Excretion Of Leukotrienes Research Articles

Divergent PGD2 and leukotriene C4 metabolite excretion following aspirin therapy: Ten patients with systemic mastocytosis

Aspirin-exacerbated respiratory disease and some cases of chronic idiopathic urticaria are disorders in which increased baseline urinary excretion of leukotriene(LT)E4 further increases following aspirin administration. Increased urinary excretion of the metabolites of prostaglandin D2, 11β-prostaglandin(PG)F2α and (2,3-dinor)-11β-PGF2α, have been documented in systemic mastocytosis (SM) and in mast cell activation syndrome (MCAS). Symptoms due to increased baseline and/or episodic release of PGD2 can be prevented with aspirin, an inhibitor of cyclooxygenase (COX)1 and COX2. Here by retrospective chart review we discovered 8 of 10 patients with SM in whom normalization of an elevated urinary (2,3-dinor)-11β-PGF2α occurred with aspirin therapy also had a parallel increased excretion of LTE4 by an average of nearly 13-fold. How widespread this phenomenon occurs in SM is unknown; however, this occurrence needs to be considered when interpreting changes in these urinary mast cell mediator metabolites during aspirin therapy.

Involvement of leukotriene pathway in the development of sevoflurane-induced pica in rats.

We previously reported that sevoflurane-induced pica, kaolin ingestion behavior, in rats has the potential to reflect postoperative nausea and vomiting (PONV) in humans. It is well-known that corticosteroids, which inhibit both prostaglandin and leukotriene syntheses due to phospholipase A2 inhibition, are effective for reducing PONV; however, the precise mechanisms remain unclear. We investigated the involvement of the prostaglandin or leukotriene pathway in the development of sevoflurane-induced pica. We found that sevoflurane-induced pica was effectively inhibited by pretreatment with a leukotriene receptor antagonist (montelukast) or an inhibitor of 5-lipoxygenase (zileuton), rather than an inhibitor of cyclooxygenase (flurbiprofen). Furthermore, we observed that sevoflurane significantly increased urinary leukotriene excretion and 5-lipoxygenase mRNA expression in the spleen, but not hypothalamus. These results suggest that the production of leukotriene may lead to the development of sevoflurane-induced pica in rats, and that inhibition of the leukotriene pathway could be potentially useful for the treatment of PONV.

Urinary leukotriene excretion profile in children with exercise-induced asthma compared with controls: A preliminary study

BackgroundLeukotrienes are among the most important mediators associated with inflammatory responses in patients with exercise induced asthma (EIA). The aim of this study was to investigate the impact of exercise on the urinary leukotriene profile. Hence, we compared post exercise changes of urinary leukotriene E4 (LTE4) concentration between children with EIA and healthy controls. MethodsTen children with EIA and 15 controls were enrolled. Both groups underwent a standardised exercise challenge test (ECT). LTE4 concentration was measured in urine samples obtained pre and post ECT, using enzyme immunoassay and adjusted by urinary creatinine concentrations. ResultsMedian (minimum–maximum) pre ECT concentration of LTE4 was 17.82 (7.58–90.23pg/ml) in EIA and 17.24 (4.64–64.02pg/ml) in controls, p=0.86. LTE4 concentration post ECT were 23.37 (4.02–93.00pg/ml) in EIA and 11.74 (0.13–25.09pg/ml) in controls, p=0.02. Changes of LTE4 concentration post ECT were 2.54 (−31.98 to 43.31pg/ml) in cases and −13.53 (−46.00 to 11.02pg/ml) in controls, p=0.03. There was no significant correlation between basal predicted FEV1 [%] and changes in LTE4 concentration in cases (i.e., rs=0.14) nor controls (i.e., rs=0.12). There was a tendency towards more pronounced changes in LTE4 concentration post ECT in children with moderate/mild persistent asthma compared to those with mild but intermittent asthma. ConclusionsChildren with EIA had significantly higher changes of urinary LTE4 concentrations post ECT compared to healthy controls. Urinary measurement of LTE4 may be an interesting and non-invasive option to assess control of EIA in children.

Sulfido‐peptide leukotrienes in coronary heart disease – relationship with disease instability and myocardial ischaemia

Urinary excretion of leukotriene (LT) E(4) is an index of LTC(4) biosynthesis and platelet-neutrophil interactions, which may occur in coronary heart disease and contribute to myocardial ischaemia. Enhanced LTC(4) biosynthesis may be a consequence of myocardial ischaemia or be linked to its pathogenetic substrate. Overnight urine collections were obtained from 17 patients with chronic stable angina, three patients with Prinzmetal's angina, 16 patients with non ST-elevation acute coronary syndromes (NSTE-ACS) and six patients with acute ST-elevation myocardial infarction (STEMI). LTE(4) excretion was measured by enzyme immunoassay after HPLC separation. Compared with healthy controls (51.1 +/- 21.3 pg mg(-1) creatinine, mean +/- SD, n = 11) and with non-coronary cardiac controls (36.6 +/- 9.8 pg mg(-1) creatinine, n = 9), LTE(4) excretion was unchanged in stable angina (40.5 +/- 25.8 pg mg(-1) creatinine), but significantly (P < 0.01) increased in NSTE-ACS (122.7 +/- 137.2 pg mg(-1) creatinine) and STEMI (213.4 +/- 172.4 pg mg(-1) creatinine). In these patients, LTE(4) excretion rapidly dropped after day 1, consistent with effective coronary reperfusion. In patients with NSTE-ACS, the increase in LTE(4) excretion was entirely restricted to patients with recent (< 48 h) spontaneous anginal episodes. Myocardial ischaemia elicited by a positive exercise stress test was not accompanied by any detectable increase in LTE(4) excretion, while a significant (P < 0.01) increase was detected after a single-vessel percutaneous coronary interventions (PCI) procedure (n = 10), as compared with diagnostic angiography (n = 9). In coronary heart disease, increased LTC(4) biosynthesis is restricted to ACS and not linked to myocardial ischaemia per se, but likely to the occurrence of plaque disruption.

Serum phospholipase A2 activity in patients with aspirin-induced asthma

Urinary excretion of leukotrienes is greater in patients with aspirin-induced asthma (AIA) than in other patients with asthma in remission, and is greater still during an aspirin-induced attack. We therefore hypothesized that increased phospholipase A2 (PLA2) activity leads to increased leukotriene synthesis when non-steroidal antiinflammatory drugs inhibit cyclooxygenase in patients with AIA, and that PLA2 activity increases further during an aspirin induced attack. To test this hypothesis, we measured the serum PLA2 activity in adult asthmatic patients, and compared the activity in those with AIA to the activity in those without AIA. The subjects were 43 patients with asthma in remission, 17 with AIA and 26 without AIA. Serum PLA2 activity was also measured before and after intravenous administration of lysine-aspirin in three patients with AIA and in one without AIA. Serum PLA2 activity was measured by radioimmunoassay. Serum PLA2 activity in patients with AIA, in those without AIA, and in healthy controls was 300.9 +/- 52.9, 294.4 +/- 65.3 and 171.7 +/- 41.8 pmol/ml/min, respectively. Serum PLA2 activity in asthmatic patients was significantly higher than in healthy controls (p < 0.01), but there was no difference between patients with and without AIA. Intravenous lysine-aspirin provoked asthmatic attacks in three patients with AIA. However, intravenous lysine-aspirin did not significantly change serum PLA2 activity in the three patients with AIA or in the patient without AIA. These results indicate that although PLA2 may be involved in the pathogenesis of bronchial asthma, it is not specific to AIA. Thus, the pathophysiology of AIA remains unclear and further investigation is needed.

Eicosanoids in exhaled breath condensates in the assessment of childhood asthma

The value of measurements of eicosanoids in exhaled breath condensate (EBC) for the evaluation of childhood asthma is still inconclusive most likely because of the limited value of the methods used. In this case-control study in 48 asthmatic and 20 healthy children, we aimed to characterize the baseline profile of the inflammatory mediators cysteinyl leukotrienes (cysLTs), 9(alpha)11(beta)PGF(2), PGE(2), PGF(2alpha), 8-isoprostane (8-iso-PGF(2alpha)) within EBC in asthmatic compared with healthy children using new methods. In addition, we investigated their relation to other inflammatory markers. The assessment included collection of EBC, measurement of fractional exhaled nitric oxide (FE(NO)) and evaluation of urinary excretion of leukotriene E(4.) cysLTs were measured directly in EBC by radioimmunoassay and prostanoids were measured using gas chromatography negative-ion chemical ionization mass spectrometry. Only cysLT levels were significantly higher in asthmatic compared with healthy children (p = 0.002). No significant differences in cysLTs were found between steroid naïve and patients receiving inhaled corticosteroids. In contrast, FE(NO) was significantly higher in steroid naïve compared with steroid-treated asthmatic and healthy children (p = 0.04 and 0.024, respectively). The diagnostic accuracy of cysLTs in EBC for asthma was 73.6% for the whole group and 78.2% for steroid-naïve asthmatic children. The accuracy to classify asthmatic for FE(NO) was poor (62.9%) for the whole group, but improved to 79.9% when only steroid-naïve asthmatic children were taken into consideration. cysLTs in EBC is an inflammatory marker which distinguishes asthmatics, as a whole group, from healthy children.

Urinary leukotriene E4 excretion: A biomarker of inflammatory bowel disease activity

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders collectively referred to as inflammatory bowel diseases (IBD). Cysteinyl leukotrienes are proinflammatory 5-lipoxygenase-derived products that play a major role in the immune and inflammatory response. Consequently, they may be involved in the pathogenesis of IBD. The aim of this study was therefore to evaluate 1) the urinary excretion of leukotriene E(4) (LTE(4)) in IBD patients and healthy volunteers, and 2) the association between LTE(4) production and the activity (relapse/remission) of the disease. IBD patients and healthy volunteers were prospectively recruited. CD and UC activity was determined on inclusion with the Crohn's Disease Activity Index and Clinical Activity Index, respectively. Urine was collected and the urinary excretion of LTE(4) was measured by liquid chromatography tandem mass spectrometry. 32 CD patients, 28 UC patients, and 30 controls were enrolled in the study. LTE(4) urinary excretion was significantly increased (P < 0.01) in CD [52.0 pg/mg creatinine (10th-90th percentiles: 26.2-148.0)] and UC [64.1 pg/mg creatinine (10th-90th percentiles: 26.7-178.0)] patients compared to controls [32.3 pg/mg creatinine (10th-90th percentiles: 21.8-58.8)]. LTE(4) levels were higher (P < 0.001) in patients with active disease than in patients in remission, for whom the levels of LTE(4) were similar to the levels of controls. Cysteinyl leukotriene pathway activation could contribute to the inflammation associated with IBD. The quantification of urinary LTE(4) could be an interesting noninvasive biomarker for the assessment of IBD activity.

Urinary leukotriene E 4 excretion is increased in type 1 diabetic patients : A quantification by liquid chromatography–tandem mass spectrometry

Objective Diabetes mellitus is associated with inflammatory state and increased cardiovascular mortality. Leukotrienes are arachidonic acid metabolites derived from the 5-lipoxygenase pathway that possess vasoactive, chemotactic and proinflammatory properties. The aim of this study was to evaluate (1) the urinary excretion of leukotriene E 4 (LTE 4) in type 1 diabetic subjects and healthy volunteers and (2) the influence of glycemic control attested by HbA 1C on LTE 4 excretion. Methods and results Urinary excretion of LTE 4, measured by liquid chromatography–tandem mass spectrometry, was significantly ( P = 0.033) increased in diabetic patients (median [10th–90th percentiles]: 42.1 pg/mg creatinine [16.7–71.4], n = 34), compared to healthy subjects (25.5 pg/mg creatinine [13.9–54.1], n = 28). Subgroup analysis indicated a trend towards increased LTE 4 excretion in patients with poor glycemic control [(HbA 1C ≥ 9% or plasma glucose >18 mmol/L): 43.3 pg/mg creatinine [21.6–70.5], n = 14], whereas no difference was observed between patients with good metabolic control [(HbA 1C ≤ 7.5%): 36.4 pg/mg creatinine [15.8–83.4], n = 20] and healthy subjects. Conclusions This study suggested that increased LTE 4 excretion in type 1 diabetic state might reflect systemic activation of the 5-lipoxygenase pathway. It could be a determinant of underlying inflammatory state and vascular disease.

Leukotriene synthesis during respiratory syncytial virus bronchiolitis: Influence of age and atopy

Respiratory syncytial virus (RSV) infection is the most common cause of bronchiolitis in infants and an important risk factor for the development of recurrent wheezing and asthma. Cysteinyl leukotrienes were implicated in the pathophysiology of these diseases, and are being targeted for their diagnosis and therapy. We measured urinary leukotriene E4 (LTE4) in infants with RSV bronchiolitis in comparison with controls without respiratory infection, and investigated whether medical and family history, age, and passive exposure to tobacco smoke are related to urinary leukotriene excretion. We studied 33 infants with bronchiolitis and 25 controls, 1-12 months of age. Demographic and historical data were obtained from informed-consent forms and questionnaires completed by the parents. RSV was detected in nasal secretions by enzyme-linked immunoassay. Urine samples were collected on day of admission and were analyzed for LTE4 with an enzyme-linked immunoassay. Urinary LTE4 was 8-fold higher in infants with bronchiolitis than in controls. Leukotriene excretion was significantly higher in infected infants <6 months of age with a medical history of eczema or dry cough and/or family history of asthma. Multivariate analysis revealed that eczema and dry cough are independently associated with high LTE4 excretion during bronchiolitis. Exposure to tobacco smoke did not affect urinary LTE4. Our study shows that leukotriene synthesis during bronchiolitis is particularly elevated in younger infants with an atopic/asthmatic background. Urinary LTE4 may become a valuable, noninvasive marker for the identification of patients who will benefit most from therapy with leukotriene modifiers for management of bronchiolitis.

Tacrolimus reduces urinary excretion of leukotriene E4 and inhibits aspirin-induced asthma to threshold dose of aspirin

The exact mechanism of aspirin-induced asthma is not clear. It has been postulated that precipitation of asthma attacks by aspirin is linked to inhibition of COX activity and massive release of cysteinyl leukotriene into the airway. Tacrolimus, a macrolide-derived immunosuppressant, is used for immunosuppression in organ transplantation and also for allergic diseases such as atopic dermatitis. We evaluated the effects of tacrolimus in aspirin-induced asthma by using a double-blind, crossover study design. Twelve patients with aspirin-induced asthma (male:female, 3:9; mean age +/- SD, 36.7 +/- 7.2 years) received either tacrolimus (0.1 mg/kg) or placebo 2 hours before the threshold dose of oral aspirin. In the placebo arm, oral aspirin significantly decreased FEV 1 concomitant with significant increases in sputum eosinophilic cationic protein and urinary leukotriene E(4) levels. Tacrolimus significantly inhibited bronchoconstriction and abrogated aspirin-induced increase in both sputum eosinophilic cationic protein and urinary leukotriene E(4) levels. The current study suggested that tacrolimus inhibited bronchoconstriction to a threshold dose of aspirin by inhibition of cysteinyl leukotriene excretion.

High levels of urinary leukotriene E 4 excretion in steroid treated patients with severe asthma

Urinary LTE 4 reflects the whole body production of the cysteinyl-leukotrienes (LTC 4, LTD 4 and LTE 4) that are established mediators in asthma. The influence of chronic inhaled and oral glucocorticoid treatment on urinary excretion of leukotriene (LT) E 4 was investigated in subjects with asthma. Enzyme immunoassay analysis of LTE 4 was performed in spot urine samples collected from 40 patients with severe asthma, 25 patients with mild–moderate asthma and 20 non-asthmatic control subjects. Urinary LTE 4 was significantly higher in patients with severe asthma (69.7±5.5) as compared to mild–moderate asthma (45.7±3.3 with P<0.0004) and control (42.5±2.5 with P<0.0001). Despite chronic systemic treatment with glucocorticoids, chronically severe asthma had presented with higher levels of LTE 4 compared to mild–moderate asthma and healthy controls. The findings support previous indications that one important component in asthmatic airway inflammation, the cysteinyl-leukotriene pathway remains relatively unopposed by oral glucocorticoids.

Biliary Excretion of Phenolphthalein Sulfate in Rats

Glucuronide and glutathione conjugates have been reported to be substrates of multidrug resistance protein 2 (Mrp2), whereas sulfates of nonbile acid organic anions have never been reported as substrates of Mrp2. To further examine the substrate specificity of Mrp2, we examined the effects of bile acid sulfates on the biliary excretion of phenolphthalein sulfate in rats. The biliary excretion of phenolphthalein sulfate was markedly delayed in Eisai hyperbilirubinemic rats, an Mrp2-deficient strain, and was markedly inhibited by taurolithocholate-3-sulfate. The biliary excretion of leukotriene C₄ metabolites and sulfobromophthalein was inhibited by phenolphthalein sulfate infusion to some extent. These findings suggest that phenolphthalein sulfate is a unique sulfated nonbile acid organic anion which is a substrate of Mrp2.

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Systemic Capillary Leak Syndrome, Leukotrienes, and Anaphylaxis

The association of cysteinyl leukotrienes with plasma exudation allowed the authors to form the hypothesis that rates of leukotriene excretion would be increased in the acute phase of systemic capillary leak syndrome (SCLS) and that leukotriene-modifier therapy would reduce the frequency and severity of life-threatening episodes. The authors report the association of SCLS in 3 cases, 1 with seafood-induced anaphylaxis. Rates of urinary leukotriene excretion were greater during the evolution of an episode than after resolution. In a third case, the rate of urinary leukotriene excretion was significantly higher when symptoms were evolving than when they were absent (230 ± 17 vs 110 ± 6 pg/mg, P &lt; 0.001). Treatment with a leukotriene receptor (cys-LT1) antagonist eliminated episodes in 1 patient. Treatment with the 5-lipoxygenase inhibitor zileuton was completely effective in another patient and prevented life-threatening episodes in the patient with SCLS after seafood exposure. The authors' finding that allergen exposure—associated episodes of SCLS were eliminated by allergen avoidance implies that anaphylaxis can present as SCLS. The acute phase of all 3 forms of SCLS (paraprotein associated, anaphylaxis associated, and idiopathic) is associated with increased excretion of cystinyl leukotrienes, and leukotriene-modifier treatment appears to control the disease.

THE CYSTEINYL LEUKOTRIENE D4 RECEPTOR ANTAGONIST MONTELUKAST FOR THE TREATMENT OF INTERSTITIAL CYSTITIS

The presence of leukotriene D4 receptors in human detrusor myocytes and increased urinary leukotriene E4 in patients with interstitial cystitis and detrusor mastocytosis imply a role for cysteinyl containing leukotrienes as proinflammatory mediators in this disease. We examined the efficacy of the cysteinyl leukotriene 1 receptor antagonist montelukast for treating patients with interstitial cystitis and detrusor mastocytosis. Ten women in whom interstitial cystitis was diagnosed according to National Institute of Diabetes and Digestive and Kidney Diseases criteria and who also had detrusor mastocytosis with a minimum of 28 mast cells per mm.2 muscle tissue were included in this study. Patients received a single dose of montelukast daily for 3 months. The efficacy of treatment was determined by 24-hour urinary frequency, nocturia and pain using visual analog scales. After 1 month of montelukast treatment there was a statistically significant decrease in 24-hour urinary frequency, nocturia and pain which persisted during the 3 months of treatment. After 3 months 24-hour urinary frequency had decreased from 17.4 to 12 voidings (p = 0.009), nocturia had decreased from 4.5 to 2.8 (p = 0.019) and pain had decreased from 46.8 to 19.6 mm. on a visual analog scale (p = 0.006). No side effects were observed during treatment. Montelukast treatment resulted in significant improvement in urinary frequency and pain. Its efficacy for decreasing urinary frequency and pain imply a role of leukotriene receptor antagonists for managing interstitial cystitis but further placebo controlled clinical studies are needed.

Increased urinary excretion of leukotriene E 4 in patients with interstitial cystitis

The cysteinyl-containing leukotrienes (CysLTs) have been implicated in the pathology of inflammatory disorders, in particular asthma. CysLTs role in patients with interstitial cystitis (IC) is unknown. The aim of the present study was to measure the concentration of leukotriene E4 (LTE4) in patients with IC and healthy subjects.

Urinary leukotriene (LT) E 4 in adolescents with dysmenorrhea: a pilot study

In the present study we measured levels of urinary leukotriene (LT) E 4 as an index of LT production during the menstrual cycle in adolescents. Mean urinary LTE 4 levels in girls with dysmenorrhea was approximately threefold higher than normal laboratory values on Day 1 of the menstrual period and approximately twofold higher than normal laboratory values on Day 5 of the menstrual period. Compared with urinary LTE 4 levels in girls with eumenorrhea, urinary LTE 4 levels in girls with dysmenorrhea were higher on Day 1 [361 ± 123 pg/mg creatinine vs. 122 ± 37 pg/mg creatinine, p = .1; not significant (NS)] and on Day 5 (202 ± 26 pg/mg creatinine vs. 117 ± 26 pg/mg creatinine, p < .05) of the menstrual period, as well as on Day 10 (159 ± 33 pg/mg creatinine vs. 88 ± 21 pg/mg creatinine, p = .1; NS) of the menstrual cycle. Increased urinary excretion of leukotrienes, inflammatory mediators known to cause potent vasoconstriction and uterine contractions, in girls with dysmenorrhea in this pilot study, suggests that these mediators may be involved in generating dysmenorrhea symptoms in adolescents.

Enhanced urinary excretion of cysteinyl leukotrienes in patients with acute alcohol intoxication

Background & Aims: Leukotrienes are proinflammatory mediators. Ethanol inhibits the catabolism of both cysteinyl leukotrienes (leukotriene E 4 [LTE 4] and N-acetyl-LTE 4) and leukotriene B 4 (LTB 4) in hepatocytes. We examined the metabolic derangement of leukotriene inactivation by ethanol in humans in vivo. Methods: LTE 4, N-acetyl-LTE 4, LTB 4, and 20-hydroxy-LTB 4 were quantified in urine samples from 16 patients with acute alcohol intoxication (mean blood ethanol, 75 mmol/L). In 9 healthy volunteers, urinary LTE 4 was determined before and after ethanol consumption (mean blood ethanol, 14 mmol/L). Results: The excretion of LTE 4 during alcohol intoxication was 286 compared with 36 nmol/mol creatinine in healthy subjects ( P < 0.01); the corresponding values for N-acetyl-LTE 4 were 101 and 11 nmol/mol creatinine, respectively ( P < 0.001). This excretion of cysteinyl leukotrienes decreased when the blood ethanol concentration returned to normal. LTB 4 and 20-hydroxy-LTB 4 were detectable only in patients with excessive blood ethanol concentrations (mean, 95 mmol/L). In healthy volunteers, LTE 4 excretion increased 3-5 hours after ethanol consumption (mean peak concentration of 1.5 nmol/L compared with 0.5 nmol/L for basal values; P < 0.005). Conclusions: Ethanol at high concentration induces increased leukotriene excretion into urine. These changes are consistent with inhibition of leukotriene catabolism and inactivation induced by ethanol, as well as with a higher leukotriene formation caused by ethanol-induced endotoxemia. GASTROENTEROLOGY 2000;118:1140-1148

Defective inactivation of leukotriene B4 in patients with Sjo ̈gren-Larsson syndrome

In 6 patients with Sjögren-Larsson syndrome (SLS), the urinary excretion of leukotriene B 4 (LTB 4) and ω-hydroxy-LTB 4 was found to be highly elevated, whereas ω-carboxy-LTB 4 was absent. This abnormal pattern of urinary excretion of LTB 4 and its metabolites appears to be unique to patients with SLS and offers a new approach to the diagnosis of this disorder. Moreover, defective inactivation of LTB 4 might be of pathophysiologic significance in the disease. (J Pediatr 2000;136:258-60)

Expression and regulation of leukotriene-synthesis enzymes in rat liver cells.

The liver plays a major role in metabolism and elimination of leukotrienes (LT). It produces cysteinyl leukotrienes (cLT), and cLT have been implicated in hepatocellular toxicity in several models of lipopolysaccharide (LPS)-associated liver injury. However, the liver cell types responsible for cLT production are poorly defined, and the expression of the LT-synthesis enzymes, 5-lipoxygenase (5-LO) and LTC4 synthase (LTC4-S), in liver cells has never been demonstrated. The aim of the present study was to examine the ability of rat liver cells to produce cLT by determining whether hepatocytes, Kupffer cells, and sinusoidal endothelial cells express mRNA and enzyme activities of the LT-synthesis enzymes and whether expression is altered by LPS. 5-LO mRNA was expressed in whole liver, and expression was enhanced by LPS. Cell fractionation studies demonstrated that expression was present in Kupffer cells and sinusoidal endothelial cells, but not in hepatocytes. LTC4-S mRNA was detected in whole liver, hepatocytes, and sinusoidal endothelial cells, but not in Kupffer cells. Semiquantitative reverse-transcriptase polymerase chain reaction (RT-PCR) showed that LPS increased LTC4-S expression in hepatocytes by a factor of 3 (n = 3; P < .03). LTC4-S enzyme activity in the microsomal fraction of hepatocytes was also increased from 0.52 +/- 0.13 to 1.90 +/- 0.66 nmol . mg protein-1 . 5 min-1 (n = 6; P < .015) after LPS treatment. These results indicate that hepatocytes do not possess the ability for de novo synthesis of cLT from arachidonic acid, but they may actively participate in cLT production by conjugation of LTA4 with glutathione to produce LTC4. LPS enhances LTC4-S expression in hepatocytes. This intrinsic cLT production may contribute to hepatocellular injury during inflammation.