N8-acetyltransferase and histone acetyltransferase activities to regenerative stimuli in rat liver.

Experiments performed in different models of hepatic regeneration at the time of maximal DNA synthesis, determined by thymidine kinase activity assay, demonstrated that spermidine N8-acetyltransferase activity increased 48 hr after CCl4 administration (2-fold), 72 hr after CCl4 plus phenobarbital (3-fold) and 24 hr after partial hepatectomy (4.5-fold). On the contrary, at these times histone acetyltransferase activity diminished (approximately twofold) and was unchanged compared with control values in the liver of hepatotoxin-treated and hepatectomized rats, respectively. Histone acetylation was, however, enhanced 1.5-fold before the onset of DNA replication (14 hr), and 3.4-fold after the peak of DNA synthesis (32 hr) in the liver of hepatectomized rats. alpha-Difluoromethylornithine, a specific and irreversible inhibitor of ornithine decarboxylase that was administered to hepatectomized rats, blocked polyamine synthesis, thymidine kinase activity and consequently liver regeneration 24 hr after the surgery. In those conditions, spermidine N8-acetyltransferase activity was decreased approximately twofold, whereas histone acetyltransferase activity was elevated approximately twofold. All these effects were reversed by putrescine coadministration. Altogether, these findings showed that nuclear spermidine N8-acetyltransferase and histone acetyltransferase activities were regulated in opposite ways during the processes associated with liver regeneration. Moreover, they suggested that the polyamines themselves might have a direct or indirect role in this regulation.     

Zinc supplementation reduces blood ammonia and increases liver ornithine transcarbamylase activity in experimental cirrhosis.

Zinc deficiency is common in cirrhosis and may be involved in the alteration of ammonia metabolism. Rats with carbon tetrachloride-induced cirrhosis have high plasma ammonia and low serum and tissue zinc levels. We used this model to examine the effects of oral zinc supplementation on activities of plasma ammonia and liver ornithine transcarbamylase (a key enzyme in the urea cycle). These parameters were examined in two consecutive experiments. Each experiment included two groups of rats treated with carbon tetrachloride; one group received zinc in the drinking water during the induction of cirrhosis, and another served as a control group. Regardless of zinc supplementation, all carbon tetrachloride-treated rats exhibited similar micronodular cirrhosis, with similar histological appearance and liver function impairment. Cirrhotic rats without zinc supplementation showed high plasma ammonia and low serum and hepatic zinc levels and reduced liver ornithine transcarbamylase activity. Serum, hepatic zinc and liver ornithine transcarbamylase activity increased significantly in the zinc-supplemented group, and these rats' plasma ammonia levels became normal. Plasma ammonia level was significantly inversely correlated with liver ornithine transcarbamylase activity and positively correlated with serum and hepatic zinc content. Our results suggest that zinc deficiency may modify hepatic ornithine transcarbamylase activity and, therefore, ammonia disposal.     

beta-Hexosaminidase in plasma and liver after partial hepatectomy in normal and cirrhotic rats

The liver and plasma level of the lysosomal enzyme beta-hexosaminidase was analyzed in partially (about 70%) hepatectomized rats with normal liver or carbon tetrachloride (CCl4)-induced cirrhosis. The enzyme level of the liver did not show marked changes after partial hepatectomy in either normal or cirrhotic rats. In contrast, the plasma basal level was significantly higher in cirrhotic rats and increased to a peak at 6 h, followed by a decrease to a minimum level 24 h after operation. The enzyme returned to its high plasma basal level at 36 h after partial hepatectomy, when the liver had recovered to 70% of its initial weight. In rats with normal liver the plasma beta-hexosaminidase showed another pattern, with a rapid increase at 6 h and thereafter gradually reaching a peak at 36 h after hepatectomy. We conclude that the cells responsible for increased plasma beta-hexosaminidase in cirrhotic rats are situated in the liver.     

Halofuginone,a collagen type I inhibitor improves liver regeneration in cirrhotic rats

BACKGROUND/AIMS: Hepatic fibrosis involves excess deposition of extracellular connective tissue of which collagen type I fibers form the predominant component. Left untreated it develops into cirrhosis, often linked with hepatocellular carcinoma. Owing to the fact that cirrhotic liver regeneration is impaired, resection of hepatocellular carcinoma associated with cirrhosis is questionable. The aim of the present study was to determine the potential of halofuginone, a collagen type I inhibitor, in improving liver regeneration in cirrhotic rats. METHODS: Partial hepatectomy (70%) was performed in thioacetamide-induced cirrhotic rats fed a halofuginone-containing diet. Liver regeneration was monitored by mass and proliferating cell nuclear antigen. The Ishak staging system and hydroxyproline content were used to evaluate the level of fibrosis. RESULTS: Halofuginone administered prior to and following partial hepatectomy did not inhibit normal liver regeneration despite the reduced levels of collagen type I mRNA. When given to rats with established fibrosis, it caused a significant reduction in alpha smooth muscle actin, TIMP-2, collagen type I gene expression and collagen deposition. Such animals demonstrated improved capacity for regeneration. CONCLUSIONS: Halofuginone may prove useful in improving survival of patients with hepatocellular carcinoma and cirrhosis undergoing surgical resection.     

Role of angiotensin‐1 receptor blockade in cirrhotic liver resection

Background: The regeneration capacity of cirrhotic livers might be affected by angiotensin‐1 (AT1) receptors located on hepatic stellate cells (HSC). The effect of AT1 receptor blockade on microcirculation, fibrosis and liver regeneration was investigated. Materials and methods: In 112 Lewis rats, cirrhosis was induced by repetitive intraperitoneal injections of CCl₄. Six hours, 3, 7 and 14 days after partial hepatectomy or sham operation, rats were sacrificed for analysis. Animals were treated with either vehicle or 5 mg/kg body weight losartan pre‐operatively and once daily after surgery by gavage. Microcirculation and portal vein flow were investigated at 6 h. The degree of cirrhosis was assessed by Azan Heidenhein staining, activation of HSC by desmin staining, apoptosis by ssDNA detection and liver regeneration by Ki‐67 staining. Changes in expression of various genes important for liver regeneration and fibrosis were analysed at 6 h and 3 days. Haemodynamic parameters and liver enzymes were monitored. Results: Losartan treatment increased sinusoidal diameter, sinusoidal blood flow and portal vein flow after partial hepatectomy (P<0.05), but not after sham operation. AT1 receptor blockade resulted in increased apoptosis early after resection. HSC activation was reduced and after 7 days, a significantly lower degree of cirrhosis in resected animals was observed. Losartan increased the proliferation of hepatocytes at late time‐points and of non‐parenchymal cells early after partial hepatectomy (P<0.05). Tumour necrosis factor (TNF)‐α was significantly upregulated at 6 h and stem cell growth factor (SCF) was downregulated at 3 days (P<0.05). Conclusion: Losartan increased hepatic blood flow, reduced HSC activation and liver fibrosis, but interfered with hepatocyte proliferation after partial hepatectomy in cirrhotic livers.     

Ethanol-Associated Alterations in the Kinetics of Putrescine Uptake and Metabolism by the Regenerating Liver

Biosynthesis of the polyamines, putrescine, spermidine, and spermine is required for DNA synthesis and liver regeneration after partial hepatectomy. We have previously reported that chronic ethanol consumption impairs polyamine synthesis and significantly retards liver regeneration after partial hepatectomy. In those studies, supplementation with putrescine restored hepatic DNA synthesis in ethanol-fed rats but exerted no effect in pair-fed controls. These differences in the response to putrescine treatment may have resulted from ethanol-associated differences in hepatic uptake, release, or metabolism of putrescine. To resolve these issues and define more completely how putrescine treatment affects DNA synthesis, we now assess the kinetics of putrescine uptake and metabolism after intraperitoneal or intravenous injection of radiolabeled putrescine (1.2 mmol/kg, specific activity 1 microCi/mmol) into rats fed 36% ethanol diets or isocaloric, nonethanol diets for 6 weeks prior to partial hepatectomy. After putrescine treatment, hepatic putrescine concentrations were greater in ethanol-fed rats than controls. Differences in post-treatment hepatic putrescine levels between ethanol and pair-fed groups could not be explained by differences in the rates of hepatic putrescine uptake or excretion into bile; residual de novo synthesis of putrescine from ornithine or metabolism of hepatic putrescine to its polyamine products, spermidine and spermine. Indeed, supplemental putrescine was not appreciably converted to spermidine or spermine in either ethanol or control rats. Hence, these latter polyamines are unlikely to be responsible for the treatment-associated improvement in DNA synthesis that has been noted in ethanol-fed rats. This suggests that putrescine itself acts to restore hepatic DNA synthesis in ethanol-fed rats.     

Effect of tamoxifen on hepatic regeneration in male rats

A number of metabolic changes within the liver occur concurrent with hepatic regeneration. These processes suggest that the administration of an antiestrogen might alter the rate of hepatic regeneration. To examine this question, male Wistar rats were treated with tamoxifen (0.1 mg/rat/day or 1.0 mg/rat/day) or vehicle for three days prior to and after partial hepatectomy, and the anatomic and biochemical process of hepatic regeneration was assessed. Tamoxifen administration caused a dose-dependent decrease in the hepatic cytosolic estrogen receptor activity and, conversely, a dose-dependent increase in cytosolic androgen receptor activity. Despite these changes in baseline hepatic sex steroid receptor status, all receptor activities were comparable between the three groups within 24 hr of partial hepatectomy. Moreover, no differences in any of the the parameters assessing hepatic regeneration following partial hepatectomy were evident: liver-body ratio, ornithine decarboxylase activity, and thymidine kinase activity. This lack of effect of tamoxifen treatment on hepatic regeneration suggests either that estrogens do not play a role in the modulation of liver growth after partial hepatectomy or that, once initiated, the regenerative process per sedetermines a series of events that regulate hepatocellular sex hormone receptor status independent of extrahepatic stimuli.This work was supported in part by the Veteran's Administration and grants from NIAAA AA06601, NIAAA AA04425, and NIDDK AM 32556.     

Hepatocyte growth factor promotes liver regeneration and protein synthesis after hepatectomy in cirrhotic rats

BACKGROUND/AIMS: Hepatocyte growth factor, a potent mitogen for hepatocytes has been reported to be a hepatrophic factor in normal livers. In this study, the effect of exogenous hepatocyte growth factor on liver regeneration in cirrhotic rats was investigated, in vitro and in vivo. METHODOLOGY: Liver cirrhosis was induced by intraperitoneal injections of an emulsion, carbon tetrachloride and olive oil, twice weekly for 10 weeks. In vitro, various amounts of exogenous hepatocyte growth factor; 0, 0.5, 1, 2.5, 5, and 10 ng/mL; were added to the hepatocytes isolated using in situ perfusion method. In vivo, partial hepatectomy (Hx), according to the procedure described by Higgins and Anderson, was performed on cirrhotic rats. Saline solution (control group) or 3 micrograms/kg of exogenous hepatocyte growth factor (HGF group) was then injected through the tail vein at intervals 12 hours after Hx. RESULTS: In vitro, DNA synthesis in hepatocytes obtained from cirrhotic livers increased following exogenous hepatocyte growth factor in dose-dependent fashion. In vivo, the labeling index of 5-bromo-2'-deoxyuridine at 24 hours after Hx was markedly increased by exogenous hepatocyte growth factor (control, 10.0 +/- 3.1%; hepatocyte growth factor, 25.8 +/- 9.8%; P < 0.01). Furthermore, serum albumin at 24 and 72 hours and a normotest at 24 hours after Hx, were significantly higher in the HGF group than in the control group. CONCLUSIONS: These results indicate that exogenous hepatocyte growth factor may promote DNA synthesis and protein synthesis during liver regeneration after Hx with cirrhosis.     

Putrescine Administration Reverses Cadmium-Associated Inhibition of Liver Regeneration

The liver is of central importance in themetabolism of essential and toxic metals such ascadmium. Cadmium pretreatment suppressed the liverregenerative response to partial hepatectomy, due to theinhibition of the enzymatic activity of thymidine kinase.Exogenous putrescine administration has been reported tostimulate liver regeneration in animal models of acuteliver failure. The purpose of this study was to document whether the administration of thispolyamine enhances the impaired regenerative capacity ofhepatocytes in cadmiumpretreated partiallyhepatectomized rats. The intraperitoneal administration of putrescine (1 or 10 mg/kg body weight), atthe time of surgery and at 4 and 8 hr postoperativelypartly restored the suppressed hepatocytedeoxyribonucleic acid (DNA) biosynthesis and thymidinekinase activity in cadmium-pretreated partiallyhepatectomized rats. Mitotic activity and the percentageof hepatocytes positive for proliferating cell nuclearantigen nuclei were in accordance with the liver proliferative status. Our results showed thatexogenous putrescine administration is able to improvediminished liver regeneration after partial hepatectomyin this animal model of acute hepatic injury.     

Liver pathology and cell proliferation after octreotide administration following partial hepatectomy in rats: an experimental study

Octreotide is a somatostatin analog introduced for clinical use that inhibits the growth of various tumors in rats. This study investigates liver pathology after octreotide treatment following partial (2/3) hepatectomy in rats. Thirty rats, weighing 250–300 g underwent partial hepatectomy and were divided in to two groups. Group A (N = 25) received octreotide subcutaneously [2 g Sandostatin (Sandoz) in 1 ml normal saline every 12 hr for 15 days]. Group B (N = 5) was injected with 1 ml normal saline subcutaneously every 12 hr for the same time period; animals in this group were used as controls. At the end of the experiment rats were sacrificed and liver tissue was obtained for pathologic examination. Liver sections from group A (octreotide administration) showed extensive cholangiolar and fibrous tissue proliferation in the hepatectomy area, and hypertrophy and swelling of Kupffer cells in the liver parenchyma. Sections from the hepatectomy surface from group B (controls) displayed signs of liver regeneration. Proliferation activity (Ki-67⁺ cells) was higher in the cholangiolar epithelium in group A and in hepatocytes in group B. In conclusion, the results of this study show that octreotide inhibits liver regeneration, which occurs after partial hepatectomy in rats and enhances hyperplasia of cholangiolar and fibrous tissue.     

The Hepatoprotective Effect of Hepatic Stimulator Substance (HSS) Against Liver Regeneration Arrest Induced by Acute Ethanol Intoxication

Male Wistar rats were randomized to receive ethanol (2.5 ml/kg by gastric intubation every 8 hr; group I), equal volumes of isocaloric to ethanol sucrose solution (group II), or ethanol and HSS (100 mg/kg intraperitoneally 10 and 16 hr after partial hepatectomy; groups III and IV, respectively) for up to 96 hr after partial hepatectomy, with ethanol administration starting 1 hr prior to partial hepatectomy. Animals were killed at 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60, and 96 hr after partial hepatectomy. The rate of liver regeneration was evaluated by the mitotic index in H&E-stained sections, immunochemical detection of Ki67 nuclear antigen, rate of [³H]thymidine incorporation into hepatic DNA, and liver thymidine kinase enzymatic activity. The biological activity of HSS in groups I and II rats was evaluated using a bioassay. Ethanol administration arrested liver regeneration during the first 32 hr after partial hepatectomy and suppressed HSS activity throughout the period examined. Liver regeneration progressed after 32 hr despite the low levels of HSS activity. HSS administration at 10 and 16 hr reversed liver regeneration arrest induced by ethanol. Acute ethanol administration induces cell cycle arrest during the first 32 hr after partial hepatectomy and suppression of HSS biological activity seems to contribute to this effect. HSS administration reversed the inhibitory effect of ethanol on liver regeneration and caused synchronized entrance of hepatocytes in the S phase of the cell cycle. HSS seems to participate in the network of growth factors controlling the G1/S cell cycle checkpoint.     

Effect of cyclosporine on hepatic cytosolic estrogen and androgen receptor levels before and after partial hepatectomy

Estrogen and androgen receptors within the liver have been reported to modulate the hepatic regenerative response to partial hepatectomy. Moreover, cyclosporine has several untoward effects that might occur as a consequence of alterations in sex hormone activity. To evaluate these questions the following experiments were performed. Estrogen and androgen receptors in cytosol were quantitated in livers of rats treated with cyclosporine or olive oil vehicle before and after partial hepatectomy or a sham operation. Ornithine decarboxylase activity and thymidine kinase activity were assessed as indices of hepatic regeneration. Preoperative levels of estrogen receptor activity in the hepatic cytosol were significantly greater in rats treated with cyclosporine as compared to vehicle treated controls (P<0.01). In contrast, preoperative levels of androgen receptor activity in the cyclosporine-treated and vehicle-treated animals were similar. Following partial hepatectomy, a reduction in the activity of both sex hormone receptors in the hepatic cytosol was observed and was compatible with results described previously in normal animals. Unexpectedly the preoperative levels of ornithine decarboxylase (P<0.01) and thymidine kinase activity (P<0.01) were significantly greater in the rats treated with cyclosporine as compared to the vehicle treated controls. As expected, ornithine decarboxylase activity (at 6 hr) and thymidine kinase activity (at 24 hr) rose and peaked in response to a partial hepatectomy but were significantly greater (P<0.05) in the rats treated with cyclosporine as compared to the vehicle. These results show that cyclosporine treatment causes an increase in the hepatic content of estrogen receptor activity that is associated with an enhanced potential for a regenerative response. These effects of cyclosporine treatment on the sex hormone receptor levels in liver may explain the mechanisms responsible for some of the untoward effects of treatment with this agent.Supported by research grants from the Veterans Administration project grant AM 29961, and from the NIDDK AM 32556, and from the NIAAA AA06601.     

Expressions of molecules associated with hepatocyte growth factor activation after hepatectomy in liver cirrhosis

BACKGROUND/AIMS: The activation pathway of hepatocyte growth factor (HGF), including HGF activator (HGFA) and HGFA inhibitor-1, 2 (HAI-1, 2), has recently been clarified. The present study examined mRNA expressions of HGF, HGFA and HAI-1 following partial hepatectomy in normal and cirrhotic rats. METHODOLOGY: Liver cirrhosis was induced by intraperitoneal injections of dimethylnitrosamine. Two weeks after, the cirrhotic and normal rats underwent 70% hepatectomy and the liver regeneration rate, DNA synthesis of hepatocytes, plasma HGF level, and mRNA expressions of HGF, HGFA, and HAI-1 in the liver, spleen, and lung were examined at different times. RESULTS: Liver regeneration in the cirrhotic rats was deteriorated with a later peak of hepatocellular DNA synthesis. Hepatic HGF mRNA and splenic HAI-1 mRNA were upregulated and liver HGFA mRNA was downregulated in the cirrhotic rats. CONCLUSIONS: Insufficient HGF activation both by a reduced expression of hepatic HGFA and an increased expression of splenic HAI-1 may be one of the reasons for the impaired liver regeneration in cirrhosis.     

Changes in polyamine metabolism of rat liver after administration of D-galactosamine. Favorable effects of putrescine administration on galactosamine-induced hepatic injury.

There are many reports showing a close relation between polyamine metabolism and tissue growth or recovery of damaged tissues, such as regenerating liver. Thus, changes in polyamine metabolism in the livers from rats treated with D-galactosamine, an inducer of experimental hepatitis, were studied. The activity of ornithine decarboxylase started to increase 14 hr after administration of galactosamine and reached 30 times the normal activity at about 25 hr, the time of maximum severity of hepatitis. The content of putrescine increased to about 10 times the control value. After increases in the putrescine content and ornithine decarboxylase activity, the hepatitis started to diminish. Increases in the activity of S-adenosylmethionine decarboxylase and the content of spermidine were observed 33-37 hr after administration of galactosamine. The maximum values of these parameters, which were significantly higher than the control values, were observed after the healing process had started.     

Effect of antiandrogen flutamide on measures of hepatic regeneration in rats

Male rat liver undergoes a process of demasculinization during hepatic regeneration following partial hepatectomy. The possibility that antiandrogens might potentiate this demasculinization process and in so doing augment the hepatic regenerative response was investigated. Adult male Wistar rats were treated with the antiandrogen flutamide (2 mg/rat/day or 5 mg/rat/day subcutaneously) or vehicle for three days prior to and daily after a 70% partial hepatectomy. At various times after hepatectomy, the liver remnants were removed and weighed. Rates of DNA and polyamine synthesis were assessed by measuring thymidine kinase and ornithine decarboxylase activities, respectively. Hepatic estrogen receptor status and the activity of alcohol dehydrogenase, an androgen-sensitive protein, were measured. Prior to surgery, the administration of 5 mg/day flutamide reduced the hepatic cytosolic androgen receptor activity by 98% and hepatic cytosolic estrogen receptor content by 92% compared to that present in vehicle-treated controls. After hepatectomy, however, all differences in sex hormone receptor activity between the treatment groups were abolished. The rate of liver growth after partial hepatectomy in the three groups was identical. Moreover, hepatectomy-induced increases in ornithine decarboxylase activity and thymidine kinase activity were comparable. These data demonstrate that, although flutamide administration initially alters the sex hormone receptor status of the liver, these affects have no effect on the hepatic regenerative response following a partial hepatectomy.This work was supported by a grant from the NIAAA AA44205 and the Veterans Administration.