| Summary: | 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 <i>Bvra</i> 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 <i>Ugt1</i><sup>−/−</sup> mice, <i>Bvra</i> deficiency appeared sufficient to prevent lethality and to normalize bilirubin level in adults. Although biliverdin accumulated in <i>Bvra</i>-deficient fetuses, both <i>Bvra</i><sup>−/−</sup> and <i>Bvra</i><sup>−/−</sup><i>Ugt1</i><sup>−/−</sup> pups were healthy and reached adulthood having normal liver, brain, and spleen histology, albeit with increased iron levels in the latter. During aging, both <i>Bvra</i><sup>−/−</sup> and <i>Bvra</i><sup>−/−</sup><i>Ugt1</i><sup>−/−</sup> mice presented normal levels of relevant hematological and metabolic parameters. Interestingly, the oxidative status in erythrocytes from 9-months-old <i>Bvra</i><sup>−/−</sup> and <i>Bvra</i><sup>−/−</sup><i>Ugt1</i><sup>−/−</sup> mice was significantly reduced. In addition, triglycerides levels in these 9-months-old <i>Bvra</i><sup>−/−</sup> mice were significantly higher than WT controls, while <i>Bvra</i><sup>−/−</sup><i>Ugt1</i><sup>−/−</sup> tested normal. The normal parameters observed in <i>Bvra</i><sup>−/−</sup><i>Ugt1</i><sup>−/−</sup> mice fed chow diet indicate that <i>Bvra</i> inhibition to treat unconjugated hyperbilirubinemia seems safe and effective.
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