<i>In vitro</i> formation of DNA adducts with bile acids

Hamada, Kazuhisa; Umemoto, Atsushi; Kajikawa, Aiichiro; Seraj, Mohammed Jabed; Monden, Yasumasa

doi:10.1093/carcin/15.9.1911

Cited by 48 publications

(21 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, bile acids may directly bind to DNA; 32 P-labeling analysis of DNA-reactive bile acids provided evidence of DNA-adduct formation. 42 Conversely, others have shown that bile acids do not bind covalently to DNA. 43 It is also possible that UDCA interacts with transcriptional factors, thereby modulating several genes of the E2F-1/ Mdm-2/p53 apoptotic pathway, as previously demonstrated.…”

Section: Discussionmentioning

confidence: 99%

Nuclear translocation of UDCA by the glucocorticoid receptor is required to reduce TGF-β1-induced apoptosis in rat hepatocytes

et al. 2005

View full text Add to dashboard Cite

Ursodeoxycholic acid (UDCA) inhibits classical mitochondrial pathways of apoptosis by either directly stabilizing mitochondrial membranes or modulating specific upstream targets. Furthermore, UDCA regulates apoptosis-related genes from transforming growth factor ␤1 (TGF-␤1)-induced hepatocyte apoptosis by a nuclear steroid receptor (NSR)-dependent mechanism. In this study, we further investigated the potential role of the glucocorticoid receptor (GR) in the antiapoptotic function of UDCA. Our results with short interference RNA (siRNA) technology confirmed that UDCA significantly reduces TGF-␤1-induced apoptosis of primary rat hepatocytes through a GR-dependent effect. Immunoprecipitation assays and confocal microscopy showed that UDCA enhanced free GR levels with subsequent GR nuclear translocation. Interestingly, when a carboxy-terminus deleted form of GR was used, UDCA no longer increased free GR and/or GR translocation, nor did it protect against TGF-␤1-induced apoptosis. In co-transfection experiments with GR response element reporter and overexpression constructs, UDCA did not enhance the transactivation of GR with TGF-␤1. Finally, using a flourescently labeled UDCA molecule, the bile acid appeared diffuse in the cytosol but was aggregated in the nucleus of hepatocytes. Both siRNA assays and transfection experiments with either wild-type or mutant forms of GR showed that nuclear trafficking occurs through a GR-dependent mechanism. In conclusion, these results further clarify the antiapoptotic mechanism(s) of UDCA and suggest that GR is crucial for the nuclear translocation of this bile acid for reducing apoptosis. (HEPATOLOGY 2005;42:925-934.)

show abstract

Section: Discussionmentioning

confidence: 99%

Nuclear translocation of UDCA by the glucocorticoid receptor is required to reduce TGF-β1-induced apoptosis in rat hepatocytes

et al. 2005

View full text Add to dashboard Cite

show abstract

“…LCA is poorly water-soluble and not reabsorbed well by the gut. At higher concentrations, LCA forms DNA adducts and inhibits DNA repair enzymes [117][118][119]. High colonic levels of LCA are implicated as a factor in colorectal cancer [120], and LCA promotes colon cancer in animal models [121].…”

Section: Bile Saltsmentioning

confidence: 99%

Evolution and Function of the NR1I Nuclear Hormone Receptor Subfamily (VDR, PXR, and CAR) with Respect to Metabolism of Xenobiotics and Endogenous Compounds

Reschly¹,

Krasowski²

2006

CDM

126

130

View full text Add to dashboard Cite

The NR1I subfamily of nuclear hormone receptors includes the 1,25-(OH) 2 -vitamin D 3 receptor (VDR; NR1I1), pregnane X receptor (PXR; NR1I2), and constitutive androstane receptor (CAR; NR1I3). PXR and VDR are found in diverse vertebrates from fish to mammals while CAR is restricted to mammals. Current evidence suggests that the CAR gene arose from a duplication of an ancestral PXR gene, and that PXR and VDR arose from duplication of an ancestral gene, represented now by a single gene in the invertebrate Ciona intestinalis. Aside from the high-affinity effects of 1,25-(OH) 2 -vitamin D 3 on VDRs, the NR1I subfamily members are functionally united by the ability to bind potentially toxic endogenous compounds with low affinity and initiate changes in gene expression that lead to enhanced metabolism and elimination (e.g., induction of cytochrome P450 3A4 expression in humans). The detoxification role of VDR seems limited to sensing high concentrations of certain toxic bile salts, such as lithocholic acid, whereas PXR and CAR have the ability to recognize structurally diverse compounds. PXR and CAR show the highest degree of crossspecies variation in the ligand-binding domain of the entire vertebrate nuclear hormone receptor superfamily, suggesting adaptation to species-specific ligands. This review examines the insights that phylogenetic and experimental studies provide into the function of VDR, PXR, and CAR, and how the functions of these receptors have expanded to evolutionary advantage in humans and other animals.

show abstract

“…It does not appear that bile acids are direct mutagens or carcinogens, because no bile acid-DNA adducts have been detected either in the colon and liver of rats that were administered various bile acids by gavage, or in cultured cells exposed to bile acids [11]. Other studies have focused on the ability of secondary bile acids to act as tumor promoters by stimulating signal transduction and cancer-promoting genes.…”

Section: Introductionmentioning

confidence: 99%

Deoxycholate induces DNA damage and apoptosis in human colon epithelial cells expressing either mutant or wild-type p53

Powolny

Loo

2001

The International Journal of Biochemistry & Cell Biology

View full text Add to dashboard Cite

Abstract:Diets rich in fat result in higher concentrations of secondary bile acids or their salts in the colon, which may adversely affect cells of the colonic epithelium. Because secondary bile acids are thought to be genotoxic, exposing colon epithelial cells to secondary bile acids may induce DNA damage that might lead to apoptosis. The requirement for the p53 tumor suppressor gene in such events is unknown. In particular, the effects of secondary bile acids on colon epithelial cells having different p53 tumor suppressor gene status have not been examined. Therefore, HCT-116 and HCT-15 human colon adenocarcinoma cells, which express the wild-type and mutant p53 genes, respectively, were exposed to physiological concentrations of deoxycholate. The cells were then analyzed for evidence of DNA damage and apoptosis. After 2 h of incubation with 300 µM deoxycholate, both cell lines had greater levels of single-strand breaks in DNA as assessed by the comet assay. After 6 h of exposure to deoxycholate, HCT-116 and HCT-15 cells showed morphological signs of apoptosis, i.e., membrane blebbing and the presence of apoptotic bodies. Chromatin condensation and fragmentation were also seen after staining DNA with 4',6-diamidino-2-phenylindole. Other apoptotic assays revealed greater binding of annexin V-fluorescein isothiocyanate, as well as greater post-enzymatic labeling with dUTPfluorescein isothiocyanate, by both cell lines exposed to deoxycholate. These data suggest that deoxycholate caused DNA damage in colon epithelial cells that was sufficient to trigger apoptosis in a p53-independent manner.

show abstract

In vitro formation of DNA adducts with bile acids

Cited by 48 publications

References 0 publications

Nuclear translocation of UDCA by the glucocorticoid receptor is required to reduce TGF-β1-induced apoptosis in rat hepatocytes

Nuclear translocation of UDCA by the glucocorticoid receptor is required to reduce TGF-β1-induced apoptosis in rat hepatocytes

Evolution and Function of the NR1I Nuclear Hormone Receptor Subfamily (VDR, PXR, and CAR) with Respect to Metabolism of Xenobiotics and Endogenous Compounds

Deoxycholate induces DNA damage and apoptosis in human colon epithelial cells expressing either mutant or wild-type p53

Contact Info

Product

Resources

About