Effects of gomisin A, a lignan component of Schizandra fruits, on experimental liver injuries and liver microsomal drug-metabolizing enzymes

Effects of oral administration of gomisin A, one of the components isolated from Schizandra fruits, on liver injuries induced by CCl4, d-galactosamine and dl-ethionine and on liver microsomal drug-metabolizing enzyme activities were investigated. Gomisin A suppressed the increase of serum transaminase activities and the appearances of histological changes such as degeneration and necrosis of hepatocyte, inflammatory cell infiltration and fatty deposition in each type of liver injury. The repeated administration of gomisin A (30 or 100 mg/kg, p.o., daily for 4 days) induced an apparent increase of liver weight in liver-injured and normal rats. Gomisin A decreased serum triglyceride and lipid contents of the liver in biochemical studies. Increases of microsomal cytochrome b5 and P-450, elevations of NADPH cytochrome C reductase, aminopyrine N-demethylase and 7-ethoxycoumarin O-deethylase activities and decrease of 3,4-benzo(a)pyrene hydroxylase activity per cytochrome P-450 were observed after the administration of gomisin A. In addition, gomisin A was found to enhance the incorporation of 14C-phenylalanine into liver protein and to shorten the hexobarbital-induced sleeping time. These changes caused by gomisin A were similar to those by phenobarbital. However, gomisin A is distinctly different from phenobarbital in the finding that phenobarbital lessened the survival ratio of CCl4-intoxicated mice, but gomisin A did not. Our observation suggest that gomisin A shows an antihepatotoxic action by oral application and also has hypolipidemic (mainly triglyceridemic) and liver protein synthesis-facilitating actions and that the enlargement of the liver seen with gomisin A is the adaptive hypertrophy which is due to the induction of drug-metabolizing enzymes.     

靛氰绿在四氯化碳染毒大鼠肝胆内转运的研究

目的　研究靛氰绿 (ICG)在四氯化碳 (CCl4 )致急性肝损伤大鼠的 (CCl4 大鼠 )肝胆内转运过程。方法　复制CCl4 大鼠模型 ,观察下列变化 :(1)各种病理学的变化 ;(2 )肝血流量和靛氰绿肝清除率的改变 ;(3 )靛氰绿的药代动力学参数。结果　靛氰绿在CCl4 染毒大鼠体内的清除减慢 ,总清除率下降至对照组的约 70 % (P <0 0 5 ) ;肝清除率和肝血流量也明显下降 (P <0 0 5 )。结论　靛氰绿在CCl4 染毒大鼠的肝清除率下降 ,药代动力学分析 ,结果提示至少与靛氰绿自血液进入肝细胞速度减慢 ,以及肝血流量的减少有关。     

Effects of gomisin A on hepatocarcinogenesis by 3'-methyl-4-dimethylaminoazobenzene in rats.

We examined the effects of gomisin A on tumor promotion in the liver after a short-term feeding of 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB) to rats, compared with the effects of phenobarbital. Male Donryu rats were fed ad libitum a diet containing 0.06% 3'-MeDAB and 0.03% or 0.01% gomisin A or water containing 0.05% phenobarbital. Gomisin A and phenobarbital did not cause any proliferative and neoplastic lesions by themselves in 40 weeks of feeding. Altered foci in the liver increased with a peak at 12 weeks after the rats were fed 3'-MeDAB. Gomisin A decreased the number of hepatic altered foci such as the clear cell and basophilic cell type foci in the early stages. Phenobarbital enhanced neoplastic alterations so that the number and size of the foci were much larger in the phenobarbital-combined group than in the 3'-MeDAB-control group. Thus, phenobarbital acted as a promoter of cells initiated by 3'-MeDAB; on the other hand, gomisin A showed a weak suppressive effect on tumor promotion.     

Effect of carbon tetrachloride on biliary excretion of 3,4-benzpyrene in rats]

14C-labelled 3,4-benzpyrene (14C-BP) in dose of 100 mug/animal was injected into female Sprague-Dawley rats under urethane anesthesia. The rats were cannulated at the duct and the output of metabolites in the bile was determined. Non-treated rats excreted 35.5% of the given dose within one hr. The main metabolites excreted in bile were fractionated chromatographically into three. One of these was a metabolite which was hydrolyzed by beta-glucuronidase, the other two were unknown substances. Unchanged BP was not detected. In rats pretreated with CCl4 (0.5 ml/kg, p.o.) 24 hr before experiment, the biliary excretion of BP-metabolites was found to be reduced, that is only 10% of the given dose was excreted within one hr. It was noted that the output within the first 90 min after injection of BP was significantly reduced. In the CCl4-treated rats, bile flow was found to be lowered. However, the reduced output of BP-metabolites was considered not as the result of lowered bile flow, but as the result of disturbance of BP-metabolism in the liver. Thus it is suggested that impaired hepatic junction as the result of CCl4 intoxication may last for more than two weeks, when the hepatic junction is evaluated in terms of biliary excretion of BP.     

Effect of colchicine on hepatobiliary function in CCl4 treated rats.

A number of toxic chemicals affect the biliary excretory function of liver. Organochlorines and halomethanes are known to enhance bile flow. Despite the demonstration that a diversity of agents modify biliary function, the mechanism by which these chemicals manifest this effect is not fully understood. This study was designed to assess the effect of colchicine (0.1, 1.0, or 2.5 mg/kg, i.p., in saline) administration on biliary excretory function 6 and 24 hr later. Additionally, the effect of colchicine (1 mg/kg, i.p. in saline) pretreatment in rats 2 hr prior to the administration of a single low dose of CCl4 (100 microL/kg, i.p., in corn oil) or corn oil alone (1 mL/kg, i.p.) on hepatic biliary excretory function was also assessed at 6 and 24 hr after the last treatment. The hepatotoxicity was evaluated by serum enzymes, alanine and aspartate aminotransferases, and histopathological alterations of the liver. Biliary excretion of intravenously administered phenolphthalein glucuronide (PG) was assessed in bile duct cannulated anesthetized rats. Only the highest dose of colchicine (2.5 mg/kg) resulted in detectable liver injury as revealed by elevations of serum transaminases. While the lowest dose of colchicine (0.1 mg/kg) did not influence bile secretion, the two higher doses caused a slight choleretic effect at 24 hr. The highest dose caused a transient inhibition of bile flow, but this effect was no longer evident at 6 hr. Biliary excretion of PG was inhibited significantly by colchicine within 6 hr after administration, an effect that was also persistent at 24 hr. Colchicine at a 1 mg/kg dose did not cause any adverse effect on hepatobiliary function. Therefore, for the interactive toxicity study with CCl4, 1 mg colchicine/kg was chosen as a moderate dose which did not cause any significant adverse effect on hepatobiliary function. Biliary excretion of PG was significantly lower in rats at 6 and 24 hr after the combination treatment with colchicine + CCl4 than in rats receiving either CCl4 or colchicine alone. In contrast, rats receiving CCl4 alone or colchicine + CCl4 showed a significant increase in cumulative bile flow at 6 hr, whereas, at 24 hr, the bile flow was increased significantly in rats receiving colchicine regardless of CCl4 treatment. The data suggest that colchicine pretreatment leads to significant inhibition of hepatobiliary excretion in CCl4 treated rats. Serum alanine transaminase and aspartate transaminase levels were elevated significantly after the colchicine + CCl4 combination, indicating hepatic injury.(ABSTRACT TRUNCATED AT 400 WORDS)     

Studies on the metabolic fate of gomisin A (TJN-101). II. Absorption and excretion in CCl4 treated rats]

The absorption and excretion of gomisin A (TJN-101) in rats whose livers were injured by carbon tetrachloride (CCl4) were investigated. After intravenous administration of TJN-101 at a dose of 5 mg/kg, the terminal elimination half-life was 1.5 h in the CCl4-treated rats, which was two times that in normal rats. The mean area under the blood concentration-time curve (AUC) value of TJN-101 in the CCl4-treated rats was twice that in normal rats, and this difference was significant (p less than 0.05). Therefore, the total body clearance of TJN-101 in the CCl4-treated rats decreased less than half of that in normal rats. Similar results were observed when it was administered orally. In the CCl4-treated rats, the serum concentration of Met. B, which was identified as a demethylenated substance and one of major metabolites, tended to decrease more than that in normal rats. On the other hand, the cumulative biliary excretion ratio of TJN-101 in 24 h after dosing in the CCl4-treated rats was 2.5 times that in normal rats. The excretion rate of Met. B in the bile in the CCl4-treated rats tended to be delayed. However, the quantitative variance of biliary excretion of Met. B was not found in both groups. The urinary excretion of TJN-101 or Met. B in 72 h after dosing in the CCl4-treated rats was lower than that in normal rats. Similar results were also observed in excretion in the feces.(ABSTRACT TRUNCATED AT 250 WORDS)     

Protective effect of Aucuba japonica against carbon tetrachloride-induced liver damage in rats

Pretreatment of rats with ethanol extract from leaves of Aucuba japonica (600 mg/kg/day, po) for two days protected against CCl4-induced depression in plasma disappearance and biliary excretion of injected sulfobromophthalein (BSP) determined 24 hr after the CCl4 challenge (0.5 ml/kg, ip). Percent recovery of BSP in bile in 60 min for control, CCl4, extract + CCl4 treated rats was 66.8 +/- 1.9, 56.2 +/- 1.4, and 68.9 +/- 2.2, respectively. Pretreatment of the extract also protected CCl4-induced increased serum glutamic-pyruvic transaminase activity and liver necrosis as demonstrated by histological evaluations. However, pretreatment of the extract did not modify the intensity of CCl4-induced lipid peroxidation process or cytochrome P-450 destruction. The results suggest that ethanol extract of Aucuba japonica protects CCl4 hepatotoxicity at a site in the chain events leading to necrosis but not the activation step of CCl4 to X CCl3 and X C1 free radicals.     

Effect of chlorpromazine on hepatic transport of indocyanine green in rats

The effect of chlorpromazine hydrochloride (CPZ) on the hepatic transport of indocyanine green (ICG) was studied in the rat, in an attempt to elucidate the mechanisms of hepatotoxicity of CPZ in vivo, by comparing the pharmacokinetic parameters of ICG after bolus and chronic administration of CPZ. Delays were shown in both plasma disappearance and biliary excretion of ICG in the CPZ-treated rats (10 and 15 mg/kg intraportal bolus administration). Significant decreases were observed in the pharmacokinetic parameters, V₂ and total body clearance (CL_tot) in CPZ 10 mg/kg treated rats and k₃₄, V₂ and CL_tot in CPZ 15 mg/kg treated rats, while a significant increase was observed in k₂₁ in both CPZ-treated groups; V₁ was not altered. The apparent liver-to-plasma concentration ratio (K_p,app) of ICG at 50 min after i.v. administration was decreased significantly in CPZ 15 mg/kg treated rats when compared to control rats, suggesting an alteration in the distribution of ICG to the liver by CPZ. Bile flow rates decreased immediately after bolus intraportal administration of CPZ in both CPZ-treated groups, and they then returned progressively to the basal levels. The output of bile acids was also inhibited by CPZ in a time-dependent and reversible manner and the bile acid independent fraction of bile flow was decreased significantly in both CPZ-treated groups. Chronic treatment with CPZ (10 or 20 mg/kg, i.p., per day for 3 weeks) did not alter either the pharmacokinetic parameters or the bile secretion profile of ICG, although there were significant decreases in body and liver weights in CPZ-treated groups. This may have been due to the rapid metabolism and excretion of CPZ in the rat when compared to humans. It is proposed that the acute toxic effect of CPZ on hepatic transport of ICG in the rat may be due mainly to the time-dependent and reversible cholestasis induced by CPZ, and that chronic treatment with CPZ may not alter the hepatic transport of ICG in the rat.     

Heterogeneity of rat hepatocytes in transport and hepatic binding of asialoalkaline phosphatase studied after induction of selective acinar damage by N-hydroxy-2-acetylaminofluorene and carbon tetrachloride

In order to investigate rat hepatocyte heterogeneity in asialoglycoprotein transport, rats were pretreated with N-hydroxy-2-acetylaminofluorene (N-OH-AAF, 90 mumol/kg, i.v.) to damage zone 1 hepatocytes, or with carbon tetrachloride (CCl4, 2.1 mmole/kg, p.o.) to damage zone 3 hepatocytes. Twenty-four hours after pretreatment, the asialoglycoprotein dog intestinal alkaline phosphatase (As-ALPase) was injected and plasma disappearance and biliary excretion were measured. In addition, the acinar distribution of the hepatic binding of As-ALPase 10 min after injection in vivo, or after incubation of fixed liver sections with As-ALPase in vitro, was determined by enzyme histochemistry. In control rats, a rapid biexponential plasma disappearance was observed and 6.4 +/- 1.5% of the dose was excreted into bile after 60 min. Hepatocyte binding occurred predominantly in zone 3, both after administration in vivo and after incubation with liver sections in vitro. In rats with zone 1 liver damage, both the half-lives of the first and of the second phase were strongly increased, but biliary excretion did not change significantly. Both in vivo and in vitro the relatively weak binding of As-ALPase in zone 1 of the liver was abolished, whereas binding to zone 3 cells was normal or only slightly decreased. After CCl4-pretreatment histochemically detectable binding to zone 3 cells was completely abolished, leaving only the relatively weak binding in zone 1. Unexpectedly, a normal plasma disappearance and biliary excretion rate were found in these rats. The discrepancy between the pharmacokinetic results, which point to a predominant involvement of zone 1 cells in As-ALPase transport, and the enzyme histochemical studies, which show preferential binding of As-ALPase in zone 3, is discussed.     

Biliary excretion of pravastatin and taurocholate in rats with bile salt export pump (Bsep) impairment

The bile salt export pump (BSEP) is expressed on the canalicular membrane of hepatocytes regulating liver bile salt excretion, and impairment of BSEP function may lead to cholestasis in humans. This study explored drug biliary excretion, as well as serum chemistry, individual bile acid concentrations and liver transporter expressions, in the SAGE Bsep knockout (KO) rat model. It was observed that the Bsep protein in KO rats was decreased to 15% of that in the wild type (WT), as quantified using LC–MS/MS. While the levels of Ntcp and Mrp2 were not significantly altered, Mrp3 expression increased and Oatp1a1 decreased in KO animals. Compared with the WT rats, the KO rats had similar serum chemistry and showed normal liver transaminases. Although the total plasma bile salts and bile flow were not significantly changed in Bsep KO rats, individual bile acids in plasma and liver demonstrated variable changes, indicating the impact of Bsep KO. Following an intravenous dose of deuterium labeled taurocholic acid (D4‐TCA, 2 mg/kg), the D4‐TCA plasma exposure was higher and bile excretion was delayed by approximately 0.5 h in the KO rats. No differences were observed for the pravastatin plasma concentration–time profile or the biliary excretion after intravenous administration (1 mg/kg). Collectively, the results revealed that these rats have significantly lower Bsep expression, therefore affecting the biliary excretion of endogenous bile acids and Bsep substrates. However, these rats are able to maintain a relatively normal liver function through the remaining Bsep protein and via the regulation of other transporters. Copyright © 2016 John Wiley & Sons, Ltd.     

CYCLOSPORINE A HEPATOTOXICITY: EFFECT OF PROLONGED TREATMENT WITH CYCLOSPORINE ON BILIARY LIPID SECRETION IN THE RAT

1. The effects of cyclosporine A (CyA) treatment on liver morphology, bile flow and biliary secretion of bile acid, cholesterol and phospholipid and some plasma biochemical indicators of liver function were examined. 2. Wistar rats were treated i.p. with 10 or 20 mg of CyA/kg per day for 1, 2, 3 or 4 weeks. 3. Treatment increased bile acid and bilirubin plasma concentration. Bile flow and biliary secretion of bile acid, cholesterol and phospholipid were reduced in CyA-treated animals. 4. All these effecs of the drug appeared at 1 week after the start of treatment and were enhanced during prolonged treatment. Cyclosporine A-induced cholestasis was due to a decrease in both the bile acid-dependent and -independent fractions of bile flow. 5. The reduction in cholesterol and phospholipid biliary output may be secondary to the inhibition of the hepatobiliary flux of bile acid; however, perturbations in the removal of lipids from the canalicular membrane as well as intracanalicular interaction between CyA and lipid vesicles/micelles could also be involved.     

Hepatic transport of indocyanine green in dogs chronically intoxicated with dimethylnitrosamine

Hepatic transport of indocyanine green (ICG) was examined in dogs chronically intoxicated with dimethylnitrosamine (DMN) (2 mg/kg) intraportally once a week for 6 weeks. In pathophysiological consequences, significant increases (p less than 0.05) were shown in both glutamic-pyruvic transaminase (GPT) and total plasma bile acids, but no significant difference was shown in body weight, liver wet weight, glutamic-oxaloacetic transaminase (GOT), plasma alkaline phosphatase activity, total plasma protein, and total plasma bilirubin. By histologic examination of livers from intoxicated dogs, increased fibrosis in periportal, perisinusoidal, and especially pericentral areas, with loss of normal architecture, was observed. Partial fibrous bridging between periportal and pericentral areas was also demonstrated, but extensive pseudolobulation with regenerative nodules was not observed. The portal venous pressure of the intoxicated dogs was increased by approximately 50% of that of control dogs. In intoxicated dogs, delays were shown in both plasma disappearance and biliary excretion of ICG and significant decreases were observed in the pharmacokinetic parameters k12 (plasma to liver transfer rate constant), V2 (distribution volume of liver compartment), and CLtot (total body-plasma clearance), while a significant increase was observed in k23 (intrahepatic diffusion and transport rate constant); the V1 (distribution volume of plasma compartment) was not altered. From these findings, it is suggested that the decrease in the intrinsic clearance of ICG for the hepatic uptake process might explain the decrease in ICG uptake rate into the liver which was observed in the DMN-intoxicated dogs. Dogs chronically intoxicated with DMN might be a good model for studying hepatic dysfunction.     

Mechanism of antihepatotoxic activity of wuweizisu C and gomisin A1

The mechanism of inhibitory action of wuweizisu C and gomisin A in carbon tetrachloride (CCl (4))-induced liver damage was investigated by determining the effects of these substances on the steps of the series of events leading to liver lesion. Although wuweizisu C and gomisin A exerted no inhibition in CCl (3) radical formation, both lignans inhibited CCl (4)-, ADP/Fe (3+)- and ascorbate/Fe (2+)-induced lipid peroxidation, and wuweizisu C elicited stronger effects than gomisin A which is parallel with the results on antihepatotoxic effects in CCl (4)-induced cytotoxicity, indicating that anti-oxidative action plays an important part in the antihepatotoxic activity of wuweizisu C and gomisin A.     

The effect of acute renal failure on the pharmacokinetics of indocyanine green in the rat

The pharmacokinetics of indocyanine green (ICG) have been studied in control rats and rats with acute renal failure (ARF). Three models of ARF were investigated, and these were produced in the following ways: by bilateral ureteral ligation (surgical model), or by parenteral injection of either uranyl nitrate or glycerol. In both control and uraemic rats, from all three models of ARF, the plasma disappearance of ICG was biexponential and from the plasma disappearance curves the rate constants for transfer from plasma to liver (k₁₂), liver to plasma (k₂₁); and liver to bile (k₂₃) were calculated. The initial removal of ICG from plasma was significantly slowed and k₁₂ significantly decreased in male rats with surgically or uranyl nitrate-induced ARF. The plasma clearance of ICG was not affected by surgically-induced ARF but clearance was reduced in the uranyl nitrate model. More complex changes occurred in male rats with glycerol-induced ARF as k₁₂, k₂₁, k₂₃ and plasma clearance of ICG were all significantly decreased. Female rats with glycerol-induced ARF showed significant decreases in k₁₂, and plasma clearance, but these changes were much smaller than in uraemic males.Of the three models of ARF studied the glycerol model was preferred because surgery alone had a pronounced effect upon the kinetics of ICG and wet liver weight was significantly decreased in the uranyl nitrate model. These changes complicated interpretation of the results from the surgical and uranyl nitrate models. The results from the glycerol model suggest that the hepatic uptake of ICG, and possibly its biliary excretion, were reduced in rats with ARF. In addition, liver function in female rats appears to be more resistant than that in males to the effects of glycerol-induced ARF.     

雪域肝胆康胶囊对小鼠实验性肝损伤及胆汁的影响

目的 研究藏药雪域肝胆康胶囊(XYGD)的保肝利胆作用.方法 以CCl4制作动物急性肝损伤模型,测定血清ALT、AST、TBIL的含量,观察XYCD对动物急性肝损伤的影响;采用麻醉大鼠行胆汁引流术,测定正常大鼠的胆汁分泌量及胆汁成分.结果 雪域肝胆康胶囊能明显降低CCl4急性肝损伤动物血清ALT、AST水平;使正常大鼠的胆汁流量明显增加,降低胆汁中胆固醇的浓度.结论 XYGD有明显保肝、利胆作用.     

Effects of butylated hydroxytoluene (BHT) on biliary excretion of xenobiotics and bile flow in rats

A significant enhancement in the biliary excretion of iv injected sulfobromophthalein (BSP), phenol- 3,6 -dibromphthalein disulfonate (DBSP), procaine amide ethobromide (PAEB) and ouabain was observed in rats maintained on diets containing 0.25% BHT for periods of 10 days. The enhanced biliary excretion of these drugs in BHT treated rats appears to be correlated with the increase in bile flow produced by BHT. The increased bile flow was due to an increase in canalicular bile production rather than a change in net ductular secretion or reabsorption of fluid since bile to plasma concentration ratios of erythritol were unchanged and no permeability change in the biliary tree was observed when mannitol was administered by retrograde intrabiliary injection. The increase in bile flow was not due to an enhanced excretion of bile salts into bile, because both the biliary bile acid concentration and total biliary excretion of bile acids were lower in BHT-treated rats than in control rats. It appears that the increase in bile flow produced by BHT is due to the osmotic choleresis related to the secretion of BHT and its metabolites into bile.     

Biliary excretion of gamma-glutamyltransferase. Selective enhancement by acute ethanol administration

To study the acute effect of ethanol on various constituents of the bile, female Wistar rats received by intravenous administration 0.9% NaCl solution either alone or containing in addition ethanol (0.1 ml ethanol 96% hr-1 100 g body weight-1). Compared to saline-treated controls there was a significant enhancement of biliary gamma-glutamyltransferase excretion after ethanol infusion for 5 hr by 166% (22.1 +/- 2.8 microU/min/100 g body weight vs. 58.2 +/- 13.7; P less than 0.0125), whereas no changes or only marginal alterations have been observed for bile flow and the biliary excretion of total bile acids and alkaline phosphatase. The selective enhancement of biliary gamma-glutamyltransferase excretion by ethanol can be ascribed to an increased solubilization of the membrane-bound enzyme originating from the bile canaliculi of the hepatocytes and/or the epithelial cells of the bile ducts. Since the biliary excretion of total bile acids remained unchanged by ethanol, the observed selective solubilization of gamma-glutamyltransferase may occur by a mechanism primarily not involving total bile acids and could be linked to a direct effect of ethanol on physico-chemical properties such as an increased fluidity of liver plasma membranes.     

Effects of Duration of Ischemia and Donor Pretreatment with Methylprednisolone or Its Macromolecular Prodrug on the Disposition of Indocyanine Green in Cold-Preserved Rat Livers

PURPOSE: Cold preservation of the liver before transplantation may change uptake and excretory functions of hepatocytes. We hypothesized that an increase in the duration of preservation would result in a progressive decrease in the hepatic uptake and/or biliary excretion of indocyanine green (ICG), which would be attenuated by pharmacologic interventions. METHODS: Donor rats (n = 40) were administered saline (control) or single 5 mg/kg doses of methylprednisolone (MP) or its liver-targeted prodrug (DMP) 2 h prior to liver harvest. Following preservation in cold University of Wisconsin solution for 0, 24, 48, or 72 h, livers were reperfused in a single-pass manner for 30 min in the presence of ICG (approximately 4 microg/ml), followed by 60 min of ICG-free perfusion. The inlet, outlet, and bile concentrations of ICG were measured periodically by high performance liquid chromatography (HPLC), and kinetic parameters were estimated. RESULTS: Effects of duration of preservation: In unpreserved livers, a significant portion of ICG dose (16%) was effluxed from the liver during the washout period. Cold preservation for 24-72 h progressively increased (p < 0.05) the efflux of ICG (>2-fold at 72 h). Similarly, average extraction ratio showed a modest (30-40%) decrease with increasing preservation time (p < 0.05). However, biliary excretion of ICG showed the most sensitivity to the preservation time (14 to >800-fold decline). Effects of pretreatment: DMP caused significant (p < 0.05) increases in biliary ICG levels (>12-fold) and bile flow rates (6-15-fold) of preserved livers. Although MP pretreatment significantly (p < 0.05) increased (6-fold) bile flow rates in 48-h preserved livers, its effects on biliary ICG levels were not significant (p > 0.05). CONCLUSIONS: Biliary excretion of ICG is the most sensitive kinetic parameter to prolonged cold ischemia-reperfusion injury in a rat liver perfusion model. The injury may be significantly attenuated by pharmacologic pretreatment of the liver donors.     

Studies on the mechanism of bile salt-independent bile flow impairment in streptozotocin-induced hepatotoxicity.

The main factors involved in the impairment of formation of the bile salt-independent bile flow (BSIF) in streptozotocin (SZ)-treated rats were examined. Twenty-four hours after SZ injection (50 mg/kg body wt, i.v.) bile flow, bile salt output and biliary excretion of the major inorganic electrolytes (sodium, chloride and bicarbonate) were significantly diminished. The relationship between bile flow and bile salt output obtained during the administration of sodium taurocholate at stepwise-increasing rates indicated that bile salt-independent bile flow (y-intercept) was diminished by 37% in SZ-treated rats. The relationship between electrolyte output and bile salt output showed that the fractions of sodium, chloride and bicarbonate excreted independently of bile salt (y-intercept) decreased to 59%, 47% and 67% of the control values respectively, while the amount of electrolyte secreted per unit of bile salt secreted was unaffected in SZ-treated rats. The hepatic activity of Na+,K(+)-adenosine triphosphatase (Na+,K(+)-ATPase) was decreased by 59% (P less than 0.05) in SZ-treated rats. Nicotinamide administered prior to SZ prevented the hyperglycemia indicative of SZ-induced diabetes, but had no effect on the decrease in Na+,K(+)-ATPase activity caused by the drug. These results suggest that SZ itself, and not its diabetogenic effect, decreases the BSIF by a mechanism that involves impairment of the biliary electrolyte excretion, which could be the result of the inhibition of the hepatic Na+,K(+)-ATPase activity.