Bile duct epithelial cells exposed to alpha-naphthylisothiocyanate produce a factor that causes neutrophil-dependent hepatocellular injury in vitro. (1/1207)

The acute hepatotoxicity induced by alpha-naphthylisothiocyanate (ANIT) in rats is manifested as neutrophil-dependent necrosis of bile duct epithelial cells (BDECs) and hepatic parenchymal cells. This hepatotoxicity mirrors that of drug-induced cholangiolitic hepatitis in humans. Since BDECs are primary targets of ANIT-induced toxicity, we hypothesized that after exposure to ANIT, BDECs produce a factor(s) that causes neutrophil chemotaxis and neutrophil-dependent hepatocellular injury. To test this hypothesis BDECs were isolated from male Sprague Dawley rats and incubated with ANIT (6.25, 12.5, 25, or 50 microM) or vehicle for 24 h. The conditioned medium (CM) was collected and placed in the bottom chamber of a two-chambered chemotaxis system, while isolated neutrophils were placed in the top chamber. Chemotaxis was indicated by neutrophil migration through a membrane to the bottom chamber. CM from BDECs exposed to each concentration of ANIT was chemotactic, whereas CM from vehicle-treated BDECs was not. ANIT alone caused a modest degree of chemotaxis at 50 microM. The conditioned media were added to isolated hepatocytes or to hepatocyte-neutrophil cocultures and incubated for 24 h. Hepatocyte toxicity was indicated by alanine aminotransferase release into the culture medium. CM from vehicle-treated BDECs did not cause hepatocyte killing in either hepatocyte-neutrophil cocultures or hepatocyte cultures. In contrast, the addition of CM from ANIT-treated BDECs (CM-BDEC-A) to hepatocyte-neutrophil cocultures resulted in hepatocyte killing. The same CM was not cytotoxic to hepatocyte cultures devoid of neutrophils. The hepatocyte killing could not be explained by residual ANIT in the CM, which was below the limit of detection (< or = 0.5 microM). The addition of antiproteases afforded protection against neutrophil-dependent hepatocellular injury induced by CM-BDEC-A. These results indicate that ANIT causes BDECs to release a factor(s) that attracts neutrophils and stimulates them to injure hepatocytes in vitro.  (+info)

Transfer of the 1-pro-R and the 1-pro-S hydrogen atoms of ethanol in metabolic reductions in vivo. (2/1207)

The transfer of deuterium from [1 R-2H]ethanol and [1 S-2H]-ethanol to reduced metabolites of administered compounds was measured in female rats provided with bile fistulas. Administered cyclohexanone was reduced to cyclohexanol, and in this reduction hydrogen was transferred only from the 1-pro-R position of the ethanol. The deuterium content in the cyclohexanol was about 67% of that in the ethanol. In the reduction of the 17-oxo group in 3beta-hydroxy-5alpha-androstan-17-one, hydrogen was transferred both from the 1-pro-R position and the 1-pro-S position, resulting in degrees of labelling that were about 25% and 2%, respectively, of those in the specific positions of the ethanols. The 1-pro-R and 1-pro-S positions of ethanol contributed about 9% and 5%, respectively, of the 3beta hydrogen in lithocholic acid formed from 3-oxo-5beta-cholanoic acid. The results indicate that alcohol dehydrogenase and aldehyde dehydrogenase do not share a common pool of NAD, and that NADH formed during acetaldehyde oxidation is utilized for reductions in the cytosol to a smaller extent than the NADH formed in the alcohol dehydrogenase reaction. This result supports the concept that aldehyde oxidation is mainly an intramitochondrial process. The relatively extensive utilization of the 1-pro-S hydrogen of ethanol in the reduction of 3-oxo-5beta-cholanoic acid, that is probably NADPH-dependent, indicates that cytosolic NADPH may be produced from malate or isocitrate formed intramitochondrially.  (+info)

Effect of its demethylated metabolite on the pharmacokinetics of unchanged TAK-603, a new antirheumatic agent, in rats. (3/1207)

A factor in the dose-dependent pharmacokinetics of ethyl 4-(3, 4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2, 4-triazol-1-yl-methyl)quinoline-3-carboxylate (TAK-603) in rats was shown to be due to the inhibition of metabolic clearance of unchanged TAK-603 by its major metabolite, M-I, in other words, product inhibition. The effect of M-I on the metabolic clearance of TAK-603 was studied using rats continuously infused i.v. with this metabolite at rates of 5.3 and 16.0 mg/h/kg. The total body clearance of TAK-603 was decreased remarkably in M-I-infused rats, and the decline of total body clearance depended on the steady-state plasma concentrations of M-I. The effect of M-I generated from the dosed parent drug on the plasma concentration-time profile of TAK-603 was investigated using bile-cannulated rats after i.v. injection of 14C-labeled TAK-603 at doses of 1 and 15 mg/kg. Elimination rates of TAK-603 from rat plasma increased in the bile-cannulated rats in which systemic M-I levels were reduced by interrupting its enterohepatic circulation. To express, simultaneously, the relationships between TAK-603 and M-I in plasma concentration-time profiles, a kinetic model based on the product inhibition was developed for the bile-cannulated rats. A good agreement between calculated curves and the observed concentrations of both TAK-603 and M-I was found at 1 and 15 mg/kg, and the calculated curves were drawn using constant parameters for the two dosages. These results show that the product inhibition by M-I is one factor responsible for the dose-dependent pharmacokinetics of TAK-603 in rats.  (+info)

Complications of cholecystectomy: risks of the laparoscopic approach and protective effects of operative cholangiography: a population-based study. (4/1207)

BACKGROUND: Previous studies suggest that laparoscopic cholecystectomy (LC) is associated with an increased risk of intraoperative injury involving the bile ducts, bowel, and vascular structures compared with open cholecystectomy (OC). Population-based studies are required to estimate the magnitude of the increased risk, to determine whether this is changing over time, and to identify ways by which this might be reduced. METHODS: Suspected cases of intraoperative injury associated with cholecystectomy in Western Australia in the period 1988 to 1994 were identified from routinely collected hospital statistical records and lists of persons undergoing postoperative endoscopic retrograde cholangiopancreatography. The case records of suspect cases were reviewed to confirm the nature and site of injury. Ordinal logistic regression was used to estimate the risk of injury associated with LC compared with OC after adjusting for confounding factors. RESULTS: After the introduction of LC in 1991, the proportion of all cholecystectomy cases with intraoperative injury increased from 0.67% in 1988-90 to 1.33% in 1993-94. Similar relative increases were observed in bile duct injuries, major bile leaks, and other injuries to bowel or vascular structures. Increases in intraoperative injury were observed in both LC and OC. After adjustment for age, gender, hospital type, severity of disease, intraoperative cholangiography, and calendar period, the odds ratio for intraoperative injury in LC compared with OC was 1.79. Operative cholangiography significantly reduced the risk of injury. CONCLUSION: Operative cholangiography has a protective effect for complications of cholecystectomy. Compared with OC, LC carries a nearly twofold higher risk of major bile, vascular, and bowel complications. Further study is required to determine the extent to which potentially preventable factors contribute to this risk.  (+info)

Investigation of bile ducts before laparoscopic cholecystectomy. (5/1207)

BACKGROUND: Since the advent of laparoscopic cholecystectomy, there has been controversy about the investigation of the bile ducts and the management of common bile duct stones. Routine peroperative cholangiography (POC) in all cases has been recommended. We have adopted a policy of not performing routine POC, and the results of 700 cases are reported. METHODS: Since 1990, all patients have undergone preoperative ultrasound scan. We have performed selective preoperative endoscopic retrograde cholangiopancreatography (ERCP) because of a clinical history of jaundice and/or pancreatitis, abnormal liver function tests and ultrasound evidence of dilated bile ducts (N=78, 11.1%). The remaining 622 patients did not have a routine POC, but selective peroperative cholangiogram (POC) was performed only in 42 patients (6%) because of unsuccessful ERCP or mild alteration in the criteria for the presence of bile duct stones. The remaining 580 patients did not undergo POC. Careful dissection of Calot's triangle was performed in all cases to reduce the risk of bile duct injuries. RESULTS: The overall operative complications, postoperative morbidity and mortality was 1.71%, 2.14% and 0.43%, respectively. Bile duct injuries occurred in two patients (0.26%) and both were recognized during the operation and repaired. There was a single incidence of retained stone in this series of 700 cases (0.14%), which required postoperative ERCP. CONCLUSIONS: This policy of selective preoperative ERCP, and not routine peroperative cholangiogram, is cost effective and not associated with significant incidence of retained stones or bile duct injuries after laparoscopic cholecystectomy.  (+info)

Acute carbon tetrachloride feeding induces damage of large but not small cholangiocytes from BDL rat liver. (6/1207)

Bile duct damage and/or loss is limited to a range of duct sizes in cholangiopathies. We tested the hypothesis that CCl4 damages only large ducts. CCl4 or mineral oil was given to bile duct-ligated (BDL) rats, and 1, 2, and 7 days later small and large cholangiocytes were purified and evaluated for apoptosis, proliferation, and secretion. In situ, we measured apoptosis by morphometric and TUNEL analysis and the number of small and large ducts by morphometry. Two days after CCl4 administration, we found an increased number of small ducts and reduced number of large ducts. In vitro apoptosis was observed only in large cholangiocytes, and this was accompanied by loss of proliferation and secretion in large cholangiocytes and loss of choleretic effect of secretin. Small cholangiocytes de novo express the secretin receptor gene and secretin-induced cAMP response. Consistent with damage of large ducts, we detected cytochrome P-4502E1 (which CCl4 converts to its radicals) only in large cholangiocytes. CCl4 induces selective apoptosis of large ducts associated with loss of large cholangiocyte proliferation and secretion.  (+info)

Aquaporin water channels in gastrointestinal physiology. (7/1207)

Fluid transport is a major function of the gastrointestinal (GI) tract with more than 9 litres of fluid being absorbed or secreted across epithelia in human salivary gland, stomach, the hepatobiliary tract, pancreas, small intestine and colon. This review evaluates the evidence that aquaporin-type water channels are involved in GI fluid transport. The aquaporins are a family of small ( approximately 30 kDa) integral membrane proteins that function as water channels. At least seven aquaporins are expressed in various tissues in the GI tract: AQP1 in intrahepatic cholangiocytes, AQP4 in gastric parietal cells, AQP3 and AQP4 in colonic surface epithelium, AQP5 in salivary gland, AQP7 in small intestine, AQP8 in liver, pancreas and colon, and AQP9 in liver. There are functional data suggesting that some GI cell types expressing aquaporins have high or regulated water permeability; however, there has been no direct evidence for a role of aquaporins in GI physiology. Recently, transgenic mice have been generated with selective deletions of various aquaporins. Preliminary evaluation of GI function suggests a role for AQP1 in dietary fat processing and AQP4 in colonic fluid absorption. Further study of aquaporin function in the GI tract should provide new insights into normal GI physiology and disease mechanisms, and may yield novel therapies to regulate fluid movement in GI diseases.  (+info)

Dihydropyrimidine dehydrogenase activity and fluorouracil pharmacokinetics with liver damage induced by bile duct ligation in rats. (8/1207)

Hepatic metabolism is the main determinant in the pharmacokinetics of 5-fluorouracil (5-FU). Its disposition might be affected with liver dysfunction. In the present study, the influence of liver damage induced by bile duct ligation on dihydropyrimidine dehydrogenase (DPD), a rate-limiting enzyme in 5-FU catabolism, CYP2B, and 5-FU pharmacokinetics were compared in male Sprague-Dawley rats. After 3 weeks of the ligation in two different groups of animals for in vitro and pharmacokinetic experiments, significant increases in serum bilirubin level and spleen weight were found in both groups. No significant differences were noted in bilirubin level or spleen weight of the bile duct ligation group between the two experiment groups. In the in vitro experiment, DPD activity and protein levels determined by Western blot analysis in the bile duct ligation group were slightly but significantly greater than those of a sham-operated group, whereas CYP2B activity and protein level were significantly reduced. These findings were supported by mRNA levels of CYP2B and DPD. When 40 mg/kg 5-FU was administered i.v. in the pharmacokinetic experiment, no significant differences in pharmacokinetic parameters were found between the bile duct ligation and sham-operated groups. These results suggested that DPD activity and protein level were maintained and that 5-FU pharmacokinetics was not altered in the presence of liver damage accompanied by a significant reduction in CYP2B activity and protein level, supporting previous clinical studies showing that mild to moderate liver dysfunction does not affect 5-FU disposition.  (+info)

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