Origin of mammalian biliprotein and rearrangement of bilirubin glucuronides in vivo in the rat.

McDonagh, Antony F.; Palma, Lucita A.; Lauff, John J.; Wu, Tai-Wing

doi:10.1172/jci111492

Cited by 82 publications

(31 citation statements)

References 22 publications

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“…Therefore, ZG and all of its isomers formed by acyl migration are capable of leading to formation of Z-protein adduct in vitro. These in vitro studies suggested that a similar protein adduct might be formed in vivo, as with bilirubin glucuronides (16,17), if ZG were to persist in plasma for a sufficient length of time. In 6 volunteers given 100 mg Z orally, the molar concentrations of ZG detected in plasma were similar to Z levels.…”

Section: Resultsmentioning

confidence: 98%

“…Another wellknown but unrelated compound that is metabolized to unstable acyl glucuronides is bilirubin. In cholestatic liver disease, bilirubin becomes irreversibly (probably covalently) bound to albumin (10)(11)(12)(13)(14)(15), and recent studies have shown that this reaction occurs via acyl glucuronide metabolites of bilirubin (16,17). Although bilirubin glucuronides accumulate in human plasma only during liver disease (15), the glucuronide of zomepirac (ZG) reaches a plasma level similar to that of Z after administration of a single oral dose of Z to healthy subjects (3,18).…”

Section: Introductionmentioning

confidence: 99%

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Irreversible binding of zomepirac to plasma protein in vitro and in vivo.

Smith¹,

McDonagh²,

Benet³

1986

J. Clin. Invest.

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164

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Zomepirac is a nonsteroidal anti-inflammatory drug recently withdrawn from use because of an unexplained high incidence of immunological reactions. It is metabolized in humans to a reactive, unstable acyl glucuronide which accumulates in plasma. Because of the similarity of zomepirac glucuronide to bilirubin glucuronide in structure and stability and the documented irreversible binding of bilirubin to albumin through its acyl glucuronide, we studied the reaction of zomepirac acyl glucuronide with albumin in vitro from pH 5 to 9 and in vivo in six healthy human volunteers who had received a single 100-mg oral dose of zomepirac. Irreversible binding of zomepirac to protein was determined by exhaustive washing of protein, followed by hydrolysis of bound zomepirac-protein adduct with base, extraction of the liberated drug, and chromatographic measurement. Irreversible binding was observed both in vitro and in vivo. The extent of binding in vitro was time-and pH-dependent. In vitro drug binding was also observed for the isomers of zomepirac glucuronide which were formed by intramolecular acyl migration. Irreversible binding in vivo correlated with overall exposure to zomepirac glucuronide when exposure was expressed as the area under the plasma concentration vs. time curve. When probenecid (500 mg, twice daily), which decreases the plasma clearance of zomepirac glucuronide, was administered concurrently with zomepirac, irreversible binding of zomepirac was increased. The nature of the zomepirac protein binding is probably covalent. Formation of irreversibly protein-bound zomepirac occurs via the acyl glucuronide as previously shown for bilirubin glucuronide, and the reaction may be general for other drugs that are metabolized to acyl glucuronides.

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Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Irreversible binding of zomepirac to plasma protein in vitro and in vivo.

Smith¹,

McDonagh²,

Benet³

1986

J. Clin. Invest.

Self Cite

164

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“…Bile flow was determined gravimetrically and total radioactivity measured in 5-to 40-MA aliquots from each bile sample before further analysis. The calculated dead volume of the biliary cannula was 12 Ml and since this introduced a lag time ofonly 35-40 s at the observed rates of bile flow, no adjustment was made for this time in the computation of data.…”

Section: Methodsmentioning

confidence: 99%

Hepatic disposition and biliary excretion of bilirubin and bilirubin glucuronides in intact rats. Differential processing of pigments derived from intra- and extrahepatic sources.

Crawford¹,

Ransil²,

Potter³

et al. 1987

J. Clin. Invest.

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Mechanisms for transport of bilirubin and its conjugates in hepatocytes have not been defined. We investigated the hepatic processing of bilirubin glucuronides and their precursors, and characterized the disposition of bile pigments arising from intraversus extrahepatic sources. Tracer doses of purified radiolabeled biliverdin, bilirubin, bilirubin monoglucuronide (BMG) or diglucuronide (BDG) were administered intravenously to intact normal or jaundiced homozygous Gunn rats. Rapid sequential analysis of radiolabeled BMG and BDG in bile revealed comparable excretion patterns following biliverdin and bilirubin injection, with BDG as the major pigment. Biliary excretion of radiolabeled conjugates from injected BMG was more rapid, with BMG predominating. Excretion of injected BDG in normal rats and BMG or BDG in Gunn rats was virtually identical to that of unaltered BMG in normal rats. Model independent analysis by deconvolution provided objective comparison of the disposition of radiolabeled pigments from the different sources. These findings indicate that bilirubin glucuronides formed in the liver from endogenous (hepatic) and exogenous (extrahepatic) sources of bilirubin follow a similar excretory pathway. BMG formed endogenously is converted preferentially to BDG, whereas circulating BMG is excreted predominantly unchanged. Exogenous conjugated bilirubins are excreted more rapidly than those generated intrahepatically, by a transcellular pathway that is largely independent of the conjugation system.

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“…Bilirubin is secreted into bile as the 1-O-acylglucuronide conjugate, 28,82 which partially undergoes acyl migration in the gallbladder and intestine to form 2-, 3-and 4-O-acyl isomers. 83,84 Deconjugation of bilirubin 1-O-acylglucuronide, but not the other positional isomers, 84 occurs within the intestinal lumen both by spontaneous nonenzymic hydrolysis 29 and through the action of mucosal and bacterial ␤-glucuronidases 30,31 present primarily in the distal small bowel and colon, where luminal bilirubin levels are the highest. 32,85 Plasma unconjugated (but not conjugated) bilirubin also enters the gut via passive diffusion across the intestinal mucosa.…”

Section: Effect Of Bilirubin On the Permeability Of Isolated Mitochonmentioning

confidence: 99%

Unconjugated bilirubin induces apoptosis in colon cancer cells by triggering mitochondrial depolarization

Keshavan¹,

Schwemberger²,

Smith³

et al. 2004

Intl Journal of Cancer

112

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Bilirubin is the principal end product of heme degradation. Prompted by epidemiologic analyses demonstrating an inverse correlation between serum bilirubin levels and cancer mortality, we examined the effect(s) of bilirubin on the growth and survival of colon adenocarcinoma cells. Adenocarcinoma cell monolayers were treated with bilirubin over a range of bilirubin:BSA molar ratios (0 -0.6), and viability was assessed colorimetrically. Apoptosis was characterized by TUNEL assay, annexin V staining and caspase-3 activation. The mechanism(s) by which bilirubin induces apoptosis was investigated by Western blotting for cytochrome c release, assaying for caspase-8 and caspase-9 activation and for mitochondrial depolarization by JC-1 staining. The direct effect of bilirubin on the membrane potential of isolated mitochondria was evaluated using light-scattering and fluorescence techniques. Bilirubin decreased the viability of all colon cancer cell lines tested in a dose-dependent manner. Cells exhibited substantial apoptosis when exposed to bilirubin concentrations ranging 0 -50 M, as demonstrated by an 8-to 10-fold increase in TUNEL and annexin V staining and in caspase-3 activity. Bilirubin treatment evokes specific activation of caspase-9, enhances cytochrome c release into the cytoplasm and triggers the mitochondrial permeability transition in colon cancer monolayers. Additionally, bilirubin directly induces the depolarization of isolated rat liver mitochondria, an effect that is not inhibited by cyclosporin A. Bilirubin stimulates apoptosis of colon adenocarcinoma cells in vitro through activation of the mitochondrial pathway, apparently by directly dissipating mitochondrial membrane potential. As this effect is triggered at concentrations normally present in the intestinal lumen, we postulate a physiologic role for bilirubin in modulating colon tumorigenesis.

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Origin of mammalian biliprotein and rearrangement of bilirubin glucuronides in vivo in the rat.

Cited by 82 publications

References 22 publications

Irreversible binding of zomepirac to plasma protein in vitro and in vivo.

Irreversible binding of zomepirac to plasma protein in vitro and in vivo.

Hepatic disposition and biliary excretion of bilirubin and bilirubin glucuronides in intact rats. Differential processing of pigments derived from intra- and extrahepatic sources.

Unconjugated bilirubin induces apoptosis in colon cancer cells by triggering mitochondrial depolarization

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