The physiological relevance of bile pigments

Bile pigments are naturally occurring compounds that are produced in the human body. These pig-ments, called bilirubin and biliverdin, are intensely coloured and can been seen in the skin during jaun-dice (bilirubin) and in the green (biliverdin) and yellow (bilirubin) colour of bruises. In the past, bile pig-ments and bilirubin in particular have been thought of as useless or even harmful compounds because jaundice is associated with disease and occasionally can be toxic. However, in the past 20 years, a growing number of research groups have investigated the possible beneficial effects of bile pigments in human body. Very important early findings showed bile pigments were part of a group of compounds called antioxidants, thereby protecting from free radicals that are produced constantly in the human body. Following studies showed that people with mildly elevated bilirubin concentrations in their blood, suffered lower rates of heart disease, which causes sudden death from heart attack. More recent evidence suggests that bile pigments also prevent compounds that cause cancer, from damaging the genetic program of cells called DNA. Co-incidentally, people with elevated bilirubin concentrations are also less likely to suffer from cancer. Before the real importance of bile pigments in the human body can be realised, the mechanism (the `how`) of their protection from heart disease and cancer must be established. When the bile pigments` mechanism of action is known then scientists can investigate new ways of altering the amount of circulating bile pigments, which existing research suggests could prevent the largest killers of people in Western society (cardio- vascular disease and cancer). A series of studies within this project will focus on revealing the protective effects of bile pigments on the development of cancer. Importantly, the studies will investigate how bile pigments protect from cancer, which is currently unknown. The studies progress from pure science investigations (chemistry) to more complex biological experiments in bacteria, animal and human cells, humans and finally in the bodies of animals. These studies will progressively establish the mechanism and potential of bile pigments to protect from cancer, finally testing whether the compounds could be beneficial in humans and animals. Once the effects of bile pigments in animal models of cancer have been established, we will be in a better position to comment on the physiological importance of these poorly understood naturally occurring compounds and apply our knowledge in humans.

Bile pigments are naturally occurring compounds that are produced in the human body. These pigments, called bilirubin and biliverdin, are intensely coloured and can been seen in the skin during jaundice (bilirubin) and in the green (biliverdin) and yellow (bilirubin) colour of bruises. In the past, bile pigments and bilirubin in particular have been thought of useless or even harmful compounds because jaundice is associated with disease and occasionally can be toxic. Today their positive effects on the organism are well known, mainly as antioxidants, but in large epidemiological studies it was observed that people with mildly elevated bilirubin concentrations in their blood, suffered lower rates of heart disease and other chronic diseases. More recent evidence suggests that bile pigments also prevent compounds that cause cancer, from damaging the genetic program of cells called DNA. Co-incidentally, people with elevated bilirubin concentrations are also less likely to suffer from cancer. Since the mechanism (the how) of their protection was not established the project was aimed to fill the gab und explore their mode of action in comprehensive studies. In bacterial studies it was shown that 8 tested bile pigments (which are all abundant in the human body) were able to reduce the effects of foodborne and chemical mutagens. In human cancer cell lines bile pigments were able to induce DNA damage and apoptosis. In a human study subjects with increased blood bilirubin levels (also known as Gilberts Syndrome) showed an improved lipid metabolism (with lower risk factors such as LDL-cholesterol), lower mediators for inflammation and a lower body mass index. Interestingly, the effects were more pronounced in older subjects. This was also approved in a rat model (normo- vs. hyperbilirubinemic rats). Protection of DNA and chromosomal damage was not observed by bilirubin. Taken together the project could show that bile pigments exhibit essential function in the organism and subjects with increased blood bilirubin are protected by chronic diseases due to their improved lipid metabolism and lower body weight. Furthermore the antimutagenic effect of bile pigments was extensively proven; especially the bile pigment which are found in the GUT were highly active.