Bilirubin Benefits: Cellular Protection by a Biliverdin Reductase Antioxidant Cycle

Bilirubin is widely known as an end product of heme metabolism. Very high levels of serum bilirubin lead to its accumulation in the brain, causing kernicterus.^1,2 Almost all newborns display some level of jaundice, and some display high enough serum bilirubin levels that phototherapy or exchange transfusion is considered.

What most of the medical profession has not appreciated is that, from a teleologic perspective, biosynthesis of bilirubin as the key catabolite of heme does not seem to make sense. Bilirubin is a secondary degradation product of heme. Heme is best known as a constituent of hemoglobin, which is released in association with the breakdown of aging red blood cells. Heme also is contained in a wide range of enzymes whose turnover also leads to free heme release. Free heme can be toxic, so nature evolved a family of heme oxygenase enzymes to degrade heme,^3,4 and their blockade leads to greatly increased excretion of unmetabolized heme in the bile.⁵ These enzymes cleave the heme ring to form biliverdin, iron, and a 1-carbon fragment as carbon monoxide (CO; Fig 1). CO is increasingly appreciated as a neurotransmitter,^6,7 and iron, itself toxic, is excreted from cells by a recently characterized pump.^8–11 Biliverdin would seem to be an appropriate end product of the pathway, being readily excreted in the bile to enter the intestine and leave the body in the feces. Indeed, in birds, reptiles, and amphibians, biliverdin is the predominant end product of heme degradation.¹² For reasons that until now have seemed obscure, in mammals, biliverdin undergoes additional metabolism, being reduced by biliverdin reductase (BVR) to bilirubin, a step that consumes the energy resource nicotinamide adenine dinucleotide phosphate (NADPH).¹³ As bilirubin is more hydrophobic and insoluble than biliverdin, …

Reprint requests to (S.H.S.) Department of Neuroscience, Johns Hopkins School of Medicine, 725 North Wolfe St, Baltimore, MD 21205. E-mail: ssnyder{at}bs.jhmi.edu