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1.
J Med Case Rep ; 16(1): 231, 2022 Jun 09.
Article in English | MEDLINE | ID: mdl-35676712

ABSTRACT

INTRODUCTION: Hepatitis A virus infections are mostly asymptomatic or mildly symptomatic, and generally this disease has a benign course and resolves spontaneously. However, intrahepatic and rarer extrahepatic manifestations can complicate typical cases of acute hepatitis. Pleural effusion is an extremely rare extrahepatic entity with 20 cases reported in literature. CASE PRESENTATION: We report herein a recent case of both pleural effusion and ascites accompanying hepatitis A infection in a 5-year-old middle eastern child, diagnosed using serological testing and imaging studies, who was treated with supportive management with full resolution after 2 weeks. In addition, we review available literature regarding hepatitis A virus associated with pleural effusion using PubMed and summarize all reported cases in a comprehensive table. RESULTS: Literature contains 20 reported cases of serology-confirmed hepatitis A virus presenting with pleural effusion, most in the pediatric population with average age at presentation of 9 years 8 months. The majority of reported patients had right-sided pleural effusion (50%) or bilateral effusion (45%), while only 5% presented with pleural effusion on the left side. Hepatomegaly and ascites occurred concurrently in 80% and 70% respectively. Supportive treatment without invasive procedures (except one chylothorax case) yielded complete recovery in 95% of cases, while only one case progressed to fulminant liver failure followed by death. CONCLUSION: Acute hepatitis A virus rarely presents with pleural effusion, usually following a benign course with spontaneous resolution in most patients. Pleural effusion does not change the prognosis or require any invasive treatment. Thus, further invasive procedures are not recommended and would only complicate this self-resolving benign condition.


Subject(s)
Chylothorax , Hepatitis A virus , Hepatitis A , Pleural Effusion , Ascites/etiology , Child , Child, Preschool , Chylothorax/diagnosis , Hepatitis A/complications , Hepatitis A/diagnosis , Humans , Pleural Effusion/complications , Pleural Effusion/etiology
2.
Case Rep Dermatol Med ; 2020: 6274053, 2020.
Article in English | MEDLINE | ID: mdl-32082644

ABSTRACT

Body reactions to drugs can manifest as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). TEN is the most severe form of cutaneous reactions with an incidence rate of 1-2 per million cases per year. Despite TEN being a critical and life-threatening condition, there is little to no evidence of clear management protocol. We reported a 5-year-old male child who presented with lamotrigine-induced TEN and was successfully treated with intravenous immune globulin (IVIG) with a burn unit care level, while TEN treatment with IVIG is an appropriate approach with predictable good outcomes, burn unit care is also effective in creating highly favorable effects. Upon reviewing the literature, several studies indicate that TEN patients treated with the combination of IVIG and burn unit care lead to decreased levels of morbidity and mortality than when treated with IVIG or burn unit care alone. Therefore, treatment involving both IVIG and burn unit care should be considered for TEN patients.

3.
J Lipid Res ; 42(1): 114-9, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11160372

ABSTRACT

A simple, sensitive, and specific liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS) method for the determination of bile acids in human bile has been developed. The bile acids were extracted with a C(18) (octadecyl) reversed-phase column and identified and quantified by simultaneous monitoring of their parent and daughter ions, using the multiple reaction monitoring mode. Identification and quantification of conjugated bile acids in bile was achieved in 5 min. The detection limit was 1 ng, and the determination was linear for concentrations up to 100 ng. The percent recovery of standards made of single conjugated (glycine and taurine) bile acid or of mixture of glycine- or taurine-conjugated cholic acid, chenodeoxycholic acid, deoxycholic acid, ursodeoxycholic acid, and lithocholic acid averaged 71.73% to 95.92%. The percent recovery of the same standard bile acids was also determined by gas chromatography-mass spectrometry (GC-MS), using the selected ion monitoring mode, and averaged 66% to 96%. A biliary bile acid profile of human gallbladder bile was obtained by LC-MS/MS and GC-MS. The results showed a good correlation between the two techniques and no significant differences between the two methods were observed. The LC-MS/MS method was also used for the analysis of serum, urine, and fecal bile acids. In conclusion, LC-MS/MS is a simple, sensitive, and rapid technique for the analysis of conjugated bile acids in bile and other biological samples. - Perwaiz, S., B. Tuchweber, D. Mignault, T. Gilat, and I. M. Yousef. Determination of bile acids in biological fluids by liquid chromatography-electrospray tandem mass spectrometry. J. Lipid Res. 2001. 42: 114;-119.


Subject(s)
Bile Acids and Salts/analysis , Body Fluids/chemistry , Gas Chromatography-Mass Spectrometry , Spectrometry, Mass, Electrospray Ionization , Bile/chemistry , Bile Acids and Salts/blood , Bile Acids and Salts/urine , Feces/chemistry , Gallbladder/chemistry , Gas Chromatography-Mass Spectrometry/methods , Glycine/metabolism , Humans , Reproducibility of Results , Sensitivity and Specificity , Spectrometry, Mass, Electrospray Ionization/methods , Taurine/metabolism
4.
Proc Natl Acad Sci U S A ; 98(4): 2011-6, 2001 Feb 13.
Article in English | MEDLINE | ID: mdl-11172067

ABSTRACT

Mutations in the sister of P-glycoprotein (Spgp) or bile salt export pump (BSEP) are associated with Progressive Familial Intrahepatic Cholestasis (PFIC2). Spgp is predominantly expressed in the canalicular membranes of liver. Consistent with in vitro evidence demonstrating the involvement of Spgp in bile salt transport, PFIC2 patients secrete less than 1% of biliary bile salts compared with normal infants. The disease rapidly progresses to hepatic failure requiring liver transplantation before adolescence. In this study, we show that the knockout of spgp gene in mice results in intrahepatic cholestasis, but with significantly less severity than PFIC2 in humans. Some unexpected characteristics are observed. Notably, although the secretion of cholic acid in mutant mice is greatly reduced (6% of wild-type), total bile salt output in mutant mice is about 30% of wild-type. Also, secretion of an unexpectedly large amount of tetra-hydroxylated bile acids (not detected in wild-type) is observed. These results suggest that hydroxylation and an alternative canalicular transport mechanism for bile acids compensate for the absence of Spgp function and protect the mutant mice from severe cholestatic damage. In addition, the spgp(-/-) mice display a significant increase in the secretion of cholesterol and phospholipids into the bile. This latter observation in spgp(-/-) mice suggests that intrahepatic, rather than intracanalicular, bile salts are the major driving force for the biliary lipid secretion. The spgp(-/-) mice thus provide a unique model for gaining new insights into therapeutic intervention for intrahepatic cholestasis and understanding mechanisms associated with lipid homeostasis.


Subject(s)
ATP-Binding Cassette Transporters/physiology , Cholestasis, Intrahepatic/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 11 , ATP-Binding Cassette Transporters/genetics , Animals , Bile Acids and Salts/metabolism , Cholestasis, Intrahepatic/etiology , Cholestasis, Intrahepatic/pathology , Cholestasis, Intrahepatic/physiopathology , Disease Progression , Female , Gene Targeting , Lipid Metabolism , Liver/metabolism , Liver/pathology , Liver/ultrastructure , Male , Mice , Mice, Inbred C57BL , Mice, Knockout
5.
Toxicol Lett ; 116(1-2): 69-77, 2000 Jul 27.
Article in English | MEDLINE | ID: mdl-10906424

ABSTRACT

The magnitude of cholestasis induced by taurolithocholic acid (TLCA) and its relationship with phase I metabolism were analyzed in rats treated with bromobenzene (BZ), a chemical that causes selective necrosis of perivenous (zone 3) hepatocytes. Forty-eight hours after BZ administration (600 mg/Kg bw), a single dose of 20 micromol/Kg bw of TLCA was injected. Bile was collected during 180 min and bile flow and total bile acid excretion rate were determined. Biliary bile acid composition was analyzed by gas-liquid chromatography-mass spectrometry. BZ administration did not affect the development of TLCA-induced cholestasis, but exacerbated the bile acid-induced decrease in bile flow during the period of recovery from cholestasis. Biliary excretion of total bile acids after TLCA injection relative to basal value was not effected by BZ. The analysis of bile acid composition in bile revealed that TLCA was partially converted to hyodeoxycholic and muricholic acids. The cumulative excretion of all exogenous bile acids and their contribution to the composition of the biliary bile acid pool were not substantially affected by zone 3 necrosis, suggesting that synthesis and secretion of hydroxylated derivatives of TLCA were maintained by zone 1 and 2 hepatocytes. The relative content of endogenous bile acids was not affected by BZ during TLCA-induced cholestasis. Thus, it seems unlikely that the exacerbation of the cholestasis in BZ-treated rats is due to different choleretic properties and/or toxicity of the bile acid pool.


Subject(s)
Cholestasis/chemically induced , Liver/cytology , Taurolithocholic Acid/toxicity , Animals , Bile/drug effects , Bile Acids and Salts/analysis , Bromobenzenes/toxicity , Male , Rats , Rats, Sprague-Dawley
6.
J Hepatol ; 32(4): 550-60, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10782902

ABSTRACT

BACKGROUND/AIMS: Biliary glutathione is an important generator of the bile-salt independent flow, and is known to be regulated by the hepatic glutathione availability. We investigated, in an acute model of phalloidin-induced cholestasis, biliary glutathione secretion and the role of hepatic glutathione, oxidative stress, and protein kinase c activation, which have been implicated in many hepatotoxin-induced hepatic dysfunctions. METHODS: Rats were given a single dose of 80 microg/100 g body weight of phalloidin and the hepatic thiols and glutathione content, redox state and vesicular activity were evaluated during both development of and recovery from cholestasis. The prophylactic effect of N-acetylcysteine (a precursor of glutathione synthesis and an antioxidant) was also examined. In addition, in the isolated perfused rat liver, we studied the prophylactic effect of the PKc inhibitor H7 on phalloidin-induced cholestasis. RESULTS: In the early stages of cholestasis, phalloidin induced a decline in bile flow, mainly related to a disruption of biliary glutathione secretion. The decline in biliary glutathione content was not associated with increased glutathione degradation, indicated by a parallel decline in biliary non-protein thiols and by the lack of an increase in biliary gamma-glutamyltranspeptidase. There was also no evidence of hepatic depletion of glutathione or of oxidative stress, as measured by the oxidized-to-reduced glutathione ratio. Moreover, phalloidin resulted in inhibition of vascular transcytosis as assessed by horseradish peroxidase labeling. Pre-treatment with N-acetylcysteine did not counteract the decline in biliary glutathione secretion and bile flow produced by phalloidin, supporting the view that the hepatic availability of glutathione and oxidative stress injury are not implicated in the early stages of cholestatic injury. Moreover, treatment with H-7 did not alter the biliary glutathione output, or the decline in bile flow induced by the toxin. CONCLUSIONS: This study suggests that the phalloidin-induced inhibition of bile formation may be attributed to rapid disruption of the hepatocanalicular transport of glutathione.


Subject(s)
Cholestasis/chemically induced , Cholestasis/etiology , Glutathione/metabolism , Oxidative Stress , Phalloidine/toxicity , Animals , Cholestasis/metabolism , Disease Models, Animal , Male , Rats , Rats, Sprague-Dawley
7.
Liver ; 20(1): 27-37, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10726958

ABSTRACT

AIMS/BACKGROUND: Previous studies have shown that the generation of the so-called "bile salt-independent flow" (BSIF) may be partly dependent on the hepatic availability and rate of canalicular secretion of osmotically active substances such as glutathione (GSH) and derived thiols. This study examined the role of common bile salts (BS) on the BSIF formation under both choleretic and cholestatic conditions, and on the relationship of the BSIF to the biliary thiol secretion. METHODS: Experiments were carried out in adult male Sprague-Dawley rats both in situ in the isolated perfused rat liver and in vivo. The effect of choleretic and cholestatic doses of BS on the biliary BS secretion rate (BSSR), BS-dependent flow (BSDF), and BSIF was evaluated. RESULTS: In the perfused rat liver, the infusion of low and physiological doses of taurocholic acid stimulated the biliary BSSR, BSDF, and BSIF. This was associated with increased biliary thiol secretion and thiol-dependent bile flow. In vivo administration of taurocholic acid, taurochenodeoxycholic acid or taurolithocholic acid in step-wise increasing doses leading to cholestasis showed that the onset of cholestasis was not accompanied by a significant decline in the BSSR or BSDF but rather by a marked inhibition of the apparent BSIE During cholestasis, the three BS produced a significant reduction of biliary thiol secretion, with a marked decrease in thiol-dependent bile flow sufficient to account for a major proportion of BSIF inhibition. This decline in thiol secretion occurred before the drop in biliary BS secretion and was more pronounced than the reduction in BS output. No change in hepatic thiol content was observed. Administration of free or glyco-conjugated BS also resulted in a significant decrease of BSIF during the cholestatic period, suggesting a common role for BSIF inhibition in BS-induced cholestasis. CONCLUSION: The changes in bile flow during BS-induced choleresis and cholestasis are mediated by changes in the portion of the BSIF regulated by the thiol secretion.


Subject(s)
Bile Acids and Salts/metabolism , Bile Ducts, Intrahepatic/metabolism , Bile/metabolism , Cholestasis/metabolism , Animals , Bile Acids and Salts/pharmacology , Bile Ducts, Intrahepatic/drug effects , Cholestasis/chemically induced , Cholestasis/physiopathology , Glutathione/metabolism , Male , Perfusion , Rats , Rats, Sprague-Dawley , Taurochenodeoxycholic Acid/pharmacology , Taurocholic Acid/pharmacology , Taurolithocholic Acid/pharmacology
8.
Toxicol Sci ; 53(1): 150-5, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10653533

ABSTRACT

Manganese-bilirubin (Mn-BR)-induced cholestasis in rats is associated with altered lipid composition of various hepatic subcellular fractions. Increased bile canalicular (BCM) cholesterol content in Mn-BR cholestasis and the intracellular source of the accumulating cholesterol were investigated. To label the total hepatic cholesterol pool, male Sprague-Dawley rats were given ip 3H-cholesterol, followed 18 h later by 2-14C-mevalonic acid (a precursor of cholesterol synthesis). To induce cholestasis, manganese (Mn, 4.5 mg/kg) and bilirubin (BR, 25 mg/kg) were injected iv; animals were killed 30 min after BR injection; canalicular and sinusoidal membranes, microsomes, mitochondria, and cytosol were isolated. Total cholesterol content of each fraction was determined by spectrophotometric techniques as well as radiolabeled techniques. In Mn-BR cholestasis, the total cholesterol concentrations of BCM and cytosol were significantly increased. Also, the contribution of 14C-labeled cholesterol (newly synthesized cholesterol) was enhanced in all isolated cellular fractions. The results are consistent with the hypothesis that accumulation of newly synthesized cholesterol in BCM is involved in Mn-BR cholestasis. An enhanced rate of synthesis of cholesterol, however, does not appear to be the causal event, as the activity of HMG-CoA reductase (rate-limiting enzyme in cholesterol synthesis), assessed in vitro, was decreased following Mn-BR treatment. Treatment with the Mn-BR combination may affect other aspects of intracellular cholesterol dynamics.


Subject(s)
Bile Canaliculi/drug effects , Bilirubin/pharmacology , Cholestasis, Intrahepatic/metabolism , Cholesterol/metabolism , Manganese Compounds/pharmacology , Sulfates/pharmacology , Animals , Bile Canaliculi/metabolism , Cell Fractionation , Cholestasis, Intrahepatic/chemically induced , Cytosol/drug effects , Cytosol/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/metabolism , Injections, Intraperitoneal , Injections, Intravenous , Intracellular Membranes/drug effects , Intracellular Membranes/metabolism , Male , Mevalonic Acid/metabolism , Microsomes/drug effects , Microsomes/enzymology , Mitochondria/drug effects , Mitochondria/metabolism , Rats , Rats, Sprague-Dawley
9.
J Food Prot ; 62(12): 1461-5, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10606152

ABSTRACT

We have shown that the addition of cholestyramine (CHA, a resin known to bind bile salts in the gastrointestinal tract) to ochratoxin A (OTA)-contaminated rat diets reduced plasma levels of the toxin and prevented OTA-induced nephrotoxicity. To elucidate the mechanism of action of CHA, we carried out in vitro experiments to determine whether the resin may bind the toxin. For comparative purposes, binding of bile salts to the resin was also examined. Results showed that CHA binds both OTA and bile salts (taurodeoxycholate [TDC] and taurocholate [TCA]). Also, CHA showed greater affinity for OTA and TDC than for TCA. At 1 mM concentration, 96% of OTA and 80% of TDC were bound to the resin, while for TCA binding was only 50%. However, saturation of the resin was reached at higher levels with bile acids compared to OTA (3.67 mmol/g resin for TCA and 3.71 mmol/g resin for TDC versus 2.85 mmol/g resin for OTA). To characterize the nature of the binding of the toxin to CHA, NaCl (0 to 200 mM) was added to a fixed amount of OTA or bile acids. As expected, TCA absorption was decreased by the addition of NaCl (<50 mM), indicating electrostatic binding. However, OTA and TDC sorption was decreased only at high concentrations of NaCl (>150 mM), suggesting a stronger binding to the resin than that shown with TCA. Sequential competitive studies demonstrated that CHA binds more OTA than TCA. The results of the in vivo study show the role of bile salts in OTA absorption. The toxin's plasma levels at 1 and 3 h after a single oral dose of OTA were significantly decreased in bile salt-depleted rats compared to the control. Thus, the alteration of the bile salt biliary pool and OTA enterohepatic circulation may be an additional mechanism of action of the resin against mycotoxin toxicity.


Subject(s)
Bile Acids and Salts/metabolism , Cholestyramine Resin/metabolism , Enterohepatic Circulation , Ochratoxins/metabolism , Ochratoxins/toxicity , Animals , Bile Acids and Salts/blood , Male , Ochratoxins/blood , Rats , Rats, Sprague-Dawley , Taurocholic Acid/blood , Taurocholic Acid/metabolism , Taurodeoxycholic Acid/blood , Taurodeoxycholic Acid/metabolism
11.
J Hepatol ; 30(4): 621-31, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10207803

ABSTRACT

BACKGROUND/AIMS: During liver fibrosis, different fibroblastic cells, i.e. hepatic stellate cells (HSCs) or portal fibroblasts, are involved in the development of lesions, and acquire myofibroblastic differentiation. We investigated, in the rat, whether pentoxifylline can influence the early phase of fibrogenesis in two animal models of fibrosis induced by either carbon tetrachloride (CCl4) plus acetone (given twice) or bile duct ligation. METHODS: The fibroproliferative response and myofibroblastic phenotypic modulation were evaluated by PCNA and alpha-smooth muscle (alpha-SM) actin immunohistochemistry, respectively, in livers taken 24 h after the last CCl4 treatment or 72 h after bile duct ligation. Desmin expression was also measured, and inflammation was evaluated by ED-1 staining. Furthermore, proliferation and alpha-SM actin expression were studied in cultured HSCs after pentoxifylline treatment. RESULTS: In the CCl4-acetone groups, pretreatment with pentoxifylline decreased the proliferative response and expression of alpha-SM actin in the HSCs. Similarly, pentoxifylline reduced the proliferation and myofibroblastic differentiation of portal fibroblasts after bile duct ligation. Pentoxifylline reduced ED-1 expression, particularly in the CCl4 model, where there was significant inflammation. In cultured pentoxifylline-treated HSCs, both proliferation and alpha-SM actin expression were decreased. CONCLUSIONS: In both animal models of fibrosis, during the early stages of tissue injury, pentoxifylline was able to reduce fibroproliferation and myofibroblastic differentiation and to reduce hepatocellular damage and the inflammatory response, particularly in the toxin-induced model. In culture, alpha-SM actin expression decreased in both growing and quiescent HSCs treated with pentoxifylline, indicating that the drug may also exert a direct effect on hepatic fibrogenic cells.


Subject(s)
Liver Cirrhosis, Experimental/pathology , Liver/pathology , Pentoxifylline/pharmacology , Acetone/toxicity , Animals , Bile Ducts/physiology , Carbon Tetrachloride Poisoning/pathology , Cell Differentiation , Cell Division/drug effects , Cells, Cultured , Fibroblasts/cytology , Fibroblasts/drug effects , Liver/cytology , Liver/drug effects , Liver Cirrhosis, Experimental/chemically induced , Male , Muscle, Smooth/cytology , Muscle, Smooth/drug effects , Phenotype , Rats , Rats, Sprague-Dawley
12.
J Gerontol A Biol Sci Med Sci ; 53(5): B340-6, 1998 Sep.
Article in English | MEDLINE | ID: mdl-9754131

ABSTRACT

We investigated the contribution of bile salts and glutathione (GSH) to the generation of bile flow in young, mature, and old female Sprague-Dawley rats, either fed ad libitum (AL) or subjected to a 40% dietary restriction (DR), which was supplemented or not with vitamins and minerals, starting from weaning. An age-related decline in bile flow was observed in the AL group. DR increased bile flow compared to age-matched AL rats, resulting in a twofold increase in the old animals. This was associated with a statistically significantly higher biliary GSH secretion rate and a moderate increase in the bile salt secretory rate. The apparent GSH-dependent flow was significantly increased in DR groups of all ages. Hepatic GSH concentration was closely related to the GSH secretion rate. These results indicate that the increase in biliary GSH content produced by DR is the major mediator of the increased bile flow, resulting in enhanced GSH and GSH-derived thiols supply to the intestinal lumen.


Subject(s)
Aging/physiology , Bile/physiology , Diet , Glutathione/physiology , Animals , Bile/chemistry , Bile Acids and Salts/chemistry , Bile Acids and Salts/physiology , Body Weight , Female , Glutathione/analysis , Intestinal Mucosa/metabolism , Liver/metabolism , Minerals/administration & dosage , Organ Size , Rats , Rats, Sprague-Dawley , Sulfhydryl Compounds/analysis , Vitamins/administration & dosage
13.
Biochim Biophys Acta ; 1393(2-3): 223-34, 1998 Aug 28.
Article in English | MEDLINE | ID: mdl-9748591

ABSTRACT

Earlier studies showed that dietary soybean lecithin increases biliary lipid secretion, which mainly comes from the contribution of high density lipoprotein (HDL) and hepatic microsomal pools of phosphatidylcholine and cholesterol. In addition, a lecithin diet enhances bile secretion and prevents bile acid-induced cholestasis. This study evaluated the contribution of choline, a component of lecithin, to the observed effect of lecithin on biliary secretory function. Rats were fed either a control diet (CD), a choline diet (ChD) or a lecithin-enriched diet (LD) for 2 weeks. Results showed that like LD, ChD induced an increase in bile flow and bile acid secretion rate when compared with the control diet. However, unlike LD, ChD did not significantly increase biliary phospholipids and cholesterol output. An increase of hydrophilic bile acids (i.e. ursodeoxycholic and muricholic acids) in bile of rats fed choline could explain why the biliary phospholipid and cholesterol secretion was not increased. During taurocholic acid infusion, both experimental diets increased bile flow and the bile acid secretion rate maximum (BASRm). The cholestasis usually observed after the BASRm is reached was inhibited by ChD and LD. Both diets induced a decrease in plasma cholesterol (total and HDL), however, only LD induced statistically significant changes. Analysis of total cholesterol and phospholipid content of microsomes and canalicular membranes indicated no statistically significant difference between control and experimental groups either under basal conditions or after bile acid infusion. Similarly, the phospholipid classes and fatty acid composition of biliary phosphatidylcholine were not altered by feeding ChD and LD. We conclude that choline contributes to the beneficial effect of a lecithin diet on bile secretion. It is postulated that this effect may be attributed to modulation of HDL and an enhancement of the cholesterol and phospholipid pools destined for biliary secretion.


Subject(s)
Bile/drug effects , Choline/pharmacology , Lipids/analysis , Phosphatidylcholines/pharmacology , Animals , Bile/metabolism , Bile Acids and Salts/analysis , Bile Canaliculi/metabolism , Cholestasis/chemically induced , Cholestasis/metabolism , Cholesterol/analysis , Cholesterol/blood , Choline/administration & dosage , Diet , Energy Intake , Fatty Acids/analysis , Intracellular Membranes/metabolism , Lipids/blood , Liver/metabolism , Liver/ultrastructure , Male , Phosphatidylcholines/administration & dosage , Phosphatidylcholines/chemistry , Phospholipids/analysis , Rats , Rats, Sprague-Dawley , Taurocholic Acid
14.
Fundam Clin Pharmacol ; 12(2): 213-9, 1998.
Article in English | MEDLINE | ID: mdl-9565777

ABSTRACT

One hypothesis concerning the pathogenesis of manganese-bilirubin (Mn-BR)-induced cholestasis is that the molecular organization of the bile canalicular membrane is altered. The purpose of the present study was to evaluate lipid composition and fluidity of hepatic membranes during cholestasis in male Sprague-Dawley rats. To induce cholestasis, manganese (Mn, 4.5 mg/kg, intravenously [i.v.]) was given 15 min before bilirubin (BR, 25 mg/kg, i.v.). The rats were killed 30 min after BR injection, at which time bile flow was decreased by approximately 40% compared to control values. Liver cell plasma membranes enriched in canalicular fractions (BCM) and plasma membranes enriched in sinusoidal and lateral fractions (PM), microsomes, mitochondria and cytosol were isolated by differential centrifugation. Total lipids were extracted and measured colorimetrically. To assess fluidity, membranes were incubated in vitro with fluorescent probes [1,6-diphenyl-1,3,5-hexatriene and 1-(4'-trimethyl-ammonium-phenyl)-6-phenyl-1,3,5-hexatriene]. After Mn-BR treatment, BCM cholesterol incorporation increased markedly (about 3-fold) accompanied by a decrease in fluidity. BCM phospholipid content was unaltered by the cholestatic challenge. In PM-enriched fractions, the changes in cholesterol and phospholipid content after Mn-BR treatment were not statistically significant (P > 0.05) compared to controls. Furthermore, the biochemical alterations in PM were not accompanied by changes in membrane fluidity. These results support the hypothesis that altered lipid composition and fluidity of BCM are involved in the pathogenesis of Mn-BR cholestasis.


Subject(s)
Cholestasis/metabolism , Cholesterol/metabolism , Liver/drug effects , Liver/metabolism , Membrane Fluidity/drug effects , Phospholipids/metabolism , 5'-Nucleotidase/metabolism , Animals , Bilirubin , Calorimetry , Cell Membrane/drug effects , Cholestasis/chemically induced , Fluorescence Polarization , Fluorescent Dyes , Glucose-6-Phosphatase/metabolism , Leucyl Aminopeptidase/metabolism , Liver/enzymology , Liver/ultrastructure , Male , Manganese , Rats , Rats, Sprague-Dawley
15.
J Toxicol Environ Health A ; 53(3): 231-50, 1998 Feb 06.
Article in English | MEDLINE | ID: mdl-9482354

ABSTRACT

Ochratoxin A (OTA) is a mycotoxin that may contaminate animal feed (oat, barley, and rye) and food (wheat, rice, coffee, beer, pig meat), leading to major health problems (e.g., nephropathy) in several animal species including humans. Several methods have been tested to reduce the toxicity of OTA in animals but with limited success. In rats, the effect of cholestyramine (CHA), a bile acid-binding resin, was investigated on OTA-induced nephrotoxicity and bioavailability. Animals were fed semisynthetic diets containing two levels of OTA: 1 or 3 ppm. At each level of OTA, the diets were enriched with 0.1, 1, and 5% of CHA. The results showed that CHA decreased the concentration of OTA in plasma. At 1 and 3 ppm of OTA in the diet, CHA is effective at a level of 0.1% and 5%, respectively. The excretion of OTA and its metabolites (ochratoxin alpha and hydroxylated ochratoxin A) in bile and urine was also decreased by addition of 5% CHA in the diet. This was associated with an increase of OTA excretion in feces. Enzymuria and renal morphology revealed that dietary CHA can decrease OTA-induced nephrotoxicity, probably by reducing renal exposure to the toxin. In conclusion, CHA can reduce OTA concentrations in plasma as well as reducing nephrotoxicity, which may be attributed to a decrease of bioavailability and/or enterohepatic circulation of the toxin.


Subject(s)
Anion Exchange Resins/pharmacology , Cholestyramine Resin/pharmacology , Feces/chemistry , Kidney Diseases/prevention & control , Kidney/drug effects , Mycotoxins/blood , Mycotoxins/toxicity , Ochratoxins/blood , Ochratoxins/toxicity , Acetylglucosaminidase/urine , Animal Feed , Animals , Anion Exchange Resins/administration & dosage , Bile/chemistry , Bile Acids and Salts/analysis , Cholestyramine Resin/administration & dosage , Dose-Response Relationship, Drug , Food Contamination , Glutathione Transferase/urine , Kidney/pathology , Kidney Diseases/chemically induced , Kidney Diseases/pathology , Male , Mycotoxins/metabolism , Ochratoxins/metabolism , Ochratoxins/urine , Rats , Rats, Sprague-Dawley
19.
Toxicol Appl Pharmacol ; 137(1): 100-11, 1996 Mar.
Article in English | MEDLINE | ID: mdl-8607135

ABSTRACT

To study the relationship between the dynamic actin web and bile secretion, we developed an acute model of cholestasis, using phalloidin, and examined sequential morphologic and biochemical events in rat liver. Biliary function (bite flow, bile, and canalicular membrane components) and cellular integrity (release of hepatic enzymes in serum and bile, canalicular structure, and microfilaments distribution) in rats given a single iv dose of phalloidin (0.8 mg/kg body weight) were assessed at 15, 45, and 90 min, 24 hr, and 5 days postinjection. Bile flow decreased significantly at 45 and 90 min, but cholestasis was transient since bile secretion returned to control levels at 24 hr. The biliary bile acid secretion rate was not modified during the same time period, indicating that cholestasis may have been due to impairment of the bile acid independent component of bile flow. Serum alanine aminotransferase and lactate dehydrogenase as well as biliary alkaline phosphatase and alkaline phosphodiesterase-1 activities were not altered by phalloidin treatment. These data, coupled with morphologic studies, provide no evidence of cell damage. Electron microscopy revealed that the pericanalicular actin web in both centrilobular and periportal hepatocytes was increased at 90 min and further enlarged at 24 hr and 5 days after phalloidin injection. At all time periods, the canalicular structure was well preserved. Na+K+ -ATPase and Mg2+ -ATPase activities in membrane fractions enriched in bile canalicular complexes decreased significantly at 15 min and remained low up to Day 5. Mg2+ -ATPase activity returned to control levels by Day 5. The lipid constituents of liver cell membranes enriched in canalicular complexes showed no significant variations 90 min after toxin treatment but, at 24 hr, phospholipid content rose and membrane fluidity increased. These results clearly indicate that the bile flow variation after a single low dose of phalloidin can be dissociated from specific pericanalicular microfilament distribution, lending further support to the view that normal biliary function is not strictly dependent on the integrity of the actin filament network.


Subject(s)
Bile Acids and Salts/metabolism , Bile/physiology , Cholestasis, Intrahepatic/chemically induced , Liver/drug effects , Phalloidine/toxicity , Actin Cytoskeleton/drug effects , Actin Cytoskeleton/ultrastructure , Alanine Transaminase/blood , Alkaline Phosphatase/metabolism , Animals , Bile Canaliculi/chemistry , Bile Canaliculi/drug effects , Bile Canaliculi/ultrastructure , Cell Membrane/enzymology , Cholestasis, Intrahepatic/metabolism , Cholestasis, Intrahepatic/pathology , Cholesterol/analysis , Injections, Intravenous , L-Lactate Dehydrogenase/blood , Leucyl Aminopeptidase/metabolism , Liver/metabolism , Liver/pathology , Liver/ultrastructure , Male , Phalloidine/administration & dosage , Phosphodiesterase I , Phospholipids/analysis , Phosphoric Diester Hydrolases/metabolism , Rats , Rats, Sprague-Dawley
20.
Hepatology ; 23(2): 294-302, 1996 Feb.
Article in English | MEDLINE | ID: mdl-8591855

ABSTRACT

In this study, the possible role of the hepatic microcirculation in phalloidin-induced cholestasis and hepatotoxicity was examined in isolated perfused rat livers (IPRL). Administration of a phalloidin bolus (1 mg/kg body weight) through the portal vein induced an immediate reduction of bile flow. In 16.9 minutes, bile flow was 50% lower than basal values. Portal pressure was only increased in 60 minutes after phalloidin injection and increased sharply from this time up to the end of perfusion (90 minutes). Under these conditions, phalloidin did not induce liver cell cytolysis, as assessed by aspartate transaminase (AST) and lactate dehydrogenase (LDH) release in the perfusate effluent. Under electron microscopy, hepatocytic vacuolization was mild 15 minutes after phalloidin administration but increased with time. At the end of perfusion, the hepatic architecture was markedly altered; erythrocyte accumulation was observed in both sinusoids and hepatocyte vacuoles. Evaluation by multiple indicator dilution curves showed that extravascular volume (EVV) was significantly affected by phalloidin. It was augmented in 30 minutes after phalloidin administration with values increasing gradually over time. Neither vascular nor cellular volume was altered. The hepatic swelling may be attributed to enlargement of the extravascular space of the liver. These results indicate that changes in the liver microcirculation are not the primary cause of phalloidin-induced cholestasis in the IPRL.


Subject(s)
Cholestasis/chemically induced , Liver Circulation/drug effects , Phalloidine/pharmacology , Animals , Bile/physiology , Bile Acids and Salts/metabolism , Blood Pressure/drug effects , Cholestasis/pathology , Female , Hemodynamics/drug effects , In Vitro Techniques , Indicator Dilution Techniques , Liver/drug effects , Liver/pathology , Microcirculation/drug effects , Perfusion , Portal System/drug effects , Rats , Rats, Sprague-Dawley , Tissue Survival/drug effects
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