Bile acid composition of dog and cat gall-bladder bile.

Washizu, Tsukimi; Ikenaga, Hidenori; Washizu, Makoto; Ishida, Takuo; Tomoda, Isamu; Kaneko, Jun

doi:10.1292/jvms1939.52.423

Cited by 38 publications

(23 citation statements)

References 1 publication

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“…First, the rate of bile flow (normalized against body weights) is approximately 7-fold higher in rats than dogs (Davies and Morris, 1993). Second, while rats and dogs predominantly have taurine-conjugated BAs, their respective BA pools have different compositions (Suzuki et al , 2013; Washizu et al , 1990). And finally, rats naturally have very high levels of BSEP activity (Jemnitz et al , 2010) that may have made them less susceptible to TAK-875-mediated transporter inhibition.…”

Section: Discussionmentioning

confidence: 99%

Fasiglifam (TAK-875) alters bile acid homeostasis in rats and dogs: a potential cause of drug induced liver injury

et al. 2017

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Fasiglifam (TAK-875), a Free Fatty Acid Receptor 1 (FFAR1) agonist in development for the treatment of type 2 diabetes, was voluntarily terminated in phase 3 due to adverse liver effects. A mechanistic investigation described in this manuscript focused on the inhibition of bile acid (BA) transporters as a driver of the liver findings. TAK-875 was an in vitro inhibitor of multiple influx (NTCP and OATPs) and efflux (BSEP and MRPs) hepatobiliary BA transporters at micromolar concentrations. Repeat dose studies determined that TAK-875 caused a dose-dependent increase in serum total BA in rats and dogs. Additionally, there were dose-dependent increases in both unconjugated and conjugated individual BAs in both species. Rats had an increase in serum markers of liver injury without correlative microscopic signs of tissue damage. Two of 6 dogs that received the highest dose of TAK-875 developed liver injury with clinical pathology changes, and by microscopic analysis had portal granulomatous inflammation with neutrophils around a crystalline deposition. The BA composition of dog bile also significantly changed in a dose-dependent manner following TAK-875 administration. At the highest dose, levels of taurocholic acid were 50% greater than in controls with a corresponding 50% decrease in taurochenodeoxycholic acid. Transporter inhibition by TAK-875 may cause liver injury in dogs through altered bile BA composition characteristics, as evidenced by crystalline deposition, likely composed of test article, in the bile duct. In conclusion, a combination of in vitro and in vivo evidence suggests that BA transporter inhibition could contribute to TAK-875-mediated liver injury in dogs.

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Section: Discussionmentioning

confidence: 99%

Fasiglifam (TAK-875) alters bile acid homeostasis in rats and dogs: a potential cause of drug induced liver injury

et al. 2017

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“…Cats also have a markedly higher physiological demand for taurine, characterised by an obligate loss of taurine in bile. In contrast to other animals, cats do not use glycine, but rely almost exclusively on taurine to conjugate bile acids into bile salts, regardless of the dietary taurine level [52,53]. Furthermore, free taurine is wasted substantially, as deconjugation of taurine-conjugated bile salt and enterohepatic recovery is limited [54].…”

Section: Feline-specific Metabolic Featuresmentioning

confidence: 99%

Peculiarities of One-Carbon Metabolism in the Strict Carnivorous Cat and the Role in Feline Hepatic Lipidosis

Verbrugghe

Bakovic

2013

Nutrients

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Research in various species has indicated that diets deficient in labile methyl groups (methionine, choline, betaine, folate) produce fatty liver and links to steatosis and metabolic syndrome, but also provides evidence of the importance of labile methyl group balance to maintain normal liver function. Cats, being obligate carnivores, rely on nutrients in animal tissues and have, due to evolutionary pressure, developed several physiological and metabolic adaptations, including a number of peculiarities in protein and fat metabolism. This has led to specific and unique nutritional requirements. Adult cats require more dietary protein than omnivorous species, maintain a consistently high rate of protein oxidation and gluconeogenesis and are unable to adapt to reduced protein intake. Furthermore, cats have a higher requirement for essential amino acids and essential fatty acids. Hastened use coupled with an inability to conserve certain amino acids, including methionine, cysteine, taurine and arginine, necessitates a higher dietary intake for cats compared to most other species. Cats also seemingly require higher amounts of several B-vitamins compared to other species and are predisposed to depletion during prolonged inappetance. This carnivorous uniqueness makes cats more susceptible to hepatic lipidosis.

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“…Thus besides endogenous sythetized taurine, an exogenous pool of transported taurine is used directly for conjugation. The cat is the animal best known to rely almost exclusively on taurine for bile acid conjugation, regardless of the dietary concentration of taurine (Rabin et al 1976;Washizu et al 1990). This animal lacks the ability to respond to changes in dietary concentrations of taurine and glycine by altering the ratio of the bile acid conjugates (Baker and Czarnecki-Maulden 1991).…”

Section: Hepatocellular Uptake Of Cysteine Sulfinate and Taurinementioning

confidence: 99%

Transport of organic anions in the liver. An update on bile acid, fatty acid, monocarboxylate, anionic amino acid, cholephilic organic anion, and anionic drug transport

Petzinger¹

1994

Reviews of Physiology, Biochemistry and Pharmacology

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Bile acid composition of dog and cat gall-bladder bile.

Cited by 38 publications

References 1 publication

Fasiglifam (TAK-875) alters bile acid homeostasis in rats and dogs: a potential cause of drug induced liver injury

Fasiglifam (TAK-875) alters bile acid homeostasis in rats and dogs: a potential cause of drug induced liver injury

Peculiarities of One-Carbon Metabolism in the Strict Carnivorous Cat and the Role in Feline Hepatic Lipidosis

Transport of organic anions in the liver. An update on bile acid, fatty acid, monocarboxylate, anionic amino acid, cholephilic organic anion, and anionic drug transport

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