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Bilirubin is metabolized by brain mitochondrial membranes. This activity increases with postnatal age, is higher in glia than in neurons, and is subject to genetic variability. The rates of oxidation are such that this mechanism probably contributes meaningfully to clearance of bilirubin from brain. Phenobarbital is a well-known inducer of bilirubin-metabolizing enzymes in the liver. Previous incomplete data had suggested that phenobarbital treatment might also affect bilirubin metabolism in brain. We studied the clearance of bilirubin from brain (branch 1) as well as the oxidation of bilirubin by brain mitochondrial membranes (branch 2) following pretreatment of young adult SPRD rats with phenobarbital 75 mg/kg i.p. daily for 7 days; controls received solvent only. On day 8, rats in branch 1 (n = 8 in both phenobarbital-treated and control groups) were anesthetized and 50 mg/kg bilirubin was infused i.v. over 5 min. Rats were sacrificed after 60 min and brain bilirubin determined by acid chloroform extraction. In branch 2 (n = 7 in both groups) rats were sacrificed with i.p. pentobarbital, brains were homogenized in 0.32 M sucrose and mitochondria separated out by differential centrifugation. The mitochondrial membrane suspension was added to a 10-µmol/l bilirubin solution, and the rate of bilirubin oxidation was measured at 440 nm. As expected following phenobarbital treatment, serum bilirubin was slightly lower in phenobarbital-treated vs. control rats [126 ± 32 vs. 140 ± 21 µmol/l (mean ± SD); p = 0.3]. Brain bilirubin values were also lower in the phenobarbital-treated rats (0.44 ± 0.06 vs. 0.52 ± 0.08 nmol/g, p = 0.044). As the lower brain bilirubin values in phenobarbital-treated rats could be due entirely to lower serum bilirubin values, we compared the brain:serum bilirubin ratios in the two groups. These were not different (0.0063 ± 0.0016 vs. 0.0064 ± 0011). The rate of bilirubin oxidation was significantly lower in phenobarbital-treated vs. control rats (256 ± 10 vs. 286 ± 26 pmol/min/mg protein, p = 0.023). We conclude that phenobarbital inhibits bilirubin metabolism in brain. However, albeit statistically significant, the difference is small and may not be biologically meaningful. Thus, pretreatment with phenobarbital had no effect on overall brain bilirubin clearance rate. We speculate that phenobarbital treatment may be neither helpful nor harmful relative to the neurotoxic effects of bilirubin in infants with already established jaundice.