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I Leier

Publications and source records attributed to I Leier.

34 records · Page 2Linked to original sources
PubMed1996

The function of the multidrug resistance proteins (MRP and cMRP) in drug conjugate transport and hepatobiliary excretion.

The MRP gene encodes a 190-kDa integral membrane glycoprotein which functions as a primary-active ATP-dependent export pump for amphiphilic anions. The MRP gene-encoded conjugate export pump and its canalicular isoform represent the transport activity which has been described earlier as multispecific organic anion transporter, non-bile acid organic anion transporter, glutathione S-conjugate export pump, or leukotriene export pump. Analyses of the substrate specificity of the human MRP pump were performed in plasma membrane vesicles from MRP-overexpressing drug-selected cells (7) and cells transfected with an MRP expression vector (8). Substrates for MRP include thioether-linked conjugates of lipophilic compounds with glutathione, cysteinyl glycine, cysteine, and N-acetyl cysteine, but also glutathione disulfide, and glucuronate conjugates such as etoposide glucuronide. This broad-specificity ATP-dependent export pump is not only overexpressed in several multidrug resistant tumor cells and tissues, but is also present in most normal cells and tissues. The expression of cMRP and MRP in human liver and of cMrp and its homolog Mrp in rat liver was demonstrated by reverse transcription PCR, cDNA sequencing, and immunoblotting (13). The important function of the cMRP gene-encoded broad-specificity conjugate export pump in hepatobiliary excretion is illustrated by the selective absence of this canalicular isoform from the hepatocyte canalicular membrane in transport-deficient mutant rats. This altered lack of cMrp is the basis for the hereditary detect of the hepatobiliary excretion of anionic conjugates in the mutant animals (13). The absence of this canalicular Mrp in the mutants is analogous to the defect in the human Dubin-Johnson syndrome which is characterized by an impaired excretion of conjugated anions across the canalicular membrane.

ATP-Binding Cassette Transporters↗
PubMed1995

Expression of the MRP gene-encoded conjugate export pump in liver and its selective absence from the canalicular membrane in transport-deficient mutant hepatocytes.

We have previously shown that the multi-drug resistance protein (MRP) mediates the ATP-dependent membrane transport of glutathione S-conjugates and additional amphiphilic organic anions. In the present study we demonstrate the expression of MRP in hepatocytes where it functions in hepatobiliary excretion. Analysis by reverse transcription-PCR of human and normal rat liver mRNA resulted in two expected cDNA fragments of MRP. Four different antibodies against MRP reacted on immunoblots with the glycoprotein of about 190 kD from human canalicular as well as basolateral hepatocyte membrane preparations. A polyclonal antibody directed against the carboxy-terminal sequence of MRP detected the rat homolog of MRP in liver. Double immunofluorescence microscopy and confocal laser scanning microscopy showed the presence of human MRP and rat Mrp in the canalicular as well as in the lateral membrane domains of hepatocytes. The transport function of the mrp gene-encoded conjugate export pump was assayed in plasma membrane vesicles with leukotriene C4 as a high-affinity glutathione S-conjugate substrate. The deficient ATP-dependent conjugate transport in canalicular membranes from TR- mutant rat hepatocytes was associated with a lack of amplification of one of the mrp cDNA fragments and with a selective loss of Mrp on immunoblots of canalicular membranes. Double immunofluorescence microscopy of livers from transport-deficient TR- mutant rats localized Mrp only to the lateral but not to the canalicular membrane. Our results indicate that the absence of Mrp or an isoform of Mrp from the canalicular membrane is the basis for the hereditary defect of the hepatobiliary excretion of anionic conjugates by the transport-deficient hepatocyte.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates.

The multidrug resistance-associated protein (MRP) is the product of an ATP-binding cassette transporter gene overexpressed in some tumor cells resistant to antineoplastic agents. We studied the transport function of MRP in membrane vesicles prepared from HeLa cells transfected with an MRP expression vector and overexpressing this 190-kDa membrane glycoprotein. ATP-dependent primary-active transport into the vesicles was demonstrated for leukotriene C4 (LTC4), LTD4, LTE4, and S-(2,4-dinitrophenyl)glutathione with relative rates, at a substrate concentration of 50 nM, of 1.0, 0.27, 0.14, and 0.16, respectively. The endogenous glutathione conjugate LTC4 had the highest affinity for this transporter with a Km of 97 nM. The Km for ATP was 19 microM. Direct photoaffinity labeling with [3H]LTC4 labeled a 190-kDa membrane protein predominantly in the MRP-transfected HeLa cells. ATP-dependent LTC4 transport was effectively inhibited by the LTD4 receptor antagonist MK 571, whereas cyclosporin A and, particularly, its analog PSC 833 were much less potent. The respective Ki values were 0.6, 5, and 27 microM, respectively. In addition, MK 571 preferentially inhibited photoaffinity labeling of the 190-kDa protein in the MRP transfectants. Our results provide direct evidence that the MRP gene encodes a primary-active ATP-dependent export pump for conjugates of lipophilic compounds with glutathione and several other anionic residues. We conclude that the biosynthetic release of LTC4 from cells is mediated by the 190-kDa product of the MRP gene.

ATP-Binding Cassette Transporters↗
PubMed1994

Hepatobiliary elimination of the peroxisome proliferator nafenopin by conjugation and subsequent ATP-dependent transport across the canalicular membrane.

Amphiphilic carboxylates acting as peroxisome proliferators and hypolipidemic drugs induce enzymes of peroxisomal lipid beta-oxidation, certain drug-metabolizing enzymes in the liver, and a number of additional proteins. The peroxisome proliferators represent a well-established class of non-genotoxic hepatocarcinogens. In this study we characterized the hepatic elimination of the peroxisome proliferator nafenopin. In the rat in vivo, 1 hr after intravenous administration of [3H]nafenopin, approx. 40% of injected radioactivity was recovered in bile. HPLC analysis of bile samples revealed that only about 10% of the radioactivity recovered in bile was associated with non-metabolized nafenopin and approx. 90% with more polar metabolites. One of the main metabolites formed in the liver and excreted into bile was identified as nafenopin glucuronide by beta-glucuronidase-catalysed reconversion to nafenopin. In mutant rats deficient in the canalicular transport of leukotriene C4 and related amphiphilic anion conjugates, recovery of [3H]nafenopin-derived radioactivity in bile was reduced to 4% of the injected dose. Although nafenopin glucuronide could not be detected in bile, it was a major metabolite in the liver from these mutant rats. Using membrane vesicles enriched in bile canalicular membranes from normal rats, transport of nafenopin glucuronide was shown to be a primary-active ATP-dependent process which was inhibited by leukotriene C4 and S-dinitrophenyl glutathione with IC50 values of 0.2 and 12 microM, respectively. ATP-dependent transport was not detectable for non-conjugated nafenopin. In canalicular membrane vesicles prepared from the mutant rats, the rate of ATP-dependent transport of nafenopin glucuronide was less than 10% of the transport observed in vesicles from normal rats. These data indicate that conjugation and subsequent transport by the ATP-dependent export carrier for leukotriene C4 and related conjugates is a major pathway for the elimination of nafenopin and structurally-related peroxisome proliferators.

Adenosine Triphosphate↗
PubMed1994

ATP-dependent transport of glutathione S-conjugates by the multidrug resistance-associated protein.

The ATP-dependent transport of the endogenous glutathione conjugate leukotriene C4 (LTC4) was more than 25-fold higher in membrane vesicles prepared from human leukemia cells (HL60/ADR) overexpressing the multidrug resistance-associated protein than from drug-sensitive parental HL60 cells or revertant cells. Similar results were obtained with S-(2,4-dinitrophenyl)glutathione as substrate. Photoaffinity labeling detected preferentially in the HL60/ADR membranes a 190-kilodalton protein binding [3H]LTC4 and 8-azido[alpha-32P]ATP. The [3H]LTC4-labeled 190-kilodalton protein was immunoprecipitated by an antiserum against the COOH-terminal sequence of multidrug resistance-associated protein. Our results indicate that multidrug resistance-associated protein mediates the ATP-dependent transport of LTC4 and structurally related anionic amphiphilic conjugates.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Characterization of the ATP-dependent leukotriene C4 export carrier in mastocytoma cells.

The biosynthesis of leukotriene C4 (LTC4) must be followed by an export of this mediator into the extracellular space where it interacts with receptors. Using mastocytoma cells we have demonstrated the existence of a primary-active, ATP-dependent transport mediating this export of LTC4 [Schaub, T., Ishikawa, T. & Keppler, D. (1991) FEBS Lett. 279, 83-86]. The following inhibitors served to characterize further this transport system in plasma membrane vesicles from mastocytoma cells: Probenecid, an inhibitor of organic anion transport, induced half-maximal inhibition of the ATP-dependent LTC4 transport at 71 microM. Cyclosporin A and its non-immunosuppressive analog PSC 833 inhibited the ATP-dependent transport with Ki values of 4.5 microM and 30 microM, respectively. The LTD4 receptor antagonist 3-([(3-(2-[7-chloro-2-quinolinyl]ethenyl)phenyl)-[(3-dimethylamino-3- oxopropyl)-thio]-methyl]thio)propanoic acid (MK 571) was the most potent competitive inhibitor of the export carrier with a Ki value of 0.8 microM. The transport inhibitor MK 571 served as competitor in the photoaffinity labeling of LTC4-binding membrane proteins using [3H]LTC4 as the photolabile ligand. Proteins with molecular masses of about 190 kDa and 35 kDa were predominantly labeled. In addition, a minor [3H]LTC4 labeling was observed in the molecular mass range of 100 kDa. The [3H]LTC4 labeling of the 190-kDa protein was competed for by MK 571. The labeled proteins resisted extraction from the membrane with 2% sodium taurocholate suggesting that they are integral membrane proteins. Treatment of the membrane proteins with peptide N-glycosidase F resulted in the appearance of an additional labeled polypeptide of about 140 kDa suggesting that the 190-kDa protein is a glycoprotein. Photoaffinity labeling with 8-azido[alpha-32P]ATP predominantly labeled the LTC4-binding 35-kDa protein. The [3H]LTC4-labeled 190-kDa protein showed a mean isoelectric point at pH 6.3 with a range of pH 5.8-6.7, while the 35-kDa protein had an isoelectric point at pH 6.8. Specific labeling of a 190-kDa membrane glycoprotein by the glutathione conjugate LTC4, which is competed for by a potent inhibitor of the ATP-dependent LTC4 export carrier, pinpoints its involvement in the ATP-dependent transport of LTC4 and related conjugates.

Adenosine Triphosphate↗
PubMed1994

Cholestasis caused by inhibition of the adenosine triphosphate-dependent bile salt transport in rat liver.

BACKGROUND/AIMS: Inhibition of bile salt transport across the hepatocyte during cholestasis induced by cyclosporin A has been shown. However, the contribution of the different bile salt transport systems in liver to cholestasis has remained controversial. METHODS: The sensitivity of different bile salt transport systems in liver to cyclosporin-induced inhibition was determined by transport assays in plasma membrane vesicles and by in vivo studies in the rat. RESULTS: Cyclosporin A--induced inhibition of sodium-dependent uptake of bile salts across the sinusoidal membrane, of potential-dependent, and of adenosine triphosphate (ATP)-dependent bile salt transport across the canalicular membrane exhibited inhibition constants (Ki) of 5, 70, and 0.2 mumol/L, respectively. The nonimmunosuppressive cyclosporin analogue PSC 833 also preferentially inhibited the ATP-dependent bile salt transport with an inhibition constant of 0.6 mumol/L. Cyclosporin A and its analogue PSC 833 [(3'-oxo-4-butenyl-4-methyl-Thr1)-(Val2)-cyclosporin] (25 mg/kg each) served as tools to interfere with [14C]taurocholate secretion into bile in vivo, causing an accumulation of [14C]-taurocholate in liver and reducing bile flow to 50%. In mutant rats deficient in the transport of leukotriene C4 and related conjugates across the canalicular membrane, bile flow was reduced to 14%. CONCLUSIONS: The cyclosporins preferentially inhibit the ATP-dependent bile salt export carrier in the canalicular membrane. This inhibition reduces bile salt-dependent bile flow and causes intrahepatic cholestasis.

Adenosine Triphosphate↗
PubMed1994

ATP-dependent export pumps and their inhibition by cyclosporins.

Cyclosporins are potent tools to inhibit several primary-active, ATP-dependent export carriers. This has been demonstrated in membrane vesicle transport assays for CsA and for its non-immunosuppressive analog PSC 833. Inhibition in the low micromolar and in the nanomolar concentration range is shown for the three distinct ATP-dependent export carriers in the liver canalicular membrane mediating the secretion into bile of leukotrienes (LTC4, other cysteinyl leukotrienes, and related conjugates), bile salts (taurocholate), and amphiphilic, mostly cationic substances (daunorubicin and other P-glycoprotein substrates). Competitive inhibition by cyclosporins is most potent for ATP-dependent taurocholate transport with Ki values of 0.2 and 0.6 microM for CsA and PSC 833, respectively. This inhibition is in agreement with in vivo studies in the rat demonstrating a block at the canalicular membrane in the hepatobiliary elimination of labeled taurocholate. The data suggest that cholestasis, as a side effect during CsA therapy, is largely due to inhibition of the ATP-dependent bile salt export carrier in the canalicular membrane. Inhibition by cyclosporins is less effective with respect to ATP-dependent leukotriene transport, both during biosynthetic release from mastocytoma cells and during hepatobiliary excretion. The Ki values for the former were 4.5 and 30 microM, and the Km/Ki ratios only 0.015 and 0.002 for CsA and PSC 833, respectively. Distinct transporters are inhibited by the cyclosporins with different potency and structurally modified cyclosporins may serve to induce preferential inhibition of a selected transporter. This is illustrated by the inhibition of the multidrug export carrier with daunorubicin as substrate using PSC 833 as inhibitor with a Ki value of 0.3 microM in an in vitro membrane transport system.

Adenosine Triphosphate↗
PubMed1992

Leukotriene uptake by hepatocytes and hepatoma cells.

The uptake of tritiated cysteinyl leukotrienes (LTC4, LTD4, LTE4) and LTB4 was investigated in freshly isolated rat hepatocytes and different hepatoma cell lines under initial-rate conditions. Leukotriene uptake by hepatocytes was independent of an Na+ gradient and a K+ diffusion potential across the hepatocyte membranes as established in experiments with isolated hepatocytes and plasma membrane vesicles. Kinetic experiments with isolated hepatocytes indicated a low-Km system and a non-saturable system for the uptake of cysteinyl leukotrienes as well as LTB4 under the conditions used. AS-30D hepatoma cells and human Hep G2 hepatoma cells were deficient in the uptake of cysteinyl leukotrienes, but showed significant accumulation of LTB4. Moreover, only LTB4 was metabolized in Hep G2 hepatoma cells. Competition studies on the uptake of LTE4 and LTB4 (10 nM each) indicated inhibition by the organic anions bromosulfophthalein, S-decyl glutathione, 4,4'-diisothiocyanato-stilbene-2,2'-disulfonate, probenecid, docosanedioate, and hexadecanedioate (100 microM each), but not by taurocholate, the amphiphilic cations verapamil and N-propyl ajmaline, and the neutral glycoside ouabain. Cholate and the glycoside digitoxin were inhibitors of LTB4 uptake only. Bromosulfophthalein, the strongest inhibitor of leukotriene uptake by hepatocytes, did not inhibit LTB4 uptake by Hep G2 hepatoma cells under the same experimental conditions. Leukotriene-binding proteins were analyzed by comparative photoaffinity labeling of human hepatocytes and Hep G2 hepatoma cells using [3H]LTE4 and [3H]LTB4 as the photolabile ligands. Predominant leukotriene-binding proteins with apparent molecular masses in the ranges of 48-58 kDa and 38-40 kDa were labeled by both leukotrienes in the particulate and in the cytosolic fraction of hepatocytes, respectively. In contrast, no labeling was obtained with [3H]LTE4 in Hep G2 cells. With [3H]LTB4 a protein with a molecular mass of about 48 kDa was predominantly labeled in the particulate fraction of the hepatoma cells, whereas in the cytosolic fraction a labeled protein in the range of 40 kDa was detected. Our results provide evidence for the existence of distinct uptake systems for cysteinyl leukotrienes and LTB4 at the sinusoidal membrane of hepatocytes; however, some of the inhibitors tested interfere with both transport systems. Only LTB4, but not cysteinyl leukotrienes, is taken up and metabolized by the transformed hepatoma cells.

Affinity Labels↗
PubMed1992

Transport and in vivo elimination of cysteinyl leukotrienes.

Transport processes control not only synthesis and release of LTC4 but also the elimination and excretion of LTC4 and its metabolites. (i) A primary-active ATP-dependent export carrier mediates the release of LTC4 from a leukotriene-generating cell, as exemplified by mastocytoma cells, and as measured in mastocytoma plasma membrane vesicles (2). (ii) Release of cysteinyl leukotrienes into the blood circulation is followed by a rapid elimination with an initial half-life of 38 sec in rats and 4.0 min in man, as measured with the labeled, representative LTC4 catabolite, N-acetyl-LTE4. (iii) 11C-labeled N-acetyl-LTE4 can serve for non-invasive studies on cysteinyl leukotriene elimination and excretion by the liver and kidney in the intact organism using positron emission tomography. An impairment of leukotriene transport from the liver across the canalicular membrane into bile, studied in mutant rats and in extrahepatic cholestasis, leads to a compensatory diversion of cysteinyl leukotriene elimination to the kidney. N-Acetyl-LTE4 labeled with a short-lived positron-emitting isotope provides quantitative insight into the pathways of cysteinyl leukotriene elimination in vivo. (iv) Cysteinyl leukotriene export from the liver into bile is mediated by an ATP-dependent primary-active export carrier. This decisive step in cysteinyl leukotriene elimination has been characterized in hepatocyte canalicular membrane vesicles (3). The leukotriene exporter is deficient in transport mutant rats. The leukotriene carrier is distinct from other ATP-dependent export carriers identified in this membrane domain, such as the ATP-dependent bile salt export carrier (25) and the multidrug export carrier (27).

Adenosine Triphosphate↗
PubMed1991

Peroxisomal degradation of leukotrienes by beta-oxidation from the omega-end.

Chain shortening via beta-oxidation from the omega-end has been recognized as the major pathway for the degradation of cysteinyl leukotrienes as well as leukotriene B4 (LTB4). The metabolic compartmentation of this pathway was studied using peroxisomes purified from normal and clofibrate-treated rat liver. beta-Oxidation products of omega-carboxy-LTB4, including omega-carboxy-dinor-LTB4 identified by gas chromatography-mass spectrometry, were formed by the isolated peroxisomes. The reaction was dependent on CoA, ATP, and NAD and was stimulated by FAD. NADPH was necessary for the further metabolism of omega-carboxy-dinor-LTB4. Together with microsomes a degradation of omega-carboxy-LTB4 also proceeded in isolated mitochondria in the presence of CoA, ATP, and carnitine. beta-Oxidation of the cysteinyl leukotriene omega-carboxy-N-acetyl-leukotriene E4 was observed only with isolated peroxisomes in combination with lipid-depleted microsomes. Direct photoaffinity labeling using omega-carboxy-[3H] LTB4 and omega-carboxy-N-[3H]acetyl-LTE4 served to identify peroxisomal leukotriene-binding proteins. The bifunctional protein (EC 4.2.1.17 and 1.1.1.35) and 3-ketoacyl-CoA thiolase (EC 2.3.1.16) of the peroxisomal beta-oxidation system were the predominantly labeled polypeptides as revealed by precipitation with monospecific antibodies. In vivo studies with N-acetyl-[3H2]LTE4, N-acetyl-[3H8]LTE4, and N-[14C]acetyl-LTE4 after treatment with the peroxisome proliferator clofibrate indicated formation and biliary excretion of large amounts of metabolites more polar than omega-carboxy-tetranor-N-acetyl-LTE3 including omega-carboxy-tetranor-delta 13-N-acetyl-LTE4 and omega-carboxy-hexanor-N-acetyl-LTE3. Increased formation of beta-oxidized catabolites of N-acetyl-LTE4 and LTB4 was also observed in hepatocytes isolated after clofibrate treatment. Our results indicate that peroxisomes play a major role in the beta-oxidation of leukotrienes from the omega-end. Whereas omega-carboxy-LTB4 was beta-oxidized both in isolated peroxisomes and mitochondria, the cysteinyl leukotriene omega-carboxy-N-acetyl-LTE4 was exclusively degraded in peroxisomes.

Affinity Labels↗
PubMed1991

Photoaffinity labeling of leukotriene binding sites in hepatocytes and hepatoma cells.

The method of direct photoaffinity labeling in the frozen state using the leukotrienes as suitable photolabile compounds may serve to identify and characterize polypeptides which interact with these eicosanoids during their hepatobiliary transport and metabolism. Furthermore, it will be a helpful technique to evaluate changes in the cell-specific protein pattern during neoplastic dedifferentiation of hepatocytes.

Affinity Labels↗
PubMed1990

Metabolism of cysteinyl leukotrienes in monkey and man.

The proinflammatory cysteinyl leukotrienes are inactivated in primates by (a) intravascular degradation, (b) hepatic and renal uptake from the blood circulation, (c) intracellular metabolism of leukotriene E4 (LTE4), and (d) biliary and renal excretion of LTC4 degradation products. We have analyzed cysteinyl leukotriene metabolites excreted into bile and urine of the monkey Macaca fascicularis and of man. In both species, hepatobiliary leukotriene elimination predominated over renal excretion. In a representative healthy human subject at least 25% of the administered radioactivity were recovered from bile and 20% from urine within 24 h. In monkey and man intravenous administration of 14,15-3H2-labeled LTC4 resulted in the biliary and urinary excretion of labeled LTE4, omega-hydroxy-LTE4, omega-carboxy-LTE4, omega-carboxy-dinor-LTE4, and omega-carboxy-tetranor-dihydro-LTE4. Small amounts of N-acetyl-LTE4 were detected in human urine only. Oxidative metabolism of LTE4 proceeded more rapidly in the monkey resulting in the formation of higher relative amounts of omega-oxidized leukotrienes in this species as compared to man. [3H]H2O amounted to less than 2% of the administered dose in monkey and human bile and urine samples. Incubation of isolated human hepatocytes with [3H2]LTC4, [3H2]LTD4, and [3H2]LTE4 showed that only [3H2]LTE4 underwent intracellular oxidative metabolism resulting in the formation of omega- and beta-oxidation products. N-Acetylated LTE4 derivatives were not detected as products formed by human hepatocytes. By a combination of reversed-phase high-performance liquid chromatography and radioimmunoassay, endogenous LTE4 and N-acetyl-LTE4 were detected in human urine in concentrations of 220 +/- 40 and 24 +/- 3 pM, corresponding to 12 +/- 1 and 1.5 +/- 0.2 nmol/mol creatinine, respectively (mean +/- SEM; n = 10). Endogenous LTD4 and LTE4 were detected in human bile (n = 3) in concentrations between 0.2-0.9 nM. Our results demonstrate that LTD4 and LTE4 are major LTC4 metabolites in human bile and/or urine and may serve as index metabolites for the measurement of endogenously generated cysteinyl leukotrienes. Moreover, omega-oxidation and subsequent beta-oxidation from the omega-end contribute to the metabolic degradation of LTE4 not only in monkey but also in man.

Acetylation↗
PubMed1990

Inhibition of leukotriene omega-oxidation by omega-trifluoro analogs of leukotrienes.

omega-Oxidation with subsequent beta-oxidation from the omega-end is the major pathway for inactivation and degradation of leukotrienes. Oxidative degradation of leukotriene E4 (LTE4), N-acetyl-LTE4, and LTB4 was inhibited by the omega-trifluoro analogs of LTE4, omega-trifluoro-LTE4 (omega-F3-LTE4), and (1S,2R)-5-(3-[1-hydroxy-15,15,15-trifluoro-2-(2-1H- tetrazol-5-ylethyl-thio)pentadeca-3(E),5(Z)-dienyl+ ++]phenyl)-1H-tetrazole (LY 245769). The latter substance inhibited the oxidative degradation of LTE4 and N-acetyl-LTE4 in the rat in vivo by 50% at a dose of 7 mumol/kg body weight. In rat hepatocyte cultures both omega-trifluoro analogs interfered with the omega-oxidation of N-acetyl-LTE4 and LTB4 with IC50 values of about 4 microM. Both analogs inhibited the omega-hydroxylation in isolated rat liver microsomes with IC50 values between 16 and 37 microM. This inhibition is apparently competitive. In addition, in liver cytosol, the conversion of the omega-hydroxylated leukotrienes to omega-carboxy-LTE4 and omega-carboxy-LTB4 was inhibited by both compounds. omega-Trifluoro analogs of leukotrienes provide a new tool for interfering with the inactivation of leukotrienes in the omega-oxidation pathway.

Animals↗