Cytotoxic effect and uptake mechanism by isolated rat hepatocytes of lithocholate and its glucuronide and sulfate

Takikawa, Hajime; Tomita, Jun; Takemura, T; Yamanaka, Masami

doi:10.1016/0167-4889(91)90058-6

Cited by 25 publications

(14 citation statements)

References 21 publications

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“…However, in several experiments we noted that the level of MMP-2 activity was lower in CaCo-2 cells incubated with SLA for 9 h and 18 h, but significantly higher than in controls after 48h. These results indicate different rates of uptake for LA and SLA, as has been shown in hepatocytes [8]. Furthermore, in this study the uptake of LA was by simple diffusion and the uptake of SLA by Na + -independent carrier, which may possibly lead to different intracellular routing and effects, as is indicated from our data.…”

Section: Insupporting

confidence: 43%

“…The sulphation of LA in CaCo-2 cells is also a cytosolic process [3], but the biological function(s) of this bile acid modification has not been defined. It has been shown that LA has toxic effects on the liver [14], and the cytotoxicity of LA in hepatocytes was greatly reduced by either glucuronidation or sulphation of this bile acid [8]. Sulphation in the intestine could therefore reduce the detrimental effects of LA in the entero-hepatic circulation.…”

Section: Discussionmentioning

confidence: 99%

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Lithocholic acid and sulphated lithocholic acid differ in the ability to promote matrix metalloproteinase secretion in the human colon cancer cell line CaCo-2

Halvorsen

Staff

LIGAARDEN

et al. 2000

Biochemical Journal

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The human colon carcinoma cell line CaCo-2 has the ability to sulphate the secondary bile acid lithocholic acid (LA), whereas other primary or secondary bile acids were not sulphated [Halvorsen, Kase, Prydz, Gharagozlian, Andresen and Kolset (1999) Biochem. J. 343, 533-539]. To study the biological implications of this modification, CaCo-2 cells were incubated with either LA or sulphated lithocholic acid (3-sulpholithocholic acid, SLA), and in some experiments with taurine-conjugated lithocholic acid. Increased secretion of matrix metalloproteinases (MMPs) correlates with transformation of colon epithelial cells. When CaCo-2 cells were incubated with LA, the secretion of MMP-2 was found to increase approx. 60 % when analysed by gelatin zymography, and 80 % when analysed by Western blotting. SLA, in contrast, did not affect the level of MMP-2 secretion, and after zymography the level of enzyme activity was

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Section: Insupporting

confidence: 43%

Section: Discussionmentioning

confidence: 99%

Lithocholic acid and sulphated lithocholic acid differ in the ability to promote matrix metalloproteinase secretion in the human colon cancer cell line CaCo-2

Halvorsen

Staff

LIGAARDEN

et al. 2000

Biochemical Journal

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“…Recently, dehydroepiandrosterone preferring sulfotransferase (Sult2a2), the exclusive sulfating enzyme for LCA (44), was described as a target gene for VDR-dependent regulation (33). The sulfate conjugate of LCA is much less cytotoxic than LCA and is more readily eliminated in the feces (12,(45)(46)(47). Moreover, a role for Sult2a2 in protection against LCA-induced hepatotoxicity has been demonstrated in mice (34,35).…”

Section: Discussionmentioning

confidence: 99%

Vitamin D Receptor-dependent Regulation of Colon Multidrug Resistance-associated Protein 3 Gene Expression by Bile Acids

McCarthy

Sinal

2005

Journal of Biological Chemistry

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“…Conjugated LCA is also transformed to 3-sulfate and 3-glucuronides by sulfotransferase and UDP-glucuronosyltransferase, respectively (6,7). LCA sulfate and LCA glucuronide were less toxic than LCA (8). These conjugations make the bile acid more hydrophilic and facilitate their elimination in the feces and urine (9 -12).…”

mentioning

confidence: 99%

Protective Role of Hydroxysteroid Sulfotransferase in Lithocholic Acid-induced Liver Toxicity

Kitada

Miyata

Nakamura

et al. 2003

Journal of Biological Chemistry

148

149

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Supplement of 1% lithocholic acid (LCA) in the diet for 5-9 days resulted in elevated levels of the marker for liver damage aspartate aminotransferase and alkaline phosphatase activities in both farnesoid X receptor (FXR)-null and wild-type female mice. The levels were clearly higher in wild-type mice than in FXR-null mice, despite the diminished expression of a bile salt export pump in the latter. Consistent with liver toxicity marker activities, serum and liver levels of bile acids, particularly LCA and taurolithocholic acid, were clearly higher in wild-type mice than in FXR-null mice after 1% LCA supplement. Marked increases in hepatic sulfating activity for LCA (5.5-fold) and hydroxysteroid sulfotransferase (St) 2a (5.8-fold) were detected in liver of FXR-null mice. A 7.4-fold higher 3␣-sulfated bile acid concentration was observed in bile of FXR-null mice fed an LCA diet compared with that of wild-type mice. Liver St2a content was inversely correlated with levels of alkaline phosphatase. In contrast, microsomal LCA 6␤-hydroxylation was not increased and was in fact lower in FXRnull mice compared in wild-type mice. Clear decreases in mRNA encoding sodium taurocholate cotransporting polypeptide, organic anion transporting polypeptide 1, and liver-specific organic anion transporter-1 function in bile acid import were detected in LCA-fed mice. These transporter levels are higher in FXR-null mice than wild-type mice after 1% LCA supplement. No obvious changes were detected in the Mrp2, Mrp3, and Mrp4 mRNAs. These results indicate hydroxysteroid sulfotransferase-mediated LCA sulfation as a major pathway for protection against LCA-induced liver damage. Furthermore, Northern blot analysis using FXR-null, pregnane X receptor-null, and FXR-pregnane X receptor double-null mice suggests a repressive role of these nuclear receptors on basal St2a expression.

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Cytotoxic effect and uptake mechanism by isolated rat hepatocytes of lithocholate and its glucuronide and sulfate

Cited by 25 publications

References 21 publications

Lithocholic acid and sulphated lithocholic acid differ in the ability to promote matrix metalloproteinase secretion in the human colon cancer cell line CaCo-2

Lithocholic acid and sulphated lithocholic acid differ in the ability to promote matrix metalloproteinase secretion in the human colon cancer cell line CaCo-2

Vitamin D Receptor-dependent Regulation of Colon Multidrug Resistance-associated Protein 3 Gene Expression by Bile Acids

Protective Role of Hydroxysteroid Sulfotransferase in Lithocholic Acid-induced Liver Toxicity

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