Effect of experimental diabetes and insulin replacement on intestinal metabolism and excretion of 4-nitrophenol in rats

Fischer, E.; Almási, Attila; Bojcsev, S; Fischer, Tamás; Kovács, Noémi Piroska; Perjési, Pál

doi:10.1139/cjpp-2015-0065

Cited by 8 publications

(14 citation statements)

References 28 publications

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“…Formation of phenyl glucuronides and phenyl sulfates are generally considered to be detoxification processes [56]. As our present and previous results [22,23,29,30,34] demonstrate, the formed phenol conjugates can be reexcreted into the gastrointestinal system both by the liver and the small intestine. At the lower PNP concentrations (up to 500 µM), a higher fraction of the absorbed dose is reexcreted into the small intestine in the PNP-G form.…”

Section: Discussionsupporting

confidence: 72%

“…p-Nitrophenol has been reported to be effectively absorbed from the small intestine [20][21][22]29]. To obtain comparable data on the intestinal absorption as well as intestinal and hepatic metabolism from the same animals, HPLC-UV-Vis determination of the disappearance of PNP from the small intestine (proximal jejunum) was carried out.…”

Section: Discussionmentioning

confidence: 99%

“…Earlier, we investigated the intestinal disappearance as well as the intestinal and hepatic phase II metabolism of p-nitrophenol in control and STZ-treated experimental animals [19][20][21][22][23]. p-Nitrophenol (PNP) was used as a model compound because it is well known that that PNP is metabolized almost exclusively by phase II metabolic reactions, namely by conjugation with glucuronic acid and sulfate [19,[24][25][26][27][28], to form the metabolites p-nitrophenyl glucuronide (PNP-G) and p-nitrophenol sulfate (PNP-S).…”

Section: Of 14mentioning

confidence: 99%

“…Using this experimental protocol, we aimed to collect simultaneous data on the amount of PNP and its two phase II conjugates excreted to the small intestine by the gut epithelium and the liver (through the bile). The parent compound and the metabolites were determined by our previously developed, validated HPLC methods [19,22,23,29,30].…”

Section: Of 14mentioning

confidence: 99%

“…The experiments were performed according to the protocol used before [19][20][21][22][23]29,30]. Male Wistar rats (weighing 220-250 g) were used.…”

Section: Animals and Experimental Proceduresmentioning

confidence: 99%

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The Relative Importance of the Small Intestine and the Liver in Phase II Metabolic Transformations and Elimination of p-Nitrophenol Administered in Different Doses in the Rat

2020

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Intestinal and hepatic function have been investigated in phase II metabolic reactions and elimination of p-nitrophenol (PNP) in the rat. A jejunal loop was cannulated and recirculated with isotonic solutions containing PNP in different concentrations (0, 20, 100, 500, 1000 µM). Samples were obtained from the perfusate at given intervals. To investigate the metabolic and excretory functions of the liver, the bile duct was cannulated, and the bile was collected. Metabolites of PNP were determined by validated HPLC (high pressure liquid chromatography) methods. The results demonstrated the relative importance of the small intestine and the liver in phase II metabolic transformations and elimination of PNP. There were significant differences between the luminal and biliary appearances of p-nitrophenol-glucuronide (PNP-G) and p-nitrophenol–sulfate (PNP-S). The PNP-G appeared in the intestinal lumen at the lower PNP concentrations (20 µM and 100 µM) at higher rate than in the bile. No significant difference was found between the intestinal and the biliary excretion of PNP-G when PNP was administered at a concentration of 500 µM. However, a reverse ratio of these parameters was observed at the administration of 1000 µM PNP. The results indicated that both the small intestine and the liver might play an important role in phase II metabolic reactions and elimination of PNP. However, the relative importance of the small intestine and the liver can be dependent on the dose of drugs.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Of 14mentioning

confidence: 99%

Section: Of 14mentioning

confidence: 99%

“…The experiments were performed according to the protocol used before [19][20][21][22][23]29,30]. Male Wistar rats (weighing 220-250 g) were used.…”

Section: Animals and Experimental Proceduresmentioning

confidence: 99%

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The Relative Importance of the Small Intestine and the Liver in Phase II Metabolic Transformations and Elimination of p-Nitrophenol Administered in Different Doses in the Rat

2020

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Evidence of glucuronidation of the glycation product LW-1: tentative structure and implications for the long-term complications of diabetes

et al. 2018

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LW-1 is a collagen-linked blue fluorophore whose skin levels increase with age, diabetes and end-stage renal disease (ESRD), and correlate with the long-term progression of microvascular disease and indices of subclinical cardiovascular disease in type 1 diabetes. The chemical structure of LW-1 is still elusive, but earlier NMR analyses showed it has a lysine residue in an aromatic ring coupled to a sugar molecule reminiscent of advanced glycation end-products (AGEs). We hypothesized and demonstrate here that the unknown sugar is a N-linked glucuronic acid. LW-1 was extracted and highly purified from ~99 g insoluble skin collagen obtained at autopsy from patients with diabetes/ESRD using multiple rounds of proteolytic digestion and purification by liquid chromatography (LC). Advanced NMR techniques (H-NMR, C-NMR,H-C HSQC, H-H TOCSY, H-C HMBC) together with LC-mass spectrometry (MS) revealed a loss of 176 amu (atomic mass unit) unequivocally point to the presence of a glucuronic acid moiety in LW-1. To confirm this data, LW-1 was incubated with β-glycosidases (glucosidase, galactosidase, glucuronidase) and products were analyzed by LC-MS. Only glucuronidase could cleave the sugar from the parent molecule. These results establish LW-1 as a glucuronide, now named glucuronidine, and for the first time raise the possible existence of a "glucuronidation pathway of diabetic complications". Future research is needed to rigorously probe this concept and elucidate the molecular origin and biological source of a circulating glucuronidine aglycone.

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Investigation of intestinal elimination and biliary excretion of ibuprofen in hyperglycemic rats

Kovács

Almási

Garai

et al. 2019

Can. J. Physiol. Pharmacol.

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An in vivo intestinal perfusion model was used to investigate how experimental hyperglycemia affects intestinal elimination and biliary excretion in the rat. Experimental diabetes was induced by administration of streptozotocin (65 mg/kg, i.v.). The intestinal perfusion medium contained 250 μM (±)-ibuprofen. An isocratic high-performance liquid chromatography method with UV–visible detection was developed to quantitate ibuprofen in the intestinal perfusate, while a gradient method was applied to quantitate ibuprofen and ibuprofen-β-d-glucuronide in the bile. The limit of quantitation of ibuprofen was found to be 0.51 μM in the perfusate of the small intestine. In the bile, the limit of quantitation of ibuprofen and ibuprofen-β-d-glucuronide was 4.42 and 10.3 μM, respectively. Unconjugated ibuprofen and ibuprofen-β-d-glucuronide were detected in the bile; however, no β-d-glucuronide of ibuprofen could be detected in the intestinal perfusate. The results indicate that experimental diabetes can cause a decrease in the disappearance of ibuprofen from the small intestine. Excretion of both ibuprofen and ibuprofen-β-d-glucuronide decreased to the bile in experimental diabetes. The results can be explained by the results of molecular biological studies indicating streptozotocin-initiated alterations in the intestinal and hepatic transport processes.

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Effect of experimental diabetes and insulin replacement on intestinal metabolism and excretion of 4-nitrophenol in rats

Cited by 8 publications

References 28 publications

The Relative Importance of the Small Intestine and the Liver in Phase II Metabolic Transformations and Elimination of p-Nitrophenol Administered in Different Doses in the Rat

The Relative Importance of the Small Intestine and the Liver in Phase II Metabolic Transformations and Elimination of p-Nitrophenol Administered in Different Doses in the Rat

Evidence of glucuronidation of the glycation product LW-1: tentative structure and implications for the long-term complications of diabetes

Investigation of intestinal elimination and biliary excretion of ibuprofen in hyperglycemic rats

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