The human UDP-glucuronosyltransferase 1A1 (UGT1A1) gene is regulated at the transcriptional level by a host
of xenobiotic nuclear receptors (XNRs), including PXR, CAR, LXRa/ß, PPARa in addition to the Ah receptor and
the antioxidant response factor Nrf2. Exposure of specific ligands that targets any of these receptors will lead to
induction of the UGT1A1 gene. UGT1A1 is expressed in many tissues, but predominantly in the liver and
gastrointestinal (GI) tract in adults. In addition, the UGT1A1 gene is developmentally regulated, with greatly
reduced expression in the liver and GI tract during neonatal development. Reduced expression of UGT1A1
during development plays an important physiological role because UGT1A1 is the sole glucuronosyltransferase
responsible for the metabolism of serum bilirubin. During neonatal development, reduced UGT1A1 expression
results in a build-up of serum bilirubin that is presented as either moderate or severe hyperbilirubinemia. While
usually benign, severe neonatal hyperbilirubinemia (SNH) can lead to acute and chronic encephalopathy,
abnormal behavior, opisthotonus, seizures, cerebellar hypoplasia, with potential linkages to autism spectrum
disorders. Thus, we hypothesize that in those children that are at heightened risk for bilirubin induced
neurotoxicity, controlling or accelerating the metabolism of bilirubin and reducing total serum bilirubin (TSB)
levels would prevent neurotoxicity. We have recently generated humanized UGT1 (hUGT1) mice where the
murine Ugt1 locus was replaced with the human UGT1 locus, including the human UGT1A1 gene. The human
UGT1A1 gene is regulated in a tissue specific and developmental fashion that is concordant with its expression
in human tissues. Importantly, hUGT1 mice develop SNH during the neonatal stage, providing us with a unique
animal model to examine the regulatory properties of the UGT1A1 gene. We have recently established that SNH
in hUGT1 mice can lead to seizures, cerebellar hypoplasia, with significant myelination defects, all of which can
be reversed by inducing either liver or GI tract UGT1A1 gene expression. With this background, three significant
discoveries, all identified with in the last 1-2 years and linking regulation of the UGT1A1 gene to SNH will be
examined in this proposal. First, the liver UGT1A1 gene is actively repressed during the neonatal period by the
corepressor protein SMRT (silencing mediatory of retinoic acid and thyroid hormone receptor). Second, oral
administration of isothiocyanates to neonatal hUGT1 mice, which are known to induce oxidative stress,
dramatically induce liver UGT1A1 gene expression by activating liver CAR. Third, regulation of intestinal
UGT1A1 expression during development is controlled by the corepressor protein NCoR1 (nuclear repressor
corepressor). We have linked repression of intestinal UGT1A1 gene expression by NCoR1 with IKKß activity and
oxidative stress. The regulatory events that we have outlined, each of which can reduce the risk of SNH, will be
examined to unravel these novel mechanisms leading to expression of the human UGT1A1 gene.