Metabolism of heme and bilirubin in rat and human small intestinal mucosa.

Hartmann, F; Bissell, D. Montgomery

doi:10.1172/jci110598

Cited by 50 publications

(21 citation statements)

References 23 publications

(30 reference statements)

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“…Alternatively, glucuronidation and glycogenesis may occur in different hepatocyte populations. The discrepant labeling of GlcUA is unlikely to be due to extrahepatic glucuronidation, which represents, at most, 12% of total glucuronidation of administered acetaminophen (36)(37)(38). Finally, it should be pointed out that even though the isotopic labeling patterns in GlcUA do not reflect those in glycogen, they do change as glycogen stores accumulate (Figs.…”

Section: Resultsmentioning

confidence: 97%

Glycoconjugates as noninvasive probes of intrahepatic metabolism: pathways of glucose entry into compartmentalized hepatic UDP-glucose pools during glycogen accumulation.

Hellerstein¹,

Greenblatt²,

Munro³

1986

Proc. Natl. Acad. Sci. U.S.A.

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Recent studies have questioned the efficiency with which administered glucose generates hepatic glycogen through the direct nonrecycling route compared with the indirect route from glucose recycled through glycolysis followed by gluconeogenesis. Using fasted and refed rats, we examined the relative access of infused (l-3H]-and [U-'4Cjglucose by way of these two pathways to liver glycogen and to hepatic glucuronic acid, the latter recovered from the urine as the glucuronide conjugated with administered acetaminophen. In fasted animals and during early refeeding, extensive dilution of administered [3HJ-and []4C~glucose recovered in glycogen showed that 60470% of the labeled glucose had undergone recycling by the indirect route. As refeeding progressed with substantial glycogen deposition, the contribution of the recycling pathway to glycogen and glucuronic acid diminished considerably. Thus, there is a shift in pathways of hepatic glucose utilization as liver glycogen accumulates.Consequently, the ratio of 3H/14C in glucuronic acid was closely correlated with the glycogen content of the liver at sacrifice, indicating that this ratio may prove useful as a noninvasive indicator of liver glycogen concentration. Since glycogen and glucuronic acid are derived by single reactions from UDP-glucose, they should show a common labeling pattern with 3H and 14C under various nutritional conditions. However, detailed analysis of their labeling patterns showed a striking divergence, implying that there must be compartmentation of the UDP-glucose pools leading to each of these end products, either because they are made in separate compartments within the same cell or because each is made in different hepatocyte populations. We favor the former explanation because galactose secreted in glycoproteins shows 3H and d4C labeling patterns similar to those of glucuronic acid conjugated with acetaminophen, and both of these conjugations occur in the endoplasmic reticulum of the liver, whereas most glycogen is present in the cytosol.A growing body of evidence (1) suggests that the intact glucose molecule is not directlyt used as such by the liver of animals refed after a fast, despite the net entry of ingested glucose carbon into the liver for glycogen deposition, lipid synthesis, etc. The proposed resolution of this "glucose paradox" is that administered glucose is first degraded to triose metabolites, presumably in the peripheral tissues, which return to the liver in the form of lactate, alanine, and pyruvate to regenerate glucose phosphates and sugar nucleotides through the gluconeogenic pathway (Fig. 1) Fig. 1) and thus lowering the 3H/14C ratio of the glucose deposited in liver glycogen. This preferential loss of 3H from administered glucose was observed in only one such study (7) but not in others (16-19), suggesting direct utilization ofglucose for glycogen deposition. However, when the specific activities of the glucosyl residues of glycogen in such studies were compared with those of the parent blood glucose, a loss of u...

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Section: Resultsmentioning

confidence: 97%

Glycoconjugates as noninvasive probes of intrahepatic metabolism: pathways of glucose entry into compartmentalized hepatic UDP-glucose pools during glycogen accumulation.

Hellerstein¹,

Greenblatt²,

Munro³

1986

Proc. Natl. Acad. Sci. U.S.A.

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“…Microsomal glucuronidation and UGT mRNA expression have been analyzed in human esophagus, stomach, and colon, establishing the role of these external surface tissues in extrahepatic glucuronidation. Although intestinal glucuronidation has been documented (26,(33)(34)(35), UGT1A and UGT2B gene regulation and biological function have not been correlated.…”

Section: Discussionmentioning

confidence: 99%

Polymorphic Gene Regulation and Interindividual Variation of UDP-glucuronosyltransferase Activity in Human Small Intestine

Strassburg¹,

Kneip²,

Topp³

et al. 2000

Journal of Biological Chemistry

226

154

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UDP-glucuronosyltransferases (UGTs) convert dietary constituents, drugs, and environmental mutagens to inactive hydrophilic glucuronides. Recent studies have shown that the expression of the UGT1 and UGT2 gene families is regulated in a tissue-specific fashion. Human small intestine represents a major site of resorption of dietary constituents and orally administered drugs and plays an important role in extrahepatic UGT directed metabolism. Expression of 13 UGT1A and UGT2B genes coupled with functional and catalytic analyses were studied using 18 small intestinal and 16 hepatic human tissue samples. Hepatic expression of UGT gene transcripts was without interindividual variation. In contrast, a polymorphic expression pattern of all the UGT genes was demonstrated in duodenal, jejunal, and ileal mucosa, with the exception of UGT1A10. To complement these studies, interindividual expression of UGT proteins and catalytic activities were also demonstrated. Hyodeoxycholic acid glucuronidation, catalyzed primarily by UGT2B4 and UGT2B7, showed a 7-fold interindividual variation in small intestinal duodenal samples, in contrast to limited variation in the presence of 4-methylumbelliferone, a substrate glucuronidated by most UGT1A and UGT2B gene products. Linkage of RNA expression patterns to protein abundance were also made with several mono-specific antibodies to the UGTs. These results are in contrast to a total absence of polymorphic variation in gene expression, protein abundance, and catalytic activity in liver. In addition, the small intestine exhibits considerable catalytic activity toward most of the different classes of substrates accepted for glucuronidation by the UGTs, which is supported by immunofluorescence analysis of UGT1A protein in the mucosal cell layer of the small intestine. Thus, tissue-specific and interindividual polymorphic regulation of UGT1A and UGT2B genes in small intestine is identified and implicated as molecular biological determinant contributing to interindividual prehepatic drug and xenobiotic metabolism in humans.

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“…This model was previously used in absorption studies of minerals and peptides (Tom e et al 1987;Atisook & Madara, 1991;Vaghefi et al 1998). The absorption and metabolism of haem iron, and their regulation depending on the dose and iron status, are known to be similar in rat and human mucosa, even if the absorption of haem iron is lower in the rodent (Wheby et al 1970;Raffin et al 1974;Hartmann & Bissel, 1982;Huebers et al 1990;Pallar es et al 1993;Roberts et al 1993). …”

Section: Discussionmentioning

confidence: 99%

Influence of the Extent of Haemoglobin Hydrolysis on the Digestive Absorption of Haem Iron in the Rat. an in Vitro Study

Vaghefi

Nedjaoum

Guillochon

et al. 2000

Experimental Physiology

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This study was designed to assess the haem‐peptide interactions which occur during progressive haemoglobin hydrolysis by digestive enzymes and their relationship with haem iron digestive absorption. The behaviour of different haemoglobin hydrolysates was studied using the Ussing chamber model. Hydrolysates were produced from enzyme digestion of bovine haemoglobin at pH 3 by pepsin and at pH 10 by subtilisin. Samples with increasing degrees of hydrolysis (0‐15%) were studied. Biochemical assays (pyridine haemochromogen method and UV absorption spectra) were used to follow haem solubility and haem‐peptide interactions in samples. Increasing the hydrolysis level of haemoglobin was associated with an enhanced iron uptake; the highest uptake rate was reached between 8 and 11% of globin hydrolysis, whichever enzyme was used. The mechanisms rendering iron soluble and available differ between the two enzymes. The comparison between biochemical and absorption data suggests that the formation of soluble peptide‐haem complexes was not sufficient to enhance haem iron absorption, since globin‐bound iron is poorly absorbed; an efficient absorption occurred only when haem was loosely bound to low molecular weight peptides.

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Metabolism of heme and bilirubin in rat and human small intestinal mucosa.

Cited by 50 publications

References 23 publications

Glycoconjugates as noninvasive probes of intrahepatic metabolism: pathways of glucose entry into compartmentalized hepatic UDP-glucose pools during glycogen accumulation.

Glycoconjugates as noninvasive probes of intrahepatic metabolism: pathways of glucose entry into compartmentalized hepatic UDP-glucose pools during glycogen accumulation.

Polymorphic Gene Regulation and Interindividual Variation of UDP-glucuronosyltransferase Activity in Human Small Intestine

Influence of the Extent of Haemoglobin Hydrolysis on the Digestive Absorption of Haem Iron in the Rat. an in Vitro Study

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