Bilirubin produces apoptosis in cultured bovine brain endothelial cells

Akin, E.; Clower, Ben R.; Tibbs, Robert E.; Tang, Jiping; Zhang, Jin

doi:10.1016/s0006-8993(02)02276-x

Cited by 37 publications

(22 citation statements)

References 33 publications

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“…Relatively low levels of UCB (5 M) induced a significant change in DNA laddering. UCB induced apoptosis in cultured bovine brain endothelial cells (Akin et al, 2002), but this effect was not concentration-dependent in the range of UCB concentrations studied (10-100 M).…”

mentioning

confidence: 81%

Bilirubin: An Endogenous Product of Heme Degradation with Both Cytotoxic and Cytoprotective Properties: Fig. 1

Kapitulnik¹

2004

Mol Pharmacol

216

180

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confidence: 81%

Bilirubin: An Endogenous Product of Heme Degradation with Both Cytotoxic and Cytoprotective Properties: Fig. 1

Kapitulnik¹

2004

Mol Pharmacol

216

180

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“…Bilirubin inhibits osteoblast proliferation 19 and stimulates apoptosis in rat brain neurons, 20 -23 astrocytes, 24 fibroblasts 24 and bovine brain endothelial cells. 25 However, many studies of bilirubininduced apoptosis have been conducted at high molar ratios of bilirubin to albumin or under serum-free conditions. Due to the low aqueous solubility at neutral pH, 26 substantial aggregation of bilirubin is likely to have occurred during the course of these experiments, making the physiologic relevance of the findings uncertain.…”

mentioning

confidence: 99%

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

Keshavan¹,

Schwemberger²,

Smith³

et al. 2004

Intl Journal of Cancer

113

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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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“…Astrocytes regulate energy homeostasis in the brain and have phagocytic, immune and detoxifi cation functions, and are the principal elements acting in accordance with endothelial cells in the formation and integrity of the BBB. One recent study has reported the toxic effect of bilirubin on endothelial cells in vitro [17] . In addition to the formation of BBB, astrocytes have neuronsupportive functions in the central nervous system and the role of astrocytes in the clearance of bilirubin has been reported [11,12] .…”

Section: Discussionmentioning

confidence: 99%

Hyperbilirubinemic Serum Is Cytotoxic and Induces Apoptosis in Murine Astrocytes

Kumral¹,

Genç²,

Genç³

et al. 2005

Neonatology

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Background: High levels of unconjugated bilirubin can be neurotoxic and gliotoxic. However, the effect of serum from patients with neonatal indirect hyperbilirubinemia on astrocyte viability has never been investigated. Objectives: In the present study, we searched for the possible toxic effect of hyperbilirubinemic serum on murine astrocytes. Methods: Heat-inactivated patient serum was added to astrocyte cultures at different concentrations varying from 1 to 20%, and cultures were incubated for 24, 48, and 72 h. Sera from healthy infants without hyperbilirubinemia were used as controls. Cytotoxicity was evaluated according to the release of lactate dehydrogenase in the culture medium. Apoptotic cell death was determined by anti-single-strand DNA immunostaining. Results: The results of the present study show that hyperbilirubinemic serum induces cytotoxicity and apoptotic astrocyte death in a concentration- and time-dependent manner. Conclusions: We conclude that serum from patients with neonatal indirect hyperbilirubinemia is cytotoxic to murine astrocytes.

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Bilirubin produces apoptosis in cultured bovine brain endothelial cells

Cited by 37 publications

References 33 publications

Bilirubin: An Endogenous Product of Heme Degradation with Both Cytotoxic and Cytoprotective Properties: Fig. 1

Bilirubin: An Endogenous Product of Heme Degradation with Both Cytotoxic and Cytoprotective Properties: Fig. 1

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

Hyperbilirubinemic Serum Is Cytotoxic and Induces Apoptosis in Murine Astrocytes

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