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Bilirubin: Physiological Role in Cancer and Inflammation

Keshavan, Pavitra

Abstract Details

2006, PhD, University of Cincinnati, Medicine : Pathobiology and Molecular Medicine.

Bilirubin is the principal end-product of heme catabolism. While bilirubin is traditionally considered a metabolic waste product, recent epidemiological analyses support an inverse association between serum bilirubin levels and cancer-related mortality; hence, we postulated that bilirubin plays a role in the suppression of tumorigenesis. To evaluate the effect of bilirubin on intestinal tumorigenesis, we administered bilirubin orally to Min mice, which develop intestinal adenomas due to an inherited mutation in the Apc gene. Bilirubin treatment resulted in a ~70% reduction in both macroscopic and microscopic tumor burden compared to untreated animals; while tumor size remained unaffected. Bilirubin did not alter the nuclear translocation of β-catenin (a hallmark of Apc lack) in intestinal crypts, suggesting that the inhibitory effect of bilirubin is exerted subsequent to tumor initiation. Furthermore, bilirubin, at physiologic concentrations, causes apoptosis of cultured colon adenocarcinoma cells by a mechanism involving mitochondrial depolarization. On the other hand, we did not observe an increase in apoptosis in the intestines of Min mice treated with bilirubin, possibly due to efficient phagocytosis of apoptotic nuclei.

Leukocyte transmigration across vascular endothelia is mediated by vascular cell adhesion molecule-1 (VCAM-1) via a mechanism involving generation of reactive oxygen species (ROS) by NADPH oxidase. As bilirubin is the most potent endogenous antioxidant, we postulated that bilirubin inhibits inflammatory responses by blocking VCAM-1 signaling through scavenging of ROS. In an in vitro model of VCAM-1-mediated lymphocyte migration, bilirubin significantly inhibited lymphocyte movement across endothelial monolayers and also VCAM-1-stimulated activation of matrix metalloproteinases-2 and -9, potentially preventing NADPH oxidase-dependent ROS production. In a mouse model of ovalbumin-induced asthma, intraperitoneal bilirubin administration blocked the pulmonary accumulation of eosinophils and lymphocytes, which is VCAM-1-dependent. As bilirubin did not alter pulmonary VCAM-1 expression or cytokine profiles, we speculate that the suppressive effect of bilirubin on lung inflammation is exerted due to the scavenging of the ROS generated by VCAM-1 activation. Taken together, these data support that bilirubin exerts an inhibitory effect on colonic tumor formation and inflammation. We speculate that bilirubin may play a vital role in the suppression of chronic inflammation-associated cancers and also modulate other ROS-regulated processes.

Stephen Zucker, MD (Committee Chair)
Elizabeth Mann, PhD (Other)
Kenneth Sherman, MD (Other)
Joanna Groden, PhD (Other)
David Askew, PhD (Other)
218 p.

Recommended Citations

Citations

  • Keshavan, P. (2006). Bilirubin: Physiological Role in Cancer and Inflammation [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1143241951

    APA Style (7th edition)

  • Keshavan, Pavitra. Bilirubin: Physiological Role in Cancer and Inflammation. 2006. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1143241951.

    MLA Style (8th edition)

  • Keshavan, Pavitra. "Bilirubin: Physiological Role in Cancer and Inflammation." Doctoral dissertation, University of Cincinnati, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1143241951

    Chicago Manual of Style (17th edition)