Binding of [<sup>3</sup>H]palmitate to BSA

Elmadhoun, B; Wang, G. Q.; Templeton, J. F.; Burczynski, Frank J.

doi:10.1152/ajpgi.1998.275.4.g638

Cited by 27 publications

(37 citation statements)

References 23 publications

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“…Earlier studies used conditions Values are means Ϯ SD; n ϭ 6 rats. CLint, palmitate metabolic clearance; PS, permeability surface area product; PS ϭ kin VE/fu, where fu is the fraction unbound in perfusate from Elmadhoun et al (13), assuming that only unbound drug penetrates hepatocytes; very large values for PS in this work are due to the very small value for fu of 3.75 ϫ 10 Ϫ5 . kin, influx constant; kout, elimination rate constant; kd, cytoplasmic diffusion constant.…”

Section: Discussionmentioning

confidence: 94%

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Fatty acid binding protein is a major determinant of hepatic pharmacokinetics of palmitate and its metabolites

Hung

Burczynski

Chang

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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kinetics of [ 3 H]palmitate and its low-molecular-weight metabolites in perfused rat livers were studied using the multiple-indicator dilution technique, a selective assay for [ 3 H]palmitate and its low-molecular-weight metabolites, and several physiologically based pharmacokinetic models. The level of liver fatty acid binding protein (L-FABP), other intrahepatic binding proteins (microsomal protein, albumin, and glutathione S-transferase) and the outflow profiles of [ 3 H]palmitate and metabolites were measured in four experimental groups of rats: 1) males; 2) clofibrate-treated males; 3) females; and 4) pregnant females. A slow-diffusion/bound model was found to better describe the hepatic disposition of unchanged [3 H]palmitate than other pharmacokinetic models. The L-FABP levels followed the order: pregnant female Ͼ clofibrate-treated male Ͼ female Ͼ male. Levels of other intrahepatic proteins did not differ significantly. The hepatic extraction ratio and mean transit time for unchanged palmitate, as well as the production of low-molecular-weight metabolites of palmitate and their retention in the liver, increased with increasing L-FABP levels. Palmitate metabolic clearance, permeability-surface area product, retention of palmitate by the liver, and cytoplasmic diffusion constant for unchanged [3 H]palmitate also increased with increasing L-FABP levels. It is concluded that the variability in hepatic pharmacokinetics of unchanged [ 3 H]palmitate and its lowmolecular-weight metabolites in perfused rat livers is related to levels of L-FABP and not those of other intrahepatic proteins.clofibrate; pregnancy; multiple indicator dilution; hepatic extraction ratio; cytoplasmic diffusion constant NONESTERIFIED, LONG-CHAIN fatty acids (hereafter referred to as fatty acids) play a vital role in many cellular processes. They are an important source for cellular energy and form the building blocks from which various cellular components are synthesized. Some fatty acids are precursors for biological mediators, whereas others may interact with the cell membrane to regulate various cellular functions. Uptake of fatty acids has been shown to parallel the level of liver fatty acid binding protein (L-FABP) (22).L-FABP levels are known to be gender dependent, with females showing higher levels than males (25). L-FABP is also altered in various conditions, such as pregnancy and clofibrate treatment (6,26,31). Although the variation in the content of various intrahepatic proteins in liver disease has been used to account for the uptake, binding, and metabolism of solutes (20), the influence of intrahepatic proteins other than L-FABP [e.g., microsomal protein (MP), cytochrome P-450 (CYP), albumin (Alb), and glutathione S-transferase (GST)] on the hepatic disposition of [ 3 H]palmitate has been studied to a limited extent. Most studies investigating the fatty acid uptake into the liver have used isolated hepatocytes with some studies using intact livers (26,38).In this work, we examined the relationship between the hepatic pharma...

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Section: Discussionmentioning

confidence: 94%

“…All chemicals including fatty acid-free Alb and clofibrate were purchased from Sigma (St. Louis, MO [ 3 H]palmitic acid was purified by the Borgstrom ethanol extraction procedure as previously described (13). Neutral organic impurities were removed by extracting the aqueous [ 3 H]palmitic acid several times with heptane.…”

Section: Methodsmentioning

confidence: 99%

Fatty acid binding protein is a major determinant of hepatic pharmacokinetics of palmitate and its metabolites

Hung

Burczynski

Chang

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…]palmitic acid was purified by the Borgstrom ethanol extraction procedure as previously described (8).…”

Section: Methodsmentioning

confidence: 99%

Reduced hepatic extraction of palmitate in steatosis correlated to lower level of liver fatty acid binding protein

Hung

Siebert²,

Chang³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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3 H]palmitate and its low-molecular-weight metabolites in perfused normal and steatotic rat liver were studied using the multiple indicator dilution technique and a physiologically based slow diffusion/bound pharmacokinetic model. The steatotic rat model was established by administration of 17␣-ethynylestradiol to female Wistar rats. Serum biochemistry markers and histology of treated and normal animals were assessed and indicated the presence of steatosis in the treatment group. The steatotic group showed a significantly higher alanine aminotransferaseto-aspartate aminotransferase ratio, lower levels of liver fatty acid binding protein and cytochrome P-450, as well as microvesicular steatosis with an enlargement of sinusoidal space. Hepatic extraction for unchanged [ 3 H]palmitate and production of low-molecular-weight metabolites were found to be significantly decreased in steatotic animals. Pharmacokinetic analysis suggested that the reduced extraction and sequestration for palmitate and its metabolites was mainly attributed to a reduction in liver fatty acid binding protein in steatosis.17␣-ethynylestradiol; hepatic palmitate disposition NONALCOHOLIC FATTY LIVER DISEASE is increasingly recognized as a major health burden and probably the most common of all liver disorders (10,22). The prevalence of excessive hepatic fat accumulation in the general population in the United States and other Western countries has been estimated to be 20 -30% (19,22,23). In the majority of cases, the condition does not develop into more severe liver disease, although ϳ20 -30% of patients at the time of diagnosis show signs of steatohepatitis and are consequently at a higher risk to progress to cirrhosis, liver failure, or hepatocellular hepatoma (1a, 6, 25). The effects of excess of intracellular fatty acid concentrations, oxidant stress, ATP depletion, and mitochondrial dysfunction apparently all contribute in different ways to the subsequent hepatocellular injury, but mitochondrial dysfunction is thought to play an especially important role in the development of the condition (23).A question remains, however, as to what are the physiological and metabolic changes occurring in the very early (and undiagnosed) stages of fatty liver disease. To date, the hepatic kinetics-associated free fatty acid disposition and metabolism in the presence of lipid deposits in hepatic tissue has been poorly characterized. We have recently related the hepatic disposition kinetics of palmitate and its low-molecular-weight metabolites with a number of quantitative parameters defining different pathological liver conditions using an in situ rat liver perfusion study (12). In the present study, we sought to examine whether the kinetics of palmitate were affected by fatty liver disease in the rat. In doing so, we also collected a range of biochemical and histological parameters to examine possible correlations. Steatosis in rats was induced by administration of 17␣-ethinylestradiol (30). Also, we sought to mimic the hepatic fatty acid accumulation and ...

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“…In plasma, long-chain fatty acids are strongly bound to circulating albumin [6,7], and FAs form high-affinity complexes with albumin to facilitate their solubility and transport in aqueous solution [8]. Albumin is composed of a single polypeptide chain that folds to form three or four spherical units.…”

Section: Introductionmentioning

confidence: 99%

The lipopolysaccharide-induced pro-inflammatory response in RAW264.7 cells is attenuated by an unsaturated fatty acid–bovine serum albumin complex and enhanced by a saturated fatty acid–bovine serum albumin complex

et al. 2011

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Binding of [³H]palmitate to BSA

Cited by 27 publications

References 23 publications

Fatty acid binding protein is a major determinant of hepatic pharmacokinetics of palmitate and its metabolites

Fatty acid binding protein is a major determinant of hepatic pharmacokinetics of palmitate and its metabolites

Reduced hepatic extraction of palmitate in steatosis correlated to lower level of liver fatty acid binding protein

The lipopolysaccharide-induced pro-inflammatory response in RAW264.7 cells is attenuated by an unsaturated fatty acid–bovine serum albumin complex and enhanced by a saturated fatty acid–bovine serum albumin complex

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Binding of [3H]palmitate to BSA

Cited by 27 publications

References 23 publications

Fatty acid binding protein is a major determinant of hepatic pharmacokinetics of palmitate and its metabolites

Fatty acid binding protein is a major determinant of hepatic pharmacokinetics of palmitate and its metabolites

Reduced hepatic extraction of palmitate in steatosis correlated to lower level of liver fatty acid binding protein

The lipopolysaccharide-induced pro-inflammatory response in RAW264.7 cells is attenuated by an unsaturated fatty acid–bovine serum albumin complex and enhanced by a saturated fatty acid–bovine serum albumin complex

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Binding of [³H]palmitate to BSA