Sulphated and unsulphated bile acids in serum, bile, and urine of patients with cholestasis.

Henegouwen, G. P. van Berge; Brandt, K H; Eyssen, H.; Parmentier, G.

doi:10.1136/gut.17.11.861

Cited by 171 publications

(61 citation statements)

References 27 publications

(21 reference statements)

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“…4,23,34 However, in contrast to mice, sulfation of bile acids is a relevant metabolic pathway in humans reflected by increased amounts in serum and urine of patients with cholestasis. 5,6 Thus, a picture is emerging in which coordinated induction of hepatic bile acid hydroxylation (i.e., Cyp2b10 and Cyp3a11; phase I) and potentially sulfation (i.e., Sult2a1; phase II) together with overexpression of adaptive bile acid export systems (i.e., Mrp3 and Mrp4; phase III) may represent therapeutically inducible, alternative pathways. Moreover, additional stimulatory effects of CAR agonists (TCPOBOP) on the expression levels of the bile acid receptor PXR might amplify such alternative pathways.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, detoxification of accumulating biliary compounds via phase I hydroxylation and phase II conjugation may counteract cholestatic liver damage by rendering hydrophobic substrates less toxic and better soluble for biliary and urinary excretion. 5,6 However, intrinsic hepatocellular adaptive induction of transporters and enzymes in cholestasis is too weak to prevent ongoing liver injury. 4,7 In addition to the classical bile acid receptor, farnesoid X receptor (FXR), also the xenobiotic receptors, constitutive androstane receptor (CAR) and pregnane X receptor (PXR), critically participate in the regulation of genes involved in the detoxification and transport of bile acids and bilirubin.…”

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CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice

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confidence: 99%

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CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice

et al. 2005

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“…Steady-state serum bile acid levels result from a combination of mechanical regurgitation of conjugated bile acids from the obstructed biliary system, transporter mediated efflux from hepatocytes, and clearance from the circulation by extrahepatic mechanisms, particularly glomerular filtration and renal tubular excretion. 30,34,35 Assuming that CBDL results in equivalent degrees of bile acid regurgitation and renal clearance in both wild-type and Mrp4Ϫ/Ϫ mice, the lower levels of serum bile acids seem most likely to be due to a reduced ability of Mrp4Ϫ/Ϫ mice to export bile acids from hepatocytes back into the systemic circulation. (This assumption discounts any role that renal Mrp4 might play in bile acid excretion, which, in its absence, would tend to minimize the serum differences.)…”

Section: Discussionmentioning

confidence: 99%

Mrp4−/− mice have an impaired cytoprotective response in obstructive cholestasis

et al. 2006

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Mrp4 is a member of the multidrug resistance-associated gene family that is expressed on the basolateral membrane of hepatocytes and undergoes adaptive upregulation in response to cholestatic injury or bile acid feeding. However, the relative importance of Mrp4 in a protective adaptive response to cholestatic injury is not known. To address this issue, common bile duct ligation (CBDL) was performed in wild-type and Mrp4؊/؊ mice and animals followed for 7 days. Histological analysis and serum aminotransferase levels revealed more severe liver injury in the absence of Mrp4 expression. Western analyses revealed that Mrp4, but not Mrp3, was significantly increased after CBDL in wild-type mice. Serum bile acid levels were significantly lower in Mrp4؊/؊ mice than in wild-type CBDL mice, whereas serum bilirubin levels were the same, suggesting that Mrp4 was required to effectively extrude bile acids from the cholestatic liver. Mrp3 and Ost␣-Ost␤ were upregulated in Mrp4؊/؊ mice but were unable to compensate for the loss of Mrp4. High-performance liquid chromatography analysis on liver extracts revealed that taurine tetrahydroxy bile acid/beta-muricholic acid ratios were increased twofold in Mrp4؊/؊ mice. In conclusion, hepatic Mrp4 plays a unique and essential protective role in the adaptive response to obstructive cholestatic liver injury. ( M ultidrug resistance-associated protein 4 (MRP4) (ABCC4) is an ATP-dependent organic anion transporter with broad substrate specificity. [1][2][3] It is a member of the ABC transporter superfamily 4 and is expressed in a variety of epithelia, including the basolateral and apical plasma membranes of the liver and kidneys, respectively. 5-7 However, this array of substrates and specific tissue localization have not provided insight into Mrp4 function in vivo.Mrp4 was first suggested to play a role in the adaptive response to the hepatic overload of bile acids following the genetic deletion of farnesoid X receptor (FXR), a bile acid sensor. 8,9 A subsequent study suggested that Mrp4 was not elevated upon feeding the hydrophobic bile acid, lithocholic acid. 10 Despite this finding, other studies have demonstrated that hepatic Mrp4 is upregulated in both rats and mice after bile duct ligation 6,11 and in pediatric patients with progressive familial intrahepatic cholestasis. 12 Recent studies demonstrate that MRP4 functions as an efflux pump for bile acids together with glutathione. 13 Further support for a role for MRP4 in hepatic bile acid overload is the recent demonstration that Mrp4 is upregulated by the constitutive androstane receptor. 14 Constitutive androstane receptor is a member of the nuclear hormone receptor superfamily that is required to elevate serum bile acids during cholestatic injury. 15 Cholestatic injury in mice, rats, and humans can also result in adaptive responses in other basolateral transporters. Examples include Mrp3, which is primarily a bilirubin conjugate transporter and also a constitutive androstane receptor target, 15 and the recently described heterodi...

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“…A certain amount of each bile acid is conjugated with amino acid such as glycine and taurine, and/or sulfate. Several studies revealed that the composition of bile acid was altered in human liver disease (van Berge Henegouwen et al, 1976;Shoda et al, 1990). We could not determine the composition of UBA in the present study, because UBA -ly oxidized non-sulfoconjugated bile acids.…”

Section: Original Articlementioning

confidence: 99%

Efficacy of urine bile acid as a non-invasive indicator of liver damage in rats

et al. 2009

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-Estimation of liver damage is important in the pathophysiological and toxicological bile acids (UBA) in a rat model of liver disease. Thioacetamide (TAA)-treated rats were used in this study. Single intraperitoneal administration of high-dose TAA induces severe damage to the liver, and thus is used as a model of acute hepatitis. Continuous administration of low-dose TAA yields mild damand chronic administration of TAA was associated with a dose-dependent elevation of UBA. The elevation of UBA content correlated with the alteration of blood biochemical indicators, and UBA screening -with abnormal serum alkaline phosphatase (ALP) activity due to chronic liver damage, which was condemonstrated that measurement of UBA is a simple, non-invasive and effective method for the screening of cholestasis in TAA-treated rats. We suggest that UBA analysis may have potent applicability for monitoring the progress of liver damage in animal models of chronic liver disease, such as cirrhosis and hepatic encephalopathy.Bile acid, Urine, Liver, Cholestasis, Cirrhosis, ThioacetamideCorrespondence: Hiroshi Kawai (E-mail: hkawai@jiu.ac.jp) Original ArticleThe Journal of Toxicological Sciences (J. Toxicol. Sci.) Vol.34, No.1, 27-38, 2009 Vol. 34 No. 1 27 the systemic circulation is small. The blood concentration -tions, but is increased in the case of a disorder in the liver or biliary tract (Dawson, 2002). Therefore, the serum bile acid level is a marker of liver disease, although it is not widely used as a routine screening test.Urine bile acids (UBA) have been detected in patients with hepatic disease since the 1950s (Rudman and Kendall, 1957; Makino et al et al., 1976;Almé et al., 1977;Simko et al., 1987;Batta et al., 1989; Shoda et al acids has been carried out mainly by gas or liquid chromatography -mass spectrometry (GC-MS, LC-MS) in recent studies. GC-MS and LC-MS can identify various structurally different bile acids precisely, and alteration of the composition of UBA can be analyzed. These methods, however, require complicated sample preparation, a long period of time, and a well-disciplined technician. A more simple and rapid method is needed for routine screening or analysis of a large number of samples. Recently, the direct enzymatic assay of urine sulfated bile acids (USBA) content was developed as a diagnostic tool (Matsui et al., 1996), and several reports revealed the clinical importance of USBA analysis (Obatake et al., 2002; Shinohara et al., 2005; Huang et al., 2007). Since a large portion of bile acids are sulfated in human urine (Palmer, 1967;Stiehl, 1974), USBA rather than non-sulfated UBA is useful in clinical application.UBA has also been analyzed in various animal species, such as hamsters (Galeazzi and Javitt, 1977), chimpanzees (Schweng et al., 1978), rabbits (Nakao et al., 1980), monkeys (Suzuki et al., 1985), and rats (Palmer, 1971; Takita et al., 1988;Lee et al., 2001). However, these studies focused on the alteration of metabolic ability of the liver and the pathogenic mechanisms of liver disease...

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Sulphated and unsulphated bile acids in serum, bile, and urine of patients with cholestasis.

Cited by 171 publications

References 27 publications

CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice

CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice

Mrp4−/− mice have an impaired cytoprotective response in obstructive cholestasis

Efficacy of urine bile acid as a non-invasive indicator of liver damage in rats

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