Metabolism - Production
Bilirubin metabolism
Production
Bilirubin is derived entirely from the protoporphyrin in hemoglobin (80%) and other iron-containing heme proteins. Heme oxygenase, an enzyme found in macrophages of the liver, spleen and bone marrow, catalyzes the conversion of heme to biliverdin, releasing iron (Fe), water and carbon monoxide (CO). The Fe released is reincorporated into hemoglobin. The CO is excreted unchanged in the lung, where the amount serves as a measure of bilirubin synthesis. The second step in bilirubin production involves biliverdin reductase, found in most cells, which catalyzes the conversion of biliverdin to bilirubin.It is interesting to speculate on why bilirubin is formed in humans in the first place. There would seem to be little reason to convert biliverdin, a green, non-toxic, water-soluble pigment to the lipid-soluble, toxic bilirubin only to need to later conjugate bilirubin in order to make it water-soluble again for excretion in the bile. These chemical reactions are all energy-consuming after all.A likely explanation is that, since bilirubin production from heme turnover occurs throughout fetal life, its removal by the placenta is key. Fetal bilirubin is maintained at levels < 2 mg/dL exclusively by placental clearance. Supporting this theory is the fact that all mammals form bilirubin from biliverdin, but reptiles and birds, non-placental animals, do not. Placental transfer of unconjugated bilirubin results both from active transport and passive diffusion. There is a chemical gradient from fetus to mother which is favored by the higher maternal albumin content. The placenta is relatively impermeable to conjugated bilirubin. Further, bilirubin is an antioxidant, whose activity increases as oxygen tensions decrease. In fact, at low oxygen tensions bilirubin is more effective than vitamin E at suppressing lipid peroxidation. It may be that bilirubin serves an important protective role, both in the low oxygen tension environment of the fetus and the oxygen-rich postnatal environment.Return to top of page