Effects of gender on hepatic HMG-CoA reductase, cholesterol 7alpha-hydroxylase, and LDL receptor in hereditary analbuminemia

Hypoalbuminemia is accompanied by hypercholesterolemia in both nephrotic syndrome and hereditary analbuminemia. Hypercholesterolemia is more severe in the female than in the male Nagase analbuminemic rats (NAR). The sex difference in plasma cholesterol diminishes after ovariectomy (OVX) and reappears after estrogen replacement in the NAR. The molecular mechanism responsible for the sex difference in severity of hypercholesterolemia in NAR is not known and was investigated here. To this end, hepatic hydroxylmethylglutaryl (HMG)-CoA reductase, cholesterol 7alpha-hydroxylase, and LDL receptor were determined in male, female, and OVX female NAR and Sprague-Dawley (SD) rats. Plasma cholesterol, triglycerides, and hepatic HMG-CoA reductase activities were greater in both female and male NAR than in SD rats. This was coupled with upregulation of cholesterol 7alpha-hydroxylase in both male and female NAR compared with SD controls. LDL receptor in male NAR was similar to that in male SD rats but was significantly reduced in female NAR. OVX partially, but significantly, reduced plasma cholesterol and triglyceride levels in female NAR. This was coupled with a significant rise in hepatic cholesterol 7alpha-hydroxylase and a modest increase in hepatic LDL receptor. In contrast, OVX resulted in a mild elevation of plasma cholesterol and no significant changes in total hepatic HMG-CoA reductase, cholesterol 7alpha-hydroxylase, or LDL receptor in female SD rats. Thus the greater severity of hypercholesterolemia in the female NAR appears to be due, in part, to a combination of the constrained compensatory upregulation of cholesterol 7alpha-hydroxylase and LDL receptor deficiency.     

Age-related changes in plasma proteins of analbuminemic rats

A mutant strain, Nagase analbuminemia rats (NAR), was established from Sprague-Dawley rats. Age-related changes in plasma proteins of NAR were investigated to obtain information of their abnormalities of protein metabolism. The total protein concentration in the serum of NAR of various ages was almost the same as that of normal rats of the same age. The albumin level of NAR was less than 0.05 mg/ml at all ages examined. The concentrations of serum alpha 1-antitrypsin, alpha-X protein, alpha 2-macroglobulin, transferrin, ceruloplasmin, IgG, IgA and IgM were higher in NAR than in normal rats except for the perinatal stage, but alpha 1-acid glycoprotein level in NAR was normal. The serum transferrin and ceruloplasmin levels were especially high in female adult NAR. The plasma fibrinogen concentration was also increased in NAR. These findings indicate that the normal total serum protein level of NAR was maintained by increase in the globulin concentration.     

Influence of dietary curcumin and cholesterol on the progression of experimentally induced diabetes in albino rat

Effect of feeding 0.5% curcumin diet or 1% cholesterol diet was examined in albino rats rendered diabetic with streptozotocin injection. Diabetic rats maintained on curcumin diet for 8 weeks excreted comparatively less amounts of albumin, urea, creatinine and inorganic phosphorus. Urinary excretion of the electrolytes sodium and potassium were also significantly lowored under curcumin treatment. Dietary curcumin also partially reversed the abnormalities in plasma albumin, urea, creatinine and inorganic phosphorus in diabetic animals. On the other hand, glucose excretion or the fasting sugar level was unaffected by dietary curcumin and so also the body weights were not improved to any significant extent. Diabetic rats fed curcumin diet had a lowered relative liver weight at the end of the study compared to other diabetic rat groups. Diabetic rats fed a curcumin diet also showed lowered lipid peroxidation in plasma and urine when compared to other diabetic groups. The extent of lipid peroxidation on the other hand, was still higher in cholesterol fed diabetic groups compared to diabetic rats fed with control diet.Thus, the study reveals that curcumin feeding improves the metabolic status in diabetic condition, despite no effect on hyperglycemic status or the body weights. The mechanism by which curcumin improves this situation is probably by virtue of its hypocholesterolemic influence, antioxidant nature and free radical scavenging property.     

Reduced activity of androgen biosynthesis in the testes of rats with analbuminemia

Steroid metabolism in Nagase Analbuminemia Rats (NAR), a mutant strain established from Sprague-Dawley rats, was studied. NAR are characterized by lack of serum albumin and hyperlipidemia. Total testosterone concentration in the serum of NAR was lower than that of normal rats, while the serum free testosterone, LH and FSH concentrations were similar. The half lives of 14C-labeled testosterone administered intravenously in NAR and normal Sprague-Dawley (SD) rats were 4.4 and 4.1 min, respectively. The plasma clearance rates of testosterone in NAR and normal rats were 34.7 and 39.1 ml/min per kg body weight. On Sephadex G-100 chromatography, a mixture of [3H]testosterone and normal rat serum gave two protein peaks eluted in the void volume and the albumin fraction, and the radioactivity was eluted all in the albumin fraction. In contrast, a mixture of [3H]testosterone and NAR serum gave a single protein peak eluted in the void volume and the radioactivity was mainly eluted with this protein peak. The association constants of testosterone to NAR and normal rat sera were 1.25 and 2.24 X 10(4) M-1. Enzyme activities related to the synthesis of testosterone by the testicular microsomal fractions of NAR and normal rats were examined. The activities of 3 beta-hydroxysteroid dehydrogenase, 5-ene-4-ene isomerase, 17 alpha-hydroxylase, C-17-C-20 lyase and 17 beta-hydroxysteroid dehydrogenase were lower in NAR than in normal rats. The activity for synthesis of testosterone from pregnenolone by the testicular microsomal fraction of NAR was about 40% of that of normal rats. These findings indicate that the low serum concentration of testosterone in NAR is mainly attributable to decreased biosynthesis of testosterone in the testes.     

Effects of gender on kidney function in magnesium-deficient rats

This study investigated the gender differences in the kidney function of magnesium (Mg)-deficient rats. Male and female rats were fed a control diet or a Mg-deficient diet for 21 d. Mg-deficient diet had no significant effect on kidney calcium (Ca) or phosphorus (P) concentration in male rats, while Ca and P concentrations in female rats were significantly higher in Mg-deficient rats than in the control rats. With regard to indicators of kidney function, no significant differences in creatinine clearance and serum urea nitrogen concentration were observed among the groups. Serum albumin concentrations were significantly lower in rats fed the Mg-deficient diet than in rats fed the control diet. In both sexes, urinary albumin excretion was significantly higher in rats fed the Mg-deficient diet than in rats fed the control diet. Gender differences had no significant influence on creatinine clearance, serum urea nitrogen concentration, serum albumin concentration and urinary albumin excretion. These results suggest that gender differences have no effect on kidney function in Mg-deficient rats under the condition used.     

Diet-induced nephrocalcinosis and urinary excretion of albumin in female rats

This study was carried out to test the hypothesis that diet-induced nephrocalcinosis causes enhanced loss of albumin in urine, irrespective of the composition of the nephrocalcinogenic diet. Female rats were fed various purified diets for 28 days. There was a control diet (0.5% Ca, 0.04% Mg, 0.4% P, 15.1% protein, wt/wt), a low Mg (0.01% Mg), a high protein (30.2% protein) and a high P diet (0.6% P). The low Mg and high P diet induced nephrocalcinosis as demonstrated histologically and by markedly increased concentrations of kidney Ca. In rats fed the high protein diet, nephrocalcinosis was essentially absent. Group mean values of urinary excretion of albumin and plasma concentrations of urea were increased in rats fed either the low Mg or high P diet. The high protein diet did not affect urinary albumin but caused lysozymuria which was not seen in the other groups. Plasma urea was increased in rats fed the high protein diet. In individual rats, the concentration of Ca in kidney and urinary albumin excretion were positively correlated. It is suggested that nephrocalcinosis in female rats induced by either low Mg or high P intake causes kidney damage which in turn leads to increased concentrations of albumin in urine and urea in plasma.     

Hyperlipoproteinemia in Nagase analbuminemic rats: effects of pravastatin on plasma (apo)lipoproteins and lecithin:cholesterol acyltransferase activity.

The present study demonstrates very high levels of plasma lipids and high density lipoprotein (HDL) apolipoproteins (apoA-I and apoE) in female Nagase analbuminemic rats (NAR) fed a semi-synthetic diet in order to further increase the hyperlipidemia present in this strain. Plasma apoB-containing lipoproteins (very low, intermediate, and low density lipoproteins) were also elevated in NAR. Plasma cholesterol was mainly present in lipoprotein particles with a density between 1.02 and 1.12 g/ml. Separation of lipoprotein classes by gel filtration showed that the major cholesterol-carrying lipoprotein fractions in NAR plasma are apoE-rich HDL and apoA-I-rich HDL. The high HDL levels in NAR are explained, at least partly, by the two- to threefold elevated activity of plasma lecithin:cholesterol acyltransferase (LCAT). The lysophosphatidylcholine generated in the LCAT reaction, as well as plasma free fatty acids, are bound to lipoproteins in NAR plasma. A study was carried out to determine whether the elevated LDL and aopoE-rich HDL levels could be corrected by administration of the HMG-CoA reductase inhibitor pravastatin (at a dose of 1 mg/kg per day). Pravastatin treatment results in a 43% decrease in plasma triglycerides in NAR, but not in Sprague-Dawley (SDR) rats, and had no significant effect on plasma total cholesterol, phospholipids apolipoproteins A-I, A-IV, B, or E, as well as on plasma LCAT activity levels in NAR or SDR.     

Anemia and potassium permeability of red blood cells in analbuminemic rats

A mutant strain, Nagase analbuminemia rats (NAR), was established from Sprague-Dawley rats. Hematological evaluations were made on NAR of 4 to 52 weeks of age. NAR had an abnormally low number of red blood cells (RBC), a low hematocrit, a reduced hemoglobin concentration and an increased number of reticulocytes. Their plasma electrolyte level was normal. Osmotic fragility of RBC was slightly increased in the rats. Thus NAR shows a slight anemia. The in vitro experiments on RBC were performed. The incubation of blood showed a hemolytic tendency and elevated potassium efflux in the blood of NAR. In addition, an increased efflux of potassium was found in the RBC of NAR, when the RBC was washed with phosphate buffered saline and then was incubated with the saline containing CaCl2. This potassium efflux was prevented in the presence of rat albumin. These findings suggest that the deficiency of serum albumin may increase the permeability of potassium in erythrocyte membrane in NAR.     

Naringenin attenuates cisplatin nephrotoxicity in rats

The effect of naringenin (NAR), a naturally occurring citrus flavanone, on the acute nephrotoxicity produced by cisplatin (7 mg/kg, i.v.) was investigated in the rat. Oral administration of NAR (20 mg/kg/day) for 10 days, starting 5 days before cisplatin single i.v. injection, produced significant protection of renal function. NAR reduced the extent of cisplatin-induced nephrotoxicity, as evidenced by significant reduction in serum urea and creatinine concentrations, decreased polyuria, reduction in body weight loss, marked reduction in urinary fractional sodium excretion and glutathione S-transferase (GST) activity, and increased creatinine clearance. Cisplatin-induced alterations in renal cortex lipid peroxides and GST activity were markedly improved by NAR. Cisplatin-induced alterations in renal cortex antioxidant defense system were greatly prevented by NAR. In cisplatin-NAR combined treatment group, antioxidant enzymes namely superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) were significantly increased to 54.5, 30.3 and 35.6%, respectively compared to cisplatin treated group. Platinum renal content was not affected by NAR treatment. The results provide further insight into the mechanisms of cisplatin-induced nephrotoxicity and confirm the antioxidant potential of NAR.     

Transport and distribution of copper injected into an albumin-deficient (analbuminemic) rat

Copper (Cu) concentrations in blood, liver, kidney, spleen and pancreas of an albumin-deficient (Nagase analbuminemic) rat (NAR) were compared with those of a control (Sprague-Dawley) rat (SDR). Cu concentrations were significantly higher in the blood and significantly lower in the liver of the NAR strain than those of the SDR strain in female control (saline-injected) groups at 8 weeks old. Female NAR and SDR 8-week-old rats were injected i.p. with Cu at a single dose of 2.0 mg/kg body wt and killed 18 hr later. Concentrations of Cu and other essential elements in the blood, liver, kidney, spleen and pancreas were determined simultaneously by inductively coupled plasma-atomic emission spectrometry. Cu concentration in the liver was significantly lower in the NAR than in the SDR strain suggesting a role for albumin as a carrier protein of free Cu ions in the blood. The effects of Cu loading on other essential elements (Zn, Fe, Ca, Mg, P) were also compared between the NAR and SDR strains.     

Comparison of plasma levels of lipid hydroperoxides and antioxidants in hyperlipidemic Nagase analbuminemic rats, Sprague-Dawley rats, and humans.

The levels of lipid hydroperoxides and antioxidants in plasma samples from Nagase analbuminemic rats (NAR) and control Sprague-Dawley rats (SDR) were measured in comparison with those from normal human subjects. Cholesteryl ester hydroperoxide (CE-OOH) was detected, but phosphatidylcholine hydroperoxide was not. The levels of CE-OOH and the ratios of CE-OOH/CE were found to increase significantly in the order of human < SDR < NAR, suggesting that oxidative stress increases in the same order. NAR have a significantly lower level of ascorbate and lower ratio of ubiquinol/ubiquinone concentrations than SDR. This also suggests that NAR are subject to more oxidative stress than SDR, since ascorbate and ubiquinol are the most effective plasma antioxidants against oxygen radicals.     

Plasma creatinine and urea: creatinine ratio in patients with raised plasma urea.

We examined the plasma urea and creatinine concentrations and the ratio between them according to diagnosis in 100 unselected and 31 selected adult hospital patients with a plasma urea concentration greater than or equal to 10 mmol/l (60mg/100ml). We also examined plasma urea and creatinine concentrations in 350 unselected consecutive patients, but found no useful relation between the two values. Congestive heart failure was the most common identifiable cause of a raised plasma urea concentration in the 100 unselected patients (36%). Among these 100 patinets the plasma creatinine concentration was a more useful discriminant between prerenal uraemia and intrinsic renal failure than was the urea:creatinine ratio or the plasma urea concentration. A plasma creatinine concentration greater than 250 mumol/1 (2-8 mg/100ml) indicated intrinsic renal failure with a 90% probability.     

Role of plasma albumin in renal elimination of a mercapturic acid. Analyses in normal and mutant analbuminemic rats

Biosynthesis of N-acetylcysteine S-conjugates of xenobiotics (mercapturic acids) occurs via interorgan metabolism and the renal transtubular transport system plays an important role in elimination of the final metabolites from the organism. To assess the behavior of a mercapturic acid in the circulation, plasma clearance of radioactive S-benzyl-N-acetylcysteine and its interaction with plasma proteins were studied in normal and mutant analbuminemic rats (NAR). Intravenously injected S-benzyl-N-acetylcysteine rapidly disappeared from the circulation both in NAR and normal animals. However, its plasma clearance was significantly higher in NAR (45.7 ml kg-1 min-1) than in normal rats (25.2 ml kg-1 min-1). Ultrafiltration analysis revealed that 18.4% and 80.1% of the mercapturate bound to plasma protein(s) from NAR and normal rats, respectively, at 50 microM ligand concentration. The mercapturic acid bound to plasma albumin with an association constant of 2.24 X 10(5) M-1 and the number of binding sites was 1.18/mol albumin. The binding was competitively inhibited by probenecid and L-tryptophan. Concomitant administration of this mercapturic acid with equimolar amounts of albumin resulted in a marked decrease in the plasma clearance (26.2 ml kg-1 min-1) and an increase in the urinary secretion of this ligand in NAR. 30 min after injection of the mercapturic acid (10 mumol/kg body weight), 27.3% and 60.4% of the injected dose was recovered from urine and kidneys of NAR and normal rats respectively. About 41% of the dose was recovered in NAR urine when the ligand was injected bound to an equimolar amount of albumin. These results suggested that albumin is important for the renal accumulation and urinary elimination of the circulating mercapturic acid.     

A high cholesterol diet ameliorates renal tubular lesions in diabetic rats

These studies examine the effect of cholesterol feeding in normal rats and in rats with streptozotocin-induced diabetes mellitus. Four groups were studied: normal rats fed either a standard rat chow or a standard rat chow supplemented with cholesterol and diabetic rats fed standard chow or standard chow plus cholesterol. Diabetic rats fed a standard diet excreted more creatinine and urea in the urine, had higher levels of blood urea nitrogen, and lower serum albumin levels than rats fed standard diet plus cholesterol. Blood glucose levels were similar in the two groups; however, diabetic rats given cholesterol had a greater body weight at the end of the study than diabetic rats eating standard chow. Urine volumes and sodium and potassium excretion in the urine were greater in diabetic rats fed a standard diet than in those fed a high cholesterol diet. Diabetic rats fed a standard diet had distinctive renal lesions characterized by swelling of tubular epithelial cells with clearing of cytoplasm. The nephron segments involved by this striking vacuolar change were the distal convoluted tubule and the thick limbs of Henle's loop. These lesions were identical to those described by Armanni-Ebstein in severely glycosuric patients. These lesions were not observed in any of the animals of the other three groups (including diabetic rats fed a high cholesterol diet). Glomeruli were normal in animals of all groups. Thus, cholesterol administration prevents the development of the Armanni-Ebstein lesions in diabetic rats despite persistent hyperglycemia. The mechanism by which cholesterol administration prevents the accumulation of glycogen in distal tubule cells has not been elucidated. It is suggested that glycogen accumulation in distal tubular segments may explain the greater urine volumes, natriuresis, kaliuresis, and proteinuria observed in diabetic animals fed a standard diet when compared with rats fed the same diet plus cholesterol.     

Bile acid profiles in analbuminemia rats

Bile acid profiles in serum, urine and bile of Nagase analbuminemia rats (NAR) and Sprague-Dawley rats (SDR) were examined. Serum bile acid levels in NAR (2.02 + 0.51 micrograms/ml, n = 15, M +/- S.E.) were markedly decreased as compared with those in SDR (20.86 +/- 3.72 micrograms/ml, n = 10). The unbound fraction of acids in serum examined by equilibrium dialysis was about ten times higher in NAR than in SDR. In the profiles of urinary and biliary bile acids in NAR and SDR, as big differences as seen for serum bile acids were not observed. Low bile acid levels in serum of NAR may reflect low bile acid binding capacity of NAR serum because the absence of albumin was thought to be one of the major causes of low bile acid levels in serum of NAR.     

Seasonal variations in physiological indices of adult female white-tailed deer in Texas

Seasonal variations in blood chemistry, urine chemistry, fat reserves, and crude protein levels of rumen contents were determined for free-ranging adult female white-tailed deer (Odocoileus virginianus Zimmermann) in central Texas. Seasonal variations (P less than 0.05) existed for serum total protein, albumin, globulin, albumin/globulin ratios, blood urea nitrogen (BUN), cholesterol, alkaline phosphatase, creatinine, phosphorus, and sodium; and urinary urea/creatinine (U/C) ratios, rumen crude protein, the kidney fat index (KFI), femur marrow fat (FMF), and dressed weights. Variations in BUN, urinary U/C ratios, dressed weights, KFI, and FMF were attributed partially to the nutritional demands of late gestation and lactation.     

Hepato-renal transport of phenolsulfonphthalein in analbuminemic rats: albumin is essential for hepatic compensatory elimination of a nephrophilic ligand in animals with renal dysfunction

To investigate a possible function of plasma albumin in partitioning organic anions into bile and urine, phenolsulfonphthalein (PSP) was administered intravenously and its in vivo fate was studied in normal and analbuminemic mutant rats (NAR). No significant change in the rate of PSP disappearance was observed in bilaterally nephrectomized normal rats. However, biliary excretion of the injected dye increased remarkably in nephrectomized normal rats. Intravenously injected PSP disappeared very rapidly from the circulation of NAR. Thus, the plasma clearance and distribution volume of PSP were significantly larger in NAR than in normal rats. Bilateral nephrectomy also failed to decrease the plasma clearance and distribution volume of the dye in NAR. In striking contrast to the experiments in normal rats, bilateral nephrectomy did not increase the biliary secretion of PSP in NAR. When PSP bound to equimolar albumin was injected into bilaterally nephrectomized NAR, the biliary excretion of PSP increased significantly with concomitant decrease in both plasma clearance and distribution volume of the dye. These results indicate that, in cases of renal transport dysfunction, albumin plays a critical role in hepatic compensatory excretion of PSP, a nephrophilic organic anion, whose molecular weight (MW 354) is close to the threshold value for partitioning a ligand to the eliminatory routes in liver and kidney of a rodent.     

Copper metabolism in analbuminaemic rats fed a high-copper diet

Copper metabolism in male Nagase analbuminaemic (NA) rats was compared with that in male Sprague Dawley (SD) rats fed purified diets containing either 5 or 100 mg Cu/kg diet. Dietary copper loading increased hepatic and kidney copper concentrations in both strains to the same extent, but baseline values were higher in the NA rats. There was no strain difference in true and apparent copper absorption nor in faecal endogenous and urinary copper excretion. NA rats had higher levels of radioactivity in kidneys at 2 hr after intraperitoneal administration of ⁶⁴Cu. As based on the distribution of added ⁶⁴Cu, about 70% of plasma copper appeared to be in the non-protein compartment in the NA rats, whereas in SD rats, it was only about 1%. It is concluded that the NA rats are able to maintain a relatively normal metabolism of copper, even after dietary copper challenge. In the NA rats, zinc concentrations in kidneys, liver and urinary zinc excretion were elevated when compared with SD rats. The high-copper diet did not affect tissue zinc concentrations and apparent zinc absorption in both strains of rats.     

Downregulation of nitric oxide synthase in nephrotic syndrome: role of proteinuria

Blood pressure is frequently elevated, blood volume is usually normal or increased and plasma renin and aldosterone are usually low in nephrotic syndrome (NS). These observations challenge the conventional view attributing sodium retention in NS to a hypoalbuminemia-induced intravascular volume contraction. Given the pivotal role of nitric oxide (NO) in regulation of renal sodium (Na) handling, vascular resistance and sympathetic activity, we considered that Na retention and hypertension in NS may be associated with impaired NO system. Urinary excretion of Na and NO metabolites (NOx), as well as immunodetectable endothelial (eNOS), inducible (iNOS) and neuronal (nNOS) NO synthases were determined in rats with puromycin aminonucleoside (PAN)-induced NS, rats with protein overload proteinuria, Nagase rats (NAR) with inherited analbuminemia, iNOS inhibitor (aminoguanidine)-treated rats, prenephrotic PAN-treated and placebo-treated control rats. The NS group showed marked proteinuria, hypoalbuminemia, decreased fractional excretion of Na (FENa), reduced urinary NOx excretion, and severe reduction of iNOS and nNOS protein abundance in the kidney. Similar results were found in rats with protein overload proteinuria in which proteinuria was present without hypoalbuminemia. In contrast, despite extreme hypoalbuminemia, NAR showed normal FENa, increased urinary NOx excretion and upregulations of iNOS and nNOS protein abundance in the kidney. Administration of aminoguanidine for 3 weeks lowered FENa in normal rats to levels approximating those found in the NS group. Animals studied 2 days after PAN administration (wherein proteinuria was absent) showed no abnormality. Thus, chronic PAN-induced NS results in downregulation of kidney iNOS and nNOS, which can contribute to the reduction of FENa by augmenting renal tubular Na reabsorption, and preglomerular vasoconstriction. Findings in the NAR, which had profound hypoalbuminemia without proteinuria, and in rats with protein overload proteinuria, which had proteinuria without hypoalbuminemia, point to proteinuria as the primary mediator of kidney iNOS and nNOS deficiency and impaired Na excretion in PAN-induced NS.     

Failure of liver cirrhosis induction by thioacetamide in Nagase analbuminaemic rats

Repeated administration of thioacetamide (TA), either intraperitoneally or in drinking water, produced liver cirrhosis in normal Sprague-Dawley rats (SDR) with significant histological alterations similar to those observed in human cirrhosis. In the present study, we evaluated the ability of TA to induce liver cirrhosis in mutant Nagase analbuminaemic SDR. Thioacetamide was administered either intraperitoneally up to 4 months or in drinking water up to 6 months to normal and to Nagase analbuminaemic SDR. Nagase analbuminaemic rats (NAR) were also administered TA in drinking water up to 10 months. Liver cirrhosis development was determined by macroscopic and microscopic analysis. In contrast to normal SDR, no histological characteristics of cirrhosis could be observed in NAR submitted to a 4 or 6 months treatment with TA. Such failure to induce cirrhosis in Nagase rats was confirmed even after prolonged TA administration in drinking water for up to 10 months. In contrast, fibrosis and cholangiolar proliferation occurred in the 10-month TA-treated analbuminaemic rats, suggesting that the mechanisms involved in cirrhosis induction are different from those involved in fibrosis development and carcinogenesis. It is unlikely that the protective effect against TA-induced cirrhosis observed in analbuminaemic rats is related to the absence of albumin in this rat strain, since a co-administration of TA with albumin in analbuminaemic rats did not restore the potential for TA to induce cirrhosis in this rat strain. In conclusion, the fact that induction of cirrhosis by TA is prevented in the inherently hyperlipidaemic and hypercholesterolaemic analbuminaemic rats could be considered for potential application in the treatment of clinical cirrhosis.