Cannabinoid receptor antagonist-induced striated muscle toxicity and ethylmalonic-adipic aciduria in beagle dogs.

Abstract

Ibipinabant (IBI), a potent cannabinoid-1 receptor (CB1R) antagonist, previously in development for the treatment of obesity, causes skeletal and cardiac myopathy in beagle dogs. This toxicity was characterized by increases in muscle-derived enzyme activity in serum and microscopic striated muscle degeneration and accumulation of lipid droplets in myofibers. Additional changes in serum chemistry included decreases in glucose and increases in non-esterified fatty acids and cholesterol, and metabolic acidosis, consistent with disturbances in lipid and carbohydrate metabolism. No evidence of CB1R expression was detected in dog striated muscle as assessed by polymerase chain reaction, immunohistochemistry, Western blot analysis, and competitive radioligand binding. Investigative studies utilized metabonomic technology and demonstrated changes in several intermediates and metabolites of fatty acid metabolism including plasma acylcarnitines and urinary ethylmalonate, methylsuccinate, adipate, suberate, hexanoylglycine, sarcosine, dimethylglycine, isovalerylglycine, and 2-hydroxyglutarate. These results indicated that the toxic effect of IBI on striated muscle in beagle dogs is consistent with an inhibition of the mitochondrial flavin-containing enzymes including dimethyl glycine, sarcosine, isovaleryl-CoA, 2-hydroxyglutarate, and multiple acyl-CoA (short, medium, long, and very long chain) dehydrogenases. All of these enzymes converge at the level of electron transfer flavoprotein (ETF) and ETF oxidoreductase. Urinary ethylmalonate was shown to be a biomarker of IBI-induced striated muscle toxicity in dogs and could provide the ability to monitor potential IBI-induced toxic myopathy in humans. We propose that IBI-induced toxic myopathy in beagle dogs is not caused by direct antagonism of CB1R and could represent a model of ethylmalonic-adipic aciduria in humans.

• Authors: Lindsay Tomlinson, Mark A Tirmenstein, Evan B Janovitz, Nelly Aranibar, Karl-Heinz Ott, John C Kozlosky, Laura M Patrone, William E Achanzar, Karen A Augustine, Kimberly C Brannen, Kenneth E Carlson, Jeffrey H Charlap, Katherine M Dubrow, Liya Kang, Laura T Rosini, Julieta M Panzica-Kelly, Oliver P Flint, Frederic J Moulin, John R Megill, Haiying Zhang, Michael J Bennett, Joseph J Horvath
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 129 Issue 2 Pg. 268-79 (Oct 2012) ISSN: 1096-0929 [Electronic] United States
• PMID: 22821849 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adipates
• DNA Primers
• Malonates
• Receptor, Cannabinoid, CB1
• ethylmalonic acid
• Carnitine

Topics

• Adipates (urine)
• Animals
• Base Sequence
• Blotting, Western
• Carnitine (blood)
• DNA Primers
• Dogs
• Female
• Gene Expression Profiling
• Immunohistochemistry
• Malonates (urine)
• Metabolomics
• Muscle, Skeletal (drug effects)
• Polymerase Chain Reaction
• Radioligand Assay
• Receptor, Cannabinoid, CB1 (antagonists & inhibitors, genetics)