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Biomedical subjects

A F Hofmann

Publications and source records attributed to A F Hofmann.

At least 37 records · Page 2Linked to original sources
PubMed1999

Identification and characterization of genes required for hyphal morphogenesis in the filamentous fungus Aspergillus nidulans.

In the filamentous fungus Aspergillus nidulans, germination of an asexual conidiospore results in the formation of a hyphal cell. A key feature of spore germination is the switch from isotropic spore expansion to polarized apical growth. Here, temperature-sensitive mutations are used to characterize the roles of five genes (sepA, hypA, podB-podD) in the establishment and maintenance of hyphal polarity. Evidence that suggests that the hypA, podB, and sepA genes are required for multiple aspects of hyphal morphogenesis is presented. Notably, podB and sepA are needed for organization of the cytoskeleton at sites of polarized growth. In contrast, podC and podD encode proteins that appear to be specifically required for the establishment of hyphal polarity during spore germination. The role of sepA and the pod genes in controlling the spatial pattern of polarized morphogenesis in germinating spores is also described. Results obtained from these experiments indicate that the normal pattern of germ-tube emergence is dependent upon the integrity of the actin cytoskeleton.

Aspergillus↗
PubMed1998

The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver.

Canalicular secretion of bile salts is a vital function of the vertebrate liver, yet the molecular identity of the involved ATP-dependent carrier protein has not been elucidated. We cloned the full-length cDNA of the sister of P-glycoprotein (spgp; Mr approximately 160,000) of rat liver and demonstrated that it functions as an ATP-dependent bile salt transporter in cRNA injected Xenopus laevis oocytes and in vesicles isolated from transfected Sf9 cells. The latter demonstrated a 5-fold stimulation of ATP-dependent taurocholate transport as compared with controls. This spgp-mediated taurocholate transport was stimulated solely by ATP, was inhibited by vanadate, and exhibited saturability with increasing concentrations of taurocholate (Km approximately 5 microM). Furthermore, spgp-mediated transport rates of various bile salts followed the same order of magnitude as ATP-dependent transport in canalicular rat liver plasma membrane vesicles, i.e. taurochenodeoxycholate > tauroursodeoxycholate = taurocholate > glycocholate = cholate. Tissue distribution assessed by Northern blotting revealed predominant, if not exclusive, expression of spgp in the liver, where it was further localized to the canalicular microvilli and to subcanalicular vesicles of the hepatocytes by in situ immunofluorescence and immunogold labeling studies. These results indicate that the sister of P-glycoprotein is the major canalicular bile salt export pump of mammalian liver.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Transport of fluorescent bile acids by the isolated perfused rat liver: kinetics, sequestration, and mobilization.

Hepatocyte transport of six fluorescent bile acids containing nitrobenzoxadiazolyl (NBD) or a fluorescein derivative on the side chain was compared with that of natural bile acids using the single-pass perfused rat liver. Compounds were infused at 40 nmol/g liver min for 15 minutes; hepatic uptake and biliary recovery were measured; fractional extraction, intrinsic basolateral clearance, and sequestration (nonrecovery after 45 minutes of additional perfusion) were calculated. Fluorescent bile acids were efficiently extracted during the first 3 minutes (70%-97%), but net extraction decreased with time mostly because of regurgitation into the perfusate. For cholylglycine and ursodeoxycholylglycine (UDC-glycine), extraction was 94% to 99%, and regurgitation did not occur. Intrinsic hepatic clearance of fluorescent bile acids (2-7 mL/g liver x min) was lower than that of cholylglycine (9.0 +/- 0.6; mean +/- SD) and UDC-glycine (21.4 +/- 0.4). Sequestration at 60 minutes was 8% to 26% for fluorescent bile acids with a cholyl moiety (cholylglycylaminofluorescein [CGamF], cholyllysylfluorescein [C-L-F], cholyl-[N epsilon-NBD]-lysine [C-L-NBD], and cholylaminofluorescein [CamF]), 32% for ursodeoxycholylaminofluorescein (UDCamF), and 88% for ursodeoxycholyl-(N epsilon-NBD)lysine (UDC-L-NBD). Cholylglycine and UDC-glycine had <3% retention. Biliary secretion of sequestered UDCamF, but not of UDC-L-NBD, was induced by adding dibutyryl cyclic adenosine monophosphate (DBcAMP) to the perfusate, possibly by translocation to the canaliculus of pericanalicular vesicles containing fluorescent bile acids. Biliary secretion of UDC-L-NBD, but not of UDCamF, was induced by adding cholyltaurine or UDC-taurine, possibly by inhibition of binding to intracellular constituents or of transport into organelles. It is concluded that fluorescent bile acids are efficiently transported across the basolateral membrane, but in contrast to natural conjugated bile acids, are sequestered in the hepatocyte (UDC derivatives > cholyl derivatives). Two modes of hepatic sequestration of fluorescent bile acids were identified. Fluorescent bile acids may be useful to characterize sequestration processes during bile acid transport through the hepatocyte.

Animals↗
PubMed1998

Gastric transit and pharmacodynamics of a two-millimeter enteric-coated pancreatin microsphere preparation in patients with chronic pancreatitis.

It has been suggested that enteric-coated pancreatin microsphere (ECPM) preparations with sphere sizes larger than 1.7 mm pass through the stomach at a slower rate than a meal and therefore may be less efficacious in restoring pancreatic enzyme activity than preparations with smaller sphere sizes. The aim of this study was to investigate the gastric transit profile of a 2-mm ECPM preparation in relation to that of a solid meal and to simultaneously measure enzyme activities in eight patients with pancreatic exocrine insufficiency due to chronic pancreatitis. Gastric transit was assessed by double-isotope scintigraphy. A pancake was labeled with 99mTc. A 2-mm ECPM preparation was labeled with 171Er. Intraluminal pancreatic enzyme activities were assessed during a 6-hr period with the cholesteryl-[14C]octanoate breath test (for carboxyl ester lipase activity) and the N-benzoyl-L-tyrosyl-p-aminobenzoic acid/p-aminosalicylic acid (NBT-PABA/PAS) test (for chymotrypsin activity). The ECPM preparation passed through the stomach more rapidly (median 24 min) than the pancake (median 52 min, P < 0.05). During ECPM therapy, mean cumulative 14CO2 outputs rose significantly from 30% to 70% (P < 0.05), but remained below outcomes in healthy volunteers. Mean cumulative plasma PABA concentrations rose significantly from 46% to 87% (P < 0.05) and were not significantly different from outcomes in healthy volunteers. In chronic pancreatitis, a 2-mm ECPM preparation does not pass through the stomach more slowly than a solid meal, but in fact faster. Digestion of ester lipids and proteins showed an improvement to subnormal and normal levels, respectively.

4-Aminobenzoic Acid↗
PubMed1998

Adjuvant cholylsarcosine during ursodeoxycholic acid treatment of primary biliary cirrhosis.

We postulated that coadministration of cholylsarcosine with ursodeoxycholic acid might provide additional benefit to primary biliary cirrhosis patients with an incomplete response to ursodeoxycholic acid. Our aim was to test the tolerability and the effect of adjuvant cholylsarcosine on liver tests and plasma cholesterol in primary biliary cirrhosis patients receiving ursodeoxycholic acid. Four primary biliary cirrhosis patients, who, despite more than a year of ursodeoxycholic acid therapy, had one or more liver tests persistently equal to or greater than twice the upper limit of normal, received cholylsarcosine (12-15 mg/kg/day) in addition to ursodeoxycholic acid (13-15 mg/kg/day) for six weeks in an open label study. Values of liver tests and plasma cholesterol, determined every two weeks, remained unchanged. One patient discontinued cholylsarcosine at week 4 because of new-onset pruritus. Analysis of duodenal bile acids in one patient showed 52% enrichment in cholylsarcosine and hydrophilic bile acids constituted 87% of total bile acids. It is concluded that the addition of cholylsarcosine to ursodeoxycholic acid did not influence liver tests in four primary biliary cirrhosis patients who had not responded completely to ursodeoxycholic acid alone. Cholylsarcosine was absorbed and became a dominant biliary bile acid; its administration was associated with increased pruritus.

Adult↗
PubMed1998

Abnormal duodenal bile composition in patients with acalculous chronic cholecystitis.

OBJECTIVE: Our goal was to characterize biliary lipid composition in patients with the syndrome of chronic biliary pain, absence of gallstones, and inflammation of the gallbladder mucosa (acalculous chronic cholecystitis). METHODS: Duodenal bile, obtained from 27 patients with a history of right upper quadrant pain and with negative imaging studies of the biliary tract, was analyzed enzymatically for bile acids, phospholipids, and cholesterol. Fifteen patients were found to have inflammation and/or fibrosis of the gallbladder at cholecystectomy. RESULTS: The 15 patients with abnormal gallbladder histology had more dilute duodenal bile, as indicated by a low bile acid concentration and a lower proportion of phospholipids (p < 0.01) when values were compared with those of duodenal bile samples from postmenopausal women without gallbladder disease or from radiolucent gallstone subjects participating in the National Cooperative Gallstone Study. Cholecystectomy relieved pain in 9 of 14 patients. CONCLUSIONS: Some patients with acalculous chronic cholecystitis have duodenal bile samples characterized by a decreased bile acid concentration and a decreased proportion of biliary phospholipids. The low biliary bile acid concentration may result from impaired gallbladder contraction and/or secretion by the biliary tract epithelium. The low proportion of phospholipid may result from posthepatic hydrolysis of luminal phosphatidylcholine followed by absorption of the hydrolysis products. The latter process could be caused by and/or contribute to mucosal inflammation and would also elevate the cholesterol saturation of bile, increasing the risk for cholesterol gallstone formation.

Adult↗
PubMed1998

Relationship between biliary and serum bile acids and response to ursodeoxycholic acid in patients with primary biliary cirrhosis.

OBJECTIVE: Ursodeoxycholic acid (UDCA) improves liver biochemistries and enriches the bile with UDCA in patients with primary biliary cirrhosis. The aim of this study was to determine whether the degree of enrichment of bile correlated with that of serum and whether either of these measures correlated with improvement in measures of liver disease. METHODS: In a randomized study, biliary and serum bile acid analyses were performed at entry and after 2 yr of UDCA or placebo. RESULTS: The percentage of ursodeoxycholic acid in bile increased by 42% in the UDCA group (n = 61) compared with 8% in the placebo group (n = 57) (p < 0.0001). Measurement of serum bile acids in 32 patients (18 ursodeoxycholic acid, 14 placebo) indicated that at 2 yr, ursodeoxycholic acid comprised 65% of serum bile acids in the treated group and 7% in the placebo group. Agreement between bile and serum was fair (r = 0.75, p < or = 0.00002) because in some patients, plasma but not biliary bile acids were enriched with UDCA. Changes in biliary ursodeoxycholic acid correlated significantly but weakly with the changes in serum alkaline phosphatase, AST, bilirubin, and in Mayo risk score. Correlations between changes in serum bile acid composition and biochemical measures of disease activity were even weaker. CONCLUSION: The measurement of biliary bile acids is superior to that of serum bile acids for assessing the compliance and changes in the circulating bile acids in patients receiving ursodeoxycholic acid for the treatment of primary biliary cirrhosis. Furthermore, measures to further increase the proportion of ursodeoxycholic acid in circulating bile acids should be explored.

Bile↗
PubMed1998

Substrate specificity of the rat liver Na(+)-bile salt cotransporter in Xenopus laevis oocytes and in CHO cells.

It has been proposed that the hepatocellular Na(+)-dependent bile salt uptake system exhibits a broad substrate specificity in intact hepatocytes. In contrast, recent expression studies in mammalian cell lines have suggested that the cloned rat liver Na(+)-taurocholate cotransporting polypeptide (Ntcp) may transport only taurocholate. To characterize its substrate specificity Ntcp was stably transfected into Chinese hamster ovary (CHO) cells. These cells exhibited saturable Na(+)-dependent uptake of [3H]taurocholate [Michaelis constant (K(m)) of approximately 34 microM] that was strongly inhibited by all major bile salts, estrone 3-sulfate, bumetanide, and cyclosporin A. Ntcp cRNA-injected Xenopus laevis oocytes and the transfected CHO cells exhibited saturable Na(+)-dependent uptake of [3H]taurochenodeoxycholate (Km of approximately 5 microM), [3H]tauroursodeoxycholate (Km of approximately 14 microM), and [14C]glycocholate (Km of approximately 27 microM). After induction of gene expression by sodium butyrate, Na(+)-dependent transport of [3H]estrone 3-sulfate (Km of approximately 27 microM) could also be detected in the transfected CHO cells. However, there was no detectable Na(+)-dependent uptake of [3H]bumetanide or [3H]cyclosporin A. These results show that the cloned Ntcp can mediate Na(+)-dependent uptake of all physiological bile salts as well as of the steroid conjugate estrone 3-sulfate. Hence, Ntcp is a multispecific transporter with preference for bile salts and other anionic steroidal compounds.

Animals↗
PubMed1998

[Hepatocellular transport of bile acids and organic anions in infection and SIRS--evidence for different mechanisms for regulating membrane transport proteins].

The alteration of proinflammatory mediators during sepsis and SIRS results in a large variety of adaptive changes of metabolic and physiologic variables. This study investigated the alterations of hepatocellular transport in a rat sepsis model (LPS i.p.) as well as in a model inducing SIRS by sterile abscess formation (turpentine i.m.). Two bile acids (Cholyltaurine and Chemodeoxycholyltaurine) and one organic anion (Sulfolithocholyltaurine) were used as marker substrates to investigate the time course of hepatocellular transport function. Experiments were performed in isolated perfused rat livers and plasma membrane vesicles. During sepsis, both, the transport of bile acids and that of the organic anion was markedly reduced. In contrast no alteration of transport was detected during SIRS. However, biliary secretion of glutathione (+90%) and bile acid independent bile flow (%) were increased. mRNA levels of bile acid and organic anion transport proteins were reduced. The lowest values were noted 12 h after injection of LPS or turpentine. Almost unchanged kinetic parameters during SIRS pointed to a normal population of transporters with regard to quantity and substrate affinity. Therefore it seems that transcriptional regulation plays an important role for the expression of transport proteins during sepsis, whereas posttranscriptional regulation may be of importance during SIRS. The clinical phenomenon of septic cholestasis including jaundice implies endotoxemia and differenciates against SIRS.

Animals↗
PubMed1998

An N-acyl glycyltaurine conjugate of deoxycholic acid in the biliary bile acids of the rabbit.

jj biliary bile acid composition of the adult and neonatal domestic rabbit, as well as that of the adult brush rabbit, was characterized. In adult domestic rabbits, the dominant bile acid present was deoxycholic acid (88% of total bile acids), a secondary bile acid formed by the bacterial 7-dehydroxylation of cholic acid. Although most of the bile acids present were conjugated with glycine, two exceptions were observed. About 3% of deoxycholic acid was conjugated, in N-acyl linkage, with glycyl-taurine. Chenodeoxycholic acid, which composed <1% of wile acids, was conjugated solely with taurine. The bile of neonatal rabbits contained a greater percentage of primary bile acids, and bile acids were conjugated to a much greater extent with taurine. The adult brush rabbit had a bile acid composition similar to that of the domestic rabbit, but about one-third of all bile acids were conjugated with taurine. In addition, lithocholic acid was present as its sulfated amidate, whereas in the domestic rabbit, lithocholic acid was conjugated solely with glycine. The biliary bile acid composition of rabbits appears to be unique both in terms of the predominant steroid moiety, as well as in the modes of conjugation.

Animals↗
PubMed1997

Comparative effects of enteric-coated pancreatin microsphere therapy after conventional and pylorus-preserving pancreatoduodenectomy.

BACKGROUND: A comparative study was performed between patients with exocrine pancreatic insufficiency after conventional pancreatoduodenectomy (Whipple's procedure) and pylorus-preserving pancreatoduodenectomy (PPPD). In these patients the pharmacodynamics of 2-mm enteric-coated pancreatin microspheres (ECPMs) and their gastric transit time in relation to that of a solid meal were investigated. The efficacy of ECPM preparations may differ after Whipple's procedure compared with PPPD, because the latter procedure does not include gastrectomy. METHODS: Gastric transit was assessed by double-isotope scintigraphy. A pancake meal was labelled with 99mTc. ECPMs were cold-labelled with 170Er and neutron activated shortly before ingestion to enable imaging with a gamma camera. Intraluminal pancreatic enzyme activity was assessed during a 6-h period with two indirect tests: the cholesteryl [14C]octanoate breath test and the N-benzoyl-L-tyrosyl-p-aminobenzoic acid-p-aminosalicylic acid (NBT-PABA-PAS) test. RESULTS: In patients who had Whipple's procedure, the gastric transit time of ECPMs and of the pancake meal was not significantly different. The outcome of the indirect pancreatic function tests during enzyme supplementation was comparable, and not significantly different, from that in healthy volunteers. In patients who had PPPD, however, the gastric transit time of microspheres was greatly delayed compared with that of the pancake meal (P < 0.05). Improvement in the outcome of the indirect pancreatic function tests during enzyme supplementation was much less and remained well below that of healthy volunteers (P < 0.05). CONCLUSION: In cases of exocrine pancreatic insufficiency after Whipple's procedure, 2-mm ECPM treatment adequately restores pancreatic enzyme activity. Following PPPD, however, ECPM treatment is often ineffective because the microspheres are retained in the stomach. In these patients, use of conventional powdered pancreatin enzyme preparations may improve the efficacy of treatment.

4-Aminobenzoic Acid↗
PubMed1997

Intestinal absorption and enterohepatic cycling of biliary iron originating from plasma non-transferrin-bound iron in rats.

In iron overload, non-transferrin-bound iron (NTBI) is found in plasma and is rapidly removed by hepatocytes. Some of this NTBI is excreted into bile. Biliary excretion of NTBI, in the form of an iron-deferiprone chelate, is greatly increased by deferiprone, an iron chelator. The aim of this study was to test whether biliary iron as such or as an iron-deferiprone chelate (both originating from plasma NTBI) is absorbed from the intestine and re-secreted into bile. In healthy biliary fistula (donor) rats, biliary 55Fe originating from plasma NTBI was obtained by injecting Fe citrate (to saturate transferrin) followed by 55Fe. This biliary 55Fe was infused into the duodenum of (recipient) rats whose transferrin was saturated or unsaturated. Similar experiments were performed using iron-overloaded (donor) rats given deferiprone, followed by infusion of the biliary 55Fe-deferiprone chelate into iron-overloaded (recipient) rats. The results show that in healthy (recipient) rats, duodenal infusion of 55Fe from NTBI was followed by increased plasma 55Fe when transferrin was unsaturated, or by biliary excretion of 55Fe when transferrin was saturated, indicating intestinal absorption of 55Fe. In iron-overloaded rats, neither plasma nor bile became radioactive, indicating no intestinal absorption of iron from the deferiprone chelate. We conclude that biliary iron, originating from NTBI, is absorbed from the intestine, and undergoes enterohepatic circulation if transferrin is saturated. In iron-overloaded rats, biliary iron originating from plasma NTBI and present as an iron-deferiprone chelate in bile is not absorbed.

Animals↗
PubMed1997

Effect of side chain length on biotransformation, hepatic transport, and choleretic properties of chenodeoxycholyl homologues in the rodent: studies with dinorchenodeoxycholic acid, norchenodeoxycholic acid, and chenodeoxycholic acid.

To assess the effect of side chain length on the metabolism and physiological effects of homologues of chenodeoxycholic acid (CDCA), dinorCDCA, the C22 homologue, was synthesized and its hepatic biotransformation, transport kinetics, and choleretic properties were defined in rat and hamster biliary fistula and in isolated perfused rat liver. Results were compared with those of norCDCA, the C23 homologue, and of CDCA, the natural C24 homologue. In the rat, dinorCDCA was secreted mostly in unconjugated form (the majority as dinor-alpha-muricholic acid); the remainder was glucuronidated. In the hamster, glucuronidation was greater, and the unconjugated fraction contained equal parts of dinorCDCA and 5beta-hydroxy-dinorCDCA. NorCDCA was glucuronidated extensively (70%, rat; 40%, hamster). CDCA, in contrast, was efficiently amidated with taurine or glycine. In the perfused liver, the initial uptake rate of all three homologues was identical; later, regurgitation and/or cholehepatic shunting of dinorCDCA and norCDCA, but not of CDCA, occurred. In rats and hamsters with biliary fistulas, dinorCDCA and norCDCA, but not CDCA, induced a bicarbonate-rich hypercholeresis of canalicular origin. Hypercholeresis was not induced by the taurine conjugate of dinorCDCA. Hepatobiliary retention of both dinorCDCA and norCDCA occurred, consistent with efficient ductular absorption (calculated to be 94%) and cholehepatic cycling of the unmetabolized bile acids. It is concluded that dinorCDCA, as norCDCA, is inefficiently amidated, is metabolized as a xenobiotic, and induces hypercholeresis. DinorCDCA is the first dihydroxy bile acid to be identified that is secreted largely in unconjugated form in bile.

Animals↗
PubMed1997

Fluorescent bile acid derivatives: relationship between chemical structure and hepatic and intestinal transport in the rat.

Studies were performed to characterize hepatic and intestinal transport, as well as biotransformation during transport, of a spectrum of fluorescent bile acids containing a fluorophore attached to the side chain. The following two classes of compounds were studied: 1) aminofluorescein (amF) coupled directly to the carboxylic group of a bile acid which was cholic, ursodeoxycholic, or cholylglycine; and 2) nitrobenzoxadiazolyl (NBD) coupled to the epsilon-amino group of a lysine conjugated bile acid, which was cholic or ursodeoxycholic. Fluorescein, a cholephilic organic anion, was studied as a control. Fluorescent bile acids were synthesized and their structures confirmed by nuclear magnetic resonance and mass spectrometry. Using the biliary fistula rat, hepatic transport, biotransformation, and choleretic activity were defined; intestinal absorption was assessed by jejunal or ileal perfusion studies. All fluorescent bile acids had hepatic transport maxima about one-sixth that reported for cholyltaurine, but derivatives of cholylglycine were transported best. Bile acids underwent little (<5%) biotransformation during hepatocyte transport. Only the amF conjugate of cholylglycine had normal choleretic activity; other compounds were hypocholeretic or cholestatic. In contrast, fluorescein was well transported, was partly glucuronidated, and had normal choleretic activity. NBD-tagged, but not amF-tagged, bile acids were actively transported by the intestine (ileum > jejunum), and no fluorescent bile acid had passive intestinal permeability; NBD-tagged bile acids were biotransformed during intestinal transport (jejunum > ileum). We conclude that the structure of the fluorophore as well as that of the bile acid influences transport by the hepatocyte and enterocyte. These fluorescent bile acids differ from fluorescein in being impermeable to cell membranes and undergoing little biotransformation during hepatocyte transport. Of these fluorescent bile acids, cholylglycylamF has hepatocyte transport and choleretic properties most closely resembling those of a natural bile acid.

Animals↗
PubMed1997

Giardia lamblia: evidence for carrier-mediated uptake and release of conjugated bile acids.

Giardia lamblia trophozoites colonize the human small intestine, where they are exposed to high concentrations of conjugated bile acids. Previous work has shown that bile acids enhance trophozoite survival, multiplication, and differentiation into the cyst stage. Therefore, experiments were performed to test whether carrier-mediated uptake of conjugated bile acids is present in this primitive parasite. Uptake of both cholyltaurine (C-tau) and cholylglycine (C-gly) was increased manyfold after culturing trophozoites in medium lacking bile acids. Absence of uptake at 4 degrees C and inhibition by other conjugated bile acids provided additional evidence for carrier-mediated uptake. Uptake of C-tau was greater than that of C-gly under all experimental conditions and appeared to be mediated by a different carrier. The major evidence for different carriers is that C-tau uptake was Na(+)-dependent, while C-gly uptake was not. In addition, C-tau uptake was more strongly inhibited by DTNB and several organic anions than C-gly uptake. Radiolabeled C-tau and C-gly were each released rapidly from trophozoites at 37 degrees C but not at 4 degrees C, suggesting that release of conjugated bile acids was also carrier-mediated. These findings are consistent with the notion that multiple transporters for conjugated bile acids are present in a lower eukaryote. We speculate that intracellular bile acids may facilitate lipid trafficking and membrane biosynthesis.

Animals↗
PubMed1997

Hepatocyte transport of bile acids and organic anions in endotoxemic rats: impaired uptake and secretion.

BACKGROUND & AIMS: In sepsis, intrahepatic cholestasis occurs frequently, suggesting impaired hepatocyte transport of bile acids and organic anions. The aim of the study was to define the magnitude, time course, and the site of impaired biliary secretion in a rat sepsis model. METHODS: Maximal transport for two bile acids (cholyltaurine and chenodeoxycholyltaurine) and two organic anions (sulfobromophthalein and sulfolithocholyltaurine) was measured in isolated perfused livers at various times after lipopolysaccharide injection. Basolateral and canalicular liver plasma membrane vesicles were used to characterize the impairment in hepatocyte transport. RESULTS: Maximal hepatocyte transport was reduced for all compounds by 60%-81% compared with controls. Bile acid-independent bile flow was reduced by 51%. Impairment was maximal 12 hours after endotoxin injection and recovered thereafter. In basolateral plasma membrane vesicles, sodium-dependent transport for bile acids was reduced by 36%-47%. Sodium-independent transport of organic anions was reduced by 40%-55%. Adenosine triphosphate-stimulated transport was greatly decreased in canalicular vesicles prepared from endotoxemic animals for all four compounds probably because of a reduced number of transport molecules, based on kinetic studies. CONCLUSIONS: Basolateral and canalicular bile acid and organic anion transport are markedly impaired in endotoxemia. These mechanisms may contribute to the cholestasis of sepsis.

Adenosine Triphosphate↗