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Journal of cancer survivorship : research and practice

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Drugs 81 , 21332137 (2021)

Bilirubin is a known major antioxidant in blood and negative associations between serum levels and numerous oxidative stress-mediated diseases including cardiovascular, certain cancer and autoimmune diseases have been published in recent years.46 In fact, hyperbilirubinemic subjects with Gilbert syndrome were shown to have substantially lower risk of colon cancer,5,7 and iatrogenic increase of serum bilirubin levels was proposed as a plausible approach to prevent oxidative stress-mediated diseases.8 In addition, bilirubin has been reported to inhibit mitochondrial cytochrome c oxidase activity,9 which causes cells to undergo premature apoptosis mediated through mitochondrial depolarization, caspase-3 activation and increased expression of mitochondria-associated pro-apoptotic Bax protein,10 or even more profound changes in mitochondrial membrane integrity.11 Simultaneously, bilirubin was demonstrated to substantially inhibit NADPH oxidase activity,12,13 and the same inhibitory action was described also for phycocyanin and phycocyanobilin.13 Bilirubin is the major product of the heme catabolic pathway in the intravascular compartment, and its production is dependent on heme oxygenase activity (HMOX), the rate-limiting enzyme of this pathway