Lipidosis Induced in the Dog Gallbladder by a Direct 5-Lipoxygenase Inhibitor

Molon-Noblot, Sylvain; Gillet, J.; Durand-Cavagna, G.; Huber, Alice; Patrick, Darryl; Duprat, Pierre

doi:10.1177/019262339602400211

Cited by 8 publications

(4 citation statements)

References 21 publications

(16 reference statements)

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“…While L-739,010 caused a dose-dependent elevation in alanine transaminase levels in dogs, suggesting that it induced hepatotoxicity, 116 histopathological analysis showed no indication of liver toxicity. 117 It initiated lipidosis in the gall bladder. 117 Binding of L-739,010 to proteins requires metabolism.…”

Section: -Substituted Furansmentioning

confidence: 99%

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Reactive Metabolites in the Biotransformation of Molecules Containing a Furan Ring

Peterson

2012

Chem. Res. Toxicol.

173

160

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Many xenobiotics containing a furan ring are toxic and/or carcinogenic. The harmful effects of these compounds require furan ring oxidation. This reaction generates an electrophilic intermediate. Depending on the furan ring substituents, the intermediate is either an epoxide or a cis-enedione with more ring substitution favoring epoxide formation. Either intermediate reacts with cellular nucleophiles such as protein or DNA to trigger toxicities. The reactivity of the metabolite determines which cellular nucleophiles are targeted. The toxicity of a particular furan is also influenced by the presence of competing metabolic pathways or efficient detoxification routes. GSH plays an important role in modulating the harmful effects of this class of compound by reacting with the reactive metabolite. However, this may not represent a detoxification step in all cases.

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Section: -Substituted Furansmentioning

confidence: 99%

“…117 It initiated lipidosis in the gall bladder. 117 Binding of L-739,010 to proteins requires metabolism. Incubation of L-739,010 with liver microsomes results in the NADPHdependent loss of the parent compound without significant formation of detectable metabolites.…”

Section: -Substituted Furansmentioning

confidence: 99%

Reactive Metabolites in the Biotransformation of Molecules Containing a Furan Ring

Peterson

2012

Chem. Res. Toxicol.

173

160

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“…Microsomal metabolism studies on L-739,010have revealed the formation of reactive intermediates at both the dioxabicyclooctanyl group and the furan ring . (b) In preclinical animal toxicity studies, 3g has shown induction of lipidosis in the dog gallbladder …”

Section: Referencesmentioning

confidence: 99%

Substituted (Pyridylmethoxy)naphthalenes as Potent and Orally Active 5-Lipoxygenase Inhibitors: Synthesis, Biological Profile, and Pharmacokinetics of L-739,010

et al. 1997

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Dioxabicyclooctanyl naphthalenenitriles have been reported as a class of potent and nonredox 5-lipoxygenase (5-LO) inhibitors. These bicyclo derivatives were shown to be metabolically more stable than their tetrahydropyranyl counterparts but were not well orally absorbed. Replacement of the phenyl ring in the naphthalenenitrile 1 by a pyridine ring leads to the potent and orally absorbed inhibitor 3g (L-739,010, 2-cyano-4-(3-furyl)-7-[[6-[3-(3-hydroxy-6,8-dioxabicyclo[3.2.1] octanyl)]-2-pyridyl]methoxy]naphthalene). Compound 3g inhibits 5-HPETE production by human 5-LO and LTB4 biosynthesis by human PMN leukocytes and human whole blood (IC50S of 20, 1.6, and 42 nM, respectively). Derivative 3g is orally active in the rat pleurisy model (inhibition of LTB4, ED50 = 0.3 mg/kg) and in the anesthetized dog model (inhibition of ex vivo whole blood LTB4 and urinary LTE4, ED50 = 0.45 and 0.23 microgram/kg/min, respectively, i.v. infusion). In addition, 3g shows excellent functional activity against ovalbumin-induced dyspnea in rats (60% inhibition at 0.5 mg/kg, 4 h pretreatment) and Ascaris-induced bronchoconstriction in conscious sheep (50% and > 85% inhibition in early and late phases, respectively at 2.5 micrograms/kg/min, i.v. infusion) and, more particularly in the conscious antigen sensitive squirrel monkey model (53% inhibition of the increase in RL and 76% in the decrease of Cdyn, at 0.1 mg/kg, po). In rats and dogs, 3g presents excellent pharmacokinetics (estimated half-lives of 5 and 16 h, respectively) and bioavailabilities (26% and 73% when dosed as its hydrochloride salt at doses of 20 and 10 mg/kg, respectively, in methocel suspension). Based on its overall biological profile, compound 3g has been selected for preclinical animal toxicity studies.

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“…Future studies designed to examine changes in the plasma lipidome and gallbladder lipid over the course of mucocele development may shed further light on this relationship. Prior descriptions of the ultrastructural appearance of canine gallbladder epithelium are infrequent [18,[28][29][30] but include a toxicology study reporting gallbladder epithelial lipidosis in dogs treated with an inhibitor of leukotriene…”

Section: Plos Onementioning

confidence: 99%

Increased lipogenesis and lipidosis of gallbladder epithelium in dogs with gallbladder mucocele formation

Gookin,

Jewell,

Aicher

et al. 2024

PLoS ONE

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Background Gallbladder disease in people is frequently associated with disorders of lipid metabolism and metabolic syndrome. A recently emergent gallbladder disease of dogs, referred to as mucocele formation, is characterized by secretion of abnormal mucus by the gallbladder epithelium and is similarly associated with hyperlipidemia, endocrinopathy, and metabolic dysfunction. The cause of gallbladder mucocele formation in dogs is unknown. Methods A prospective case-controlled study was conducted to gain insight into disease pathogenesis by characterization of plasma lipid abnormalities in 18 dogs with gallbladder mucocele formation and 18 age and breed matched control dogs using direct infusion mass spectrometry for complex plasma lipid analysis. This analysis was complemented by histochemical and ultrastructural examination of gallbladder mucosa from dogs with gallbladder mucocele formation and control dogs for evidence of altered lipid homeostasis of the gallbladder epithelium. Results Gallbladder mucocele formation in dogs carried a unique lipidomic signature of increased lipogenesis impacting 50% of lipid classes, 36% of esterified fatty acid species, and 11% of complex lipid species. Broad enrichment of complex lipids with palmitoleic acid (16:1) and decreased abundance within complex lipids of presumptive omega-3 fatty acids eicosapentaenoic (20:5) and docosahexaenoic (22:6) was significant. Severe lipidosis of gallbladder epithelium pinpoints the gallbladder as involved causally or consequently in abnormal lipid metabolism. Conclusion Our study supports a primary increase in lipogenesis in dogs with mucocele formation and abnormal gallbladder lipid metabolism in disease pathogenesis.

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Lipidosis Induced in the Dog Gallbladder by a Direct 5-Lipoxygenase Inhibitor

Abstract: The direct 5-lipoxygenase inhibitor L-739,010

Cited by 8 publications

References 21 publications

Reactive Metabolites in the Biotransformation of Molecules Containing a Furan Ring

Reactive Metabolites in the Biotransformation of Molecules Containing a Furan Ring

Substituted (Pyridylmethoxy)naphthalenes as Potent and Orally Active 5-Lipoxygenase Inhibitors: Synthesis, Biological Profile, and Pharmacokinetics of L-739,010

Increased lipogenesis and lipidosis of gallbladder epithelium in dogs with gallbladder mucocele formation

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