Accumulation of neurotoxic
bilirubin due to a transient neonatal or persistent inherited deficiency of
bilirubin glucuronidation activity can cause irreversible brain damage and death. Strategies to inhibit
bilirubin production and prevent neurotoxicity in neonatal and adult settings seem promising. We evaluated the impact of Bvra deficiency in neonatal and aged mice, in a background of unconjugated
hyperbilirubinemia, by abolishing
bilirubin production. We also investigated the disposal of
biliverdin during fetal development. In Ugt1-/- mice, Bvra deficiency appeared sufficient to prevent lethality and to normalize
bilirubin level in adults. Although
biliverdin accumulated in Bvra-deficient fetuses, both Bvra-/- and Bvra-/-Ugt1-/- pups were healthy and reached adulthood having normal liver, brain, and spleen histology, albeit with increased
iron levels in the latter. During aging, both Bvra-/- and Bvra-/-Ugt1-/- mice presented normal levels of relevant hematological and metabolic parameters. Interestingly, the oxidative status in erythrocytes from 9-months-old Bvra-/- and Bvra-/-Ugt1-/- mice was significantly reduced. In addition,
triglycerides levels in these 9-months-old Bvra-/- mice were significantly higher than WT controls, while Bvra-/-Ugt1-/- tested normal. The normal parameters observed in Bvra-/-Ugt1-/- mice fed chow diet indicate that Bvra inhibition to treat unconjugated
hyperbilirubinemia seems safe and effective.