Kernicterus in Rats Lacking Glucuronyl Transferase

Johnson, Lois

doi:10.1001/archpedi.1961.04020040050007

Cited by 87 publications

(26 citation statements)

References 72 publications

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“…These are consistent with previous biochemical studies in adult Gunn rats (3,9,10,27), and support the notion that the sulfonamide acts to promote the net transfer of bilirubin out of the circulation and into tissue such as the central nervous system (3,(7)(8)(9)28).…”

Section: Methodssupporting

confidence: 91%

Acute Brainstem Auditory Evoked Potential Abnormalities in Jaundiced Gunn Rats Given Sulfonamide

Shapiro

1988

Pediatr Res

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Section: Methodssupporting

confidence: 91%

Acute Brainstem Auditory Evoked Potential Abnormalities in Jaundiced Gunn Rats Given Sulfonamide

Shapiro

1988

Pediatr Res

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“…Regarding the susceptibility to bilirubin-induced injury, early studies on neonates who had hemolytic disease demonstrated a male predominance in neonatal mortality attributable to kernicterus [54][55][56], a finding also reported in hyperbilirubinemic premature neonates [57]. Studies in the hyperbilirubinemic Gunn rat model of kernicterus are also consistent with the notion of an increased male susceptibility to bilirubin-induced injury, demonstrating an increased prevalence of kernicterus [58] and higher cerebellar brain bilirubin contents in jaundiced male pups [59] as contrasted with their jaundiced female counterparts. The similar total serum bilirubin and serum albumin levels in hyperbilirubinemic male and female Gunn rat pups in the latter study suggest sex-specific differences in:…”

Section: Male Sex and Risksupporting

confidence: 64%

Hyperbilirubinemia and Bilirubin Toxicity in the Late Preterm Infant

Watchko

2006

Clinics in Perinatology

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“…Sulfadimethoxine was used to displace bilirubin from albumin in hyperbilirubinemic j/j Gunn rat pups increasing their brain bilirubin content, risk of acute bilirubin-induced brain injury (kernicterus) and prevalence of overt neurobehavioral abnormalities. 4,6,[15][16][17][18][19][20] Saline (nonsulfadimethoxine)-treated hyperbilirubinemic j/j pups show no obvious neurobehavioral abnormalities but extensive neuronal degeneration of Purkinje cells in the cerebellar roof nuclei 16 and resultant cerebellar hypoplasia. 4,16 Non-jaundiced heterozygous J/j pups show normal neurobehavior and postnatal cerebellar weights whether treated with sulfadimethoxine or not, that is, no evidence of acute or chronic bilirubin-induced brain injury.…”

mentioning

confidence: 99%

Calculated free bilirubin levels and neurotoxicity

2009

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Although most bilirubin in the circulation is bound to albumin, a relatively small fraction remains unbound. The concentration of this 'free' bilirubin (B F ) is believed to dictate the biologic effects of bilirubin in jaundiced newborns, including its neurotoxicity. The threshold at which B F produces changes in cellular function culminating in permanent cell injury and cell death has been the subject of considerable debate. The objective of this study was to compare calculated central nervous system (CNS) B F levels in Gunn rat pups during (i) peak postnatal hyperbilirubinemia and (ii) sulfadimethoxine-induced acute bilirubin encephalopathy (ABE) previously reported from our laboratory with those predicted in human neonates with peak total serum bilirubin (TSB) levels of 35 mg per 100 ml (599 mmol l À1 ), a clinical cohort that often evidence moderate-to-severe adverse post-icteric neurodevelopmental sequelae. Homozygous j/j Gunn rat pups with neonatal hyperbilirubinemia due to a deficiency of the bilirubin conjugating enzyme uridine-diphosphate-glucuronosyl transferase 1A1 were studied along with non-jaundiced littermate heterozygous J/j controls. Sulfadimethoxine was used to displace bilirubin from albumin in hyperbilirubinemic j/j Gunn rat pups to increase their brain bilirubin content and induce ABE. Calculated Gunn rat CNS B F levels were determined as a function of genotype, sulfadimethoxine exposure and albumin-bilirubin binding constant. These data were compared with the human CNS B F predicted from the calculated serum B F in human neonates with a TSB of 35 mg per 100 ml as a function of albumin-bilirubin binding constant, albumin concentration and the assumption that at this hazardous bilirubin level there may be rapid equilibration of B F between serum and brain. There was a large gap between the upper limit of the calculated CNS B F 95% confidence interval (CI) range in non-jaundiced J/j pups (for example, 112 nM at k ¼ 9.2 l mmol À1 ) and the lower limit seen in the saline-treated hyperbilirubinemic j/j pups (556 nM at k ¼ 9.2 l mmol À1 ) as well as between the upper limit in saline-treated hyperbilirubinemic j/j pups (1110 nM at k ¼ 9.2 l mmol À1 ) and the lower limit seen in sulfadimethoxine-treated jaundiced j/j littermates (3461 nM at k ¼ 9.2 l mmol À1 ). There was considerable overlap and remarkable similarity between the predicted human CNS B F values at a TSB of 35 mg per 100 ml for a range of reported human serum bilirubin-albumin binding constants and albumin concentrations, and those calculated for saline-treated hyperbilirubinemic j/j Gunn rat pups. This exercise yielded strikingly similar apparent calculated neurotoxic B F levels for Gunn rat pups and human neonates rather than orders of magnitude differences that might have been predicted at the outset and add to a growing literature aimed at defining clinically germane neurotoxic B F thresholds.

show abstract

Kernicterus in Rats Lacking Glucuronyl Transferase

Abstract: In previous papers,20,5,55 we have described the occurrence of kernicterus in the Gunn strain of rats, as well as some of the factors which influence its incidence and pathogenesis. This paper concludes our current study of the rats and summarizes approximately 2 years of observation.

Cited by 87 publications

References 72 publications

Acute Brainstem Auditory Evoked Potential Abnormalities in Jaundiced Gunn Rats Given Sulfonamide

Acute Brainstem Auditory Evoked Potential Abnormalities in Jaundiced Gunn Rats Given Sulfonamide

Hyperbilirubinemia and Bilirubin Toxicity in the Late Preterm Infant

Calculated free bilirubin levels and neurotoxicity

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