Toxicity of Bilirubin

The toxic action of bilirubin on tissue metabolism has been demonstrated both by in vitro and in vivo experiments. Lathe (LI) added bilirubin to brain brei, in concentrations such as occur in hemolytic disease of the newborn and prematurity, and observed a decrease in oxygen consumption. Day (D3) was able to reverse this depressed respiration by the addition of cytochrome c or methylene blue. Bowen and Waters (B16) then showed that this reversal could also be efFected by diphosphopyridine nucleotide. Zetterstrom and Ernster (Zl), using isolated rat liver mitochondria, showed that bilirubin in concentrations 

---

Prevention alone is often not enough. Children still become jaundiced even after careful assessment. When this occurs.it is important to assess the risk of developing significant hyperbilirubinemia. The main concern is that the child will develop acute bilirubin encephalopathy, which is caused by the toxicity of bilirubin on the basal ganglia and other brain stem nuclei. There are early, middle, and late stages of acute bilirubin encephalopathy (Table 22-3). The term kernicterus is applied to chronic... 

This problem was addressed by refining analysis techniques to permit analysis of energy metabolites in small 20-80 mg brain samples (Schenker et al., 1966). This approach permitted analysis in cortex, subcortex, and cerebellum of ATP in symptomatic animals without inclusion in the kemicteric samples of normal tissue. Results showed a 13% depletion in the cerebellum of mildly symptomatic Gunn rats, and a 27% depletion of ATP in animals with advanced symptoms. Cortex and subcortex (nonstained) samples were unchanged. This supported the concept, based on symptomatology, and neuropathologic findings, that the toxicity of bilirubin in vivo is limited to the cerebral areas affected. 

Increased toxicity of irinotecan, increased levels of bilirubin... 

The activity of glucuronidation is low in the newborn, especially in premature babies (6). This is evident in the jaundice observed in many newborns because the major clearance pathway for bilirubin is glucuronidation. This can also lead to increased toxicity of some drugs in the newborn such as the grey baby syndrome seen in newborns treated with chloramphenicol. 

Jaundice is notitseifa disease but is an important diagnostic indicator of many underiying conditions, in newborns, jaundice can iead to toxic encephalopathy due to deposition of bilirubin within the lipid regions of membranes of the brain (kernicterus). 

Sulfonamides compete for sites on plasma proteins that are responsible for the binding of bilirubin. As a result, less bilirubin is bound, and in the newborn, the unbound bilirubin can be deposited in the basal ganglia and subthalamic nuclei, causing kernicterus, a toxic encephalopathy. For this reason, sulfonamides should not be administered to newborns or to women during the last 2 months of pregnancy. 

The extract from Berberis vulgaris as well as that of the alkaloids berberine, oxyacanthine, berbamine, jatrorrhizine, and columbamine stimulate secretion of the bile (480, 481). The strongest effect was produced by berberine, followed by berbamine and oxyacanthine. The choleretic effect of berberine was also studied by Vartazaryan (482). Turova et al. (483) examined the effect of berberine on 225 patients with chronic cholecystitis. Peroral doses of 5-20 mg three times daily before meals over a period of 24-48 hours caused disappearance of the clinical symptoms, decrease in the level of bilirubin, and increase in the bile volume in the gall bladder. Berberine also had a favorable effect in patients with toxic hepatitis induced by intoxication. No side effects were observed on the liver functions or the blood composition. The effect of berberine on the stimulation of bile secretion was also studied by Samaj et al. (484). 

The bilirubin that is produced in phagocytic cells from degradation of hemoglobin represents the majority of the bilirubin that is produced and must be eliminated. This initially requires transport of bilirubin from the phagocytic cells to the liver. Normally, bilirubin is secreted from phagocytic cells and complexed with albumin for transport to the liver. It is essential that bilirubin is transported through the circulation bound to albumin. The toxicity of... 

TOXICITY Hemolytic anemia kemicterus (deposition of bilirubin in the brain) in newborns. 

Dopamin and phenazopyridine in therapeutically relevant concentrations can produce elevated bilirubin levels. Toxical concentration of indomethacin, oxytetracylin and pyritinol may cause an increase of bilirubin values. 

Hepatocytes growing in microcarrier systems are used for the study of liver failure and drug metabolism. Transplantation experiments of hepatocytes grown on microcarriers showed detoxification of ammonium and reduction of bilirubin concentrations after induced acute liver failure (Nagaki et aL, 1990). Furthermore, co-cultivation assays using hepatocytes and Balb/c 3T3 fibroblasts as target cells have been applied to analyse the metabolism-mediated toxicity of xenobiotics in vitro (Voss Seibert, 1992). 

Many important steps in nitrogen metabolism occur in the liver. Liver disease can be severe enough so that urea production may be compromised. Blood urea nitrogen (BUN) levels will decrease, and levels of the toxic compound ammonia will increase. Because the liver is involved in converting bilirubin to the diglucuronide that is excreted in the bile, the levels of bilirubin will increase in the body and jaundice will occur. When liver cells are damaged, enzymes such as aspartate transaminase (AST, also known as GOT, glutamate-oxaloacetate transaminase) will leak into the blood. 

---