Hepatic uptake and metabolic disposition of leukotriene B4 in rats

Hagmann, Wolfgang; Körte, Martin

doi:10.1042/bj2670467

Cited by 18 publications

(7 citation statements)

References 46 publications

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“…When rats were injected with radiolabeled LTB 4 , both bile and urine were found to contain metabolites. The bile contained 20 -25% of the injected radioactivity, whereas the urine contained less than 10% of the injected dose (33). Reversed phase HPLC analysis of the bile and urine revealed that most metabolites were less lipophilic than LTB 4 ; however, structural identification of these metabolites was not reported.…”

Section: Discussionmentioning

confidence: 92%

Urinary Metabolites of Leukotriene B4 in the Human Subject

Berry

Borgeat²,

Gosselin³

et al. 2003

Journal of Biological Chemistry

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Leukotriene B 4 (LTB 4 ) is a potent chemoattractant for neutrophils and is thought to play a role in a variety of inflammatory responses in humans. The metabolism of LTB 4 in vitro is complex with several competing pathways of biotransformation, but metabolism in vivo, especially for normal human subjects, is poorly understood. As part of a Phase I Clinical Trial of human tolerance to LTB 4 , four human subjects were injected with 150 nmol/kg LTB 4 with one additional subject as placebo control. The urine of the subjects was collected in two separate pools (0 -6 and 7-24 h), and aliquots from these urine collections were analyzed using high performance liquid chromatography, UV spectroscopy, and negative ion electrospray ionization tandem mass spectrometry for metabolites of LTB 4 . In the current investigation, 11 different metabolites of LTB 4 were identified in the urine from those subjects injected with LTB 4 , and none were present in the urine from the placebo-injected subject. The unconjugated LTB 4 metabolites found in urine were structurally characterized as 18-carboxy-LTB 4 , 10,11-dihydro-18-carboxy-LTB 4 , 20-carboxy-LTB 4 , and 10,11-dihydro-20-carboxy-LTB 4 . Several glucuronide-conjugated metabolites of LTB 4 were characterized including 17-, 18-, 19-, and 20-hydroxy-LTB 4 , 10-hydroxy-4,6,12-octadecatrienoic acid, LTB 4 , and 10,11-dihydro-LTB 4 . The amount of LTB 4 glucuronide (16.7-29.4 pmol/ml) and 20-carboxy-LTB 4 (18.9 -30.6 pmol/ml) present in the urine of subjects injected with LTB 4 was determined using an isotope dilution mass spectrometric assay before and after treatment of the urine samples with ␤-glucuronidase. The urinary metabolites of LTB 4 identified in this investigation were excreted in low amounts, yet it is possible that one or more of these metabolites could be used to assess LTB 4 biosynthesis following activation of the 5-lipoxygenase pathway in vivo.Leukotriene B 4 (LTB 4 , 1 (5S,12R)-dihydroxy-6,14Z-8,10E-eicosatetraenoic acid) is a biologically active metabolite of arachidonic acid that is chemotactic for the human neutrophil and a potent lipid mediator of inflammation (1). LTB 4 is not stored within a cell but synthesized following activation of certain cells through release of arachidonic acid by the cytosolic phospholipase A 2 (2) and activation of the enzyme 5-lipoxygenase (3). The immediate product of the 5-lipoxygenase pathway is the reactive epoxide intermediate leukotriene A 4 that is transformed by leukotriene A 4 hydrolase into LTB 4 (4). A specific G-protein-coupled receptor for LTB 4 has now been cloned and expressed (5) and is known to be expressed by many cell types including the neutrophil (6). Through this receptor, LTB 4 is a potent stimulus of many functional responses of cells that are involved in immune responses (7) such as neutrophils, monocytes, macrophages, and various lymphocytes. LTB 4 is therefore thought to be an important component of the host defense mechanisms and is currently under investigation as a potent drug for the prophylaxis and/...

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Section: Discussionmentioning

confidence: 92%

Urinary Metabolites of Leukotriene B4 in the Human Subject

Berry

Borgeat²,

Gosselin³

et al. 2003

Journal of Biological Chemistry

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“…Although leukocytes, especially neutrophils, are known to efficiently catalyze the degradation and inactivation of LTB 4 , the role of the liver would also be of major importance, since this tissue is also responsible for the elimination of LA and AA metabolites released into systemic circulation (48)(49)(50).…”

Section: Discussionmentioning

confidence: 99%

Glucuronidation of arachidonic and linoleic acid metabolites by human UDP-glucuronosyltransferases

Turgeon

Chouinard

Bélanger

et al. 2003

Journal of Lipid Research

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Arachidonic acids (AA) and linoleic acids (LAs) are metabolized, in several tissues, to hydroxylated metabolites that are important mediators of many physiological and pathophysiological processes. The conjugation of leukotriene B 4 (LTB 4 ), 5-hydroxyeicosatetraenoic acid (HETE), 12-HETE, 15-HETE, and 13-hydroxyoctadecadienoic acid (HODE) by the human UDP-glucuronosyltransferase (UGT) enzymes was investigated. All substrates tested were efficiently conjugated by human liver microsomes to polar derivatives containing the glucuronyl moiety as assessed by mass spectrometry. The screening analyses with stably expressed UGT enzymes in HK293 showed that glucuronidation of LTB 4 was observed with UGT1A1, UGT1A3, UGT1A8, and UGT2B7, whereas UGT1A1, UGT1A3, UGT1A4, and UGT1A9 also conjugated most of the HETEs and 13-HODE. LA and AA metabolites also appear to be good substrates for the UGT2B subfamily members, especially for UGT2B4 and UGT2B7 that conjugate all HETE and 13-HODE. Interestingly, UGT2B10 and UGT2B11, which are considered as orphan enzymes since no conjugation activity has so far been demonstrated with these enzymes, conjugated 12-HETE, 15-HETE, and 13-HODE. In summary, our data showed that several members of UGT1A and UGT2B families are capable of converting LA and AA metabolites into glucuronide derivatives, which is considered an irreversible step to inactivation and elimination of endogenous substances from the body. -Turgeon, D., S. Chouinard, P. Bélanger, S. Picard, J-F. Labbé, P. Borgeat, and A. Bélanger. Glucuronidation of arachidonic and linoleic acid metabolites by human UDPglucuronosyltransferases. J. Lipid Res. 2003. 44: 1182-1191.

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“…These studies suggest that metabolism in the liver and kidney may be important in the regulation of LTB4 levels in vivo. Accordingly, evaluation of the metabolic disposition of LTB4 in vivo confirmed extensive P-oxidation of LTB4 in the monkey and the rabbit (Serafin et al, 1984) and intrahepatic a-oxidation followed by Poxidation from the Q-end in the rat (Hagmann & Korte, 1990), leading mainly to the production of volatile derivatives, with no intact LTB4 detected in the bile or the urine. In the present study, we provide a detailed kinetic analysis of LTB4 in conscious rabbits after single i.v.…”

Section: Introductionmentioning

confidence: 88%

“…Previous studies on the metabolism of LTB4 in vitro and in vivo (Harper et al, 1986;Hagmann & Korte, 1990) have suggested that 0-and P-oxidation-resistant analogues of LTB4 might be protected from rapid degradation in vivo. Our results show that, despite its in vitro a-oxidation resistant property (Tanaka et al, 1988), 20-F3-LTB4 is rapidly and efficiently removed from the circulation after a single i.v.…”

Section: Disposition Of Ltb4 Analoguesmentioning

confidence: 98%

Metabolic disposition of leukotriene B₄ (LTB4) and oxidation‐resistant analogues of LTB4 in conscious rabbits

Marleau

Dallaire

Poubelle

et al. 1994

British J Pharmacology

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1 The kinetics of leukotriene B4 (LTB4), after single i.v. injections of doses of 0.1 to 1 fig kg-', were investigated in conscious rabbits and compared with those of the Q-and 13-oxidation resistant bioactive analogues, 20, 20, 0.53 ± 0.03 min, and an apparent Vd of 85 ± 9 ml kg-, similar to the parameters obtained after LTB4 boluses.5 The disposition of LTB4 analogues, whether resistant to a-or to P-oxidation in vitro, did not differ significantly from the disposition of the LTB4 molecule. The half-lives of 20-F3-LTB4 and 3-thio-LTB4 in the circulation were 0.52 ± 0.07 min and 0.70 ± 0.11 min, respectively. 6 In summary, our results showed that LTB4, as well as a-oxidation-and P-oxidation-resistant analogues were cleared very rapidly from the rabbit circulation and indicate that in situ, metabolism in blood is not a rate-limiting factor for the elimination of LTB4.

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Hepatic uptake and metabolic disposition of leukotriene B4 in rats

Cited by 18 publications

References 46 publications

Urinary Metabolites of Leukotriene B4 in the Human Subject

Urinary Metabolites of Leukotriene B4 in the Human Subject

Glucuronidation of arachidonic and linoleic acid metabolites by human UDP-glucuronosyltransferases

Metabolic disposition of leukotriene B₄ (LTB4) and oxidation‐resistant analogues of LTB4 in conscious rabbits

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Hepatic uptake and metabolic disposition of leukotriene B4 in rats

Cited by 18 publications

References 46 publications

Urinary Metabolites of Leukotriene B4 in the Human Subject

Urinary Metabolites of Leukotriene B4 in the Human Subject

Glucuronidation of arachidonic and linoleic acid metabolites by human UDP-glucuronosyltransferases

Metabolic disposition of leukotriene B4 (LTB4) and oxidation‐resistant analogues of LTB4 in conscious rabbits

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Metabolic disposition of leukotriene B₄ (LTB4) and oxidation‐resistant analogues of LTB4 in conscious rabbits