Metabolism and Disposition of C14-Bilirubin in Congenital Nonhemolytic Jaundice*

Schmid, Rudi; Hammaker, Lydia

doi:10.1172/jci104858

Cited by 223 publications

(162 citation statements)

References 35 publications

(47 reference statements)

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“…The production rates of UCB in the organ and the permeability to UCB of the blood-organ barriers (10) determine the supply of UCB. Because Gunn (jj) rats cannot conjugate bilirubin, the cellular export of UCB (15,16,18,19) and UCB oxidation (12,14,(26)(27)(28) might play a role in UCB removal from the brain of these animals.…”

Section: Discussionmentioning

confidence: 99%

Bilirubin accumulation and Cyp mRNA expression in selected brain regions of jaundiced Gunn rat pups

et al. 2012

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Section: Discussionmentioning

confidence: 99%

Bilirubin accumulation and Cyp mRNA expression in selected brain regions of jaundiced Gunn rat pups

et al. 2012

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“…13 In addition, UCB can diffuse from the blood, across the intestinal mucosa, into the intestinal lumen. 14,15 Particularly when plasma UCB levels are high, as in Crigler-Najjar disease, large amounts of UCB can enter the intestinal lumen via extrabiliary (transintestinal) excretion. 14,15 In humans, under certain conditions up to 25% of the total amount of bilirubin that enters the intestine might be reabsorbed as UCB.…”

mentioning

confidence: 99%

“…14,15 Particularly when plasma UCB levels are high, as in Crigler-Najjar disease, large amounts of UCB can enter the intestinal lumen via extrabiliary (transintestinal) excretion. 14,15 In humans, under certain conditions up to 25% of the total amount of bilirubin that enters the intestine might be reabsorbed as UCB. 16 Amorphous calcium phosphate (CaP) was shown to bind to UCB in vitro, 17 and intestinal capture of UCB by CaP decreased plasma UCB concentrations in Gunn rats, 18 a wellestablished animal model for Crigler-Najjar disease type I.…”

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confidence: 99%

Effective oral treatment of unconjugated hyperbilirubinemia in Gunn rats

et al. 2005

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We sought to develop an oral treatment for unconjugated hyperbilirubinemia. In the Gunn rat model of unconjugated hyperbilirubinemia, dietary supplementation with the lipase inhibitor orlistat (Orl) or with calcium phosphate (CaP) decreases plasma unconjugated bilirubin (UCB) levels. We determined whether Orl, CaP, or their combination is superior to phototherapy, the conventional treatment, and whether the effects of Orl and CaP are influenced by dietary fat content. Gunn rats were treated with Orl (200 mg/kg chow), CaP (20 g/kg chow), Orl ؉ CaP, or continuous phototherapy (19 W/cm 2 /nm) during a low-fat (LF) diet (13 energy%) or high-fat (HF) diet (35 energy%). Plasma UCB and fecal fat excretion were measured before, during, and/or at the end of treatment. Orl treatment for 2 weeks (HF diet) reduced plasma UCB concentrations similar to phototherapy (؊34% and ؊28%, respectively); the combination of both was more effective than either treatment alone (؊48%; P < .001). After 3 weeks of a HF diet, plasma UCB was 46% lower compared with the LF diet (P < .001). Plasma UCB concentrations were negatively correlated with fecal fat excretion (r ‫؍‬ ؊0.96; P < .001). Irrespective of dietary fat content, 3 weeks of combined treatment (Orl ؉ CaP) decreased plasma UCB by approximately 50% (P < .01) and was more effective than phototherapy (P < .05) at the intensity provided. C rigler-Najjar disease is characterized by a permanent unconjugated hyperbilirubinemia due to absent (type I) or decreased (type II) activity of the hepatic enzyme bilirubin-UDP-glucuronosyltransferase. 1 Severe unconjugated hyperbilirubinemia can lead to bilirubin encephalopathy, kernicterus, and death. 2,3 Phenobarbital treatment can usually control unconjugated hyperbilirubinemia in Crigler-Najjar type II patients via residual enzyme induction. 4,5 Phenobarbital is not effective in Crigler-Najjar disease type I, however, so these patients have to undergo daily phototherapy, which has considerable disadvantages. Phototherapy becomes less effective with age, probably due to skin alterations, 6,7 a decrease in the surface area to body mass ratio, 8 and a diminishing compliance to the intensive phototherapy regimen, which may take up to 12 hours per day. 6 To prevent irreversible brain damage due to kernicterus, many patients with CriglerNajjar disease type I undergo liver transplantation in their second decade. 9,10 We sought to develop an alternative treatment for unconjugated hyperbilirubinemia based on oral administration and with equal or higher efficacy than phototherapy. The oral treatment strategy used in the present study is based on reducing the reabsorption of UCB 11,12 through intestinal capture. Reabsorption of UCB can contribute substantially to the pathogenesis

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“…To evaluate the significance of this effect for our studies, the turnover of labeled bilirubin was measured in permanently bile-diverted Gunn rats and compared with sham-operated rats with an intact enterohepatic circulation. We were aware of the fact that such an experiment has been performed in the past, 14 but a major difference is that, in those early experiments, the rats underwent sur- FIG. 4.…”

Section: Discussionmentioning

confidence: 99%

“…Second, UCB is thought to diffuse from the blood across the intestinal wall into the intestinal lumen and is excreted via the feces. 14,16 This pathway is not very efficient. From studies in rats, 17 neonates, 18 and humans [19][20][21] it is known that Abbreviations: UCB, unconjugated bilirubin; HPLC, high-pressure liquid chromatogra-UCB can be reabsorbed from the intestinal lumen.…”

Section: Phosphate Diet (P å 004) After 30 Weeks Plasma Biliru-mentioning

confidence: 99%

Influence of dietary calcium phosphate on the disposition of bilirubin in rats with unconjugated hyperbilirubinemia

et al. 1996

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type II patients have a less severe form of the disease because The aim of this study was to test a possible form of of residual enzyme activity. Genetic analysis of a number of therapy that could be used in the management of unconCrigler-Najjar patients 3 has revealed that type I patients jugated hyperbilirubinemia. We hypothesized that unhave mutations in both alleles of the UGT1 gene that lead conjugated bilirubin (UCB) can permeate the intestinal to complete inactivation or absence of the enzyme, whereas, wall and can thus be secreted with the feces. We have in type II patients, the mutations in the gene may be such previously observed that UCB binds to amorphous calthat the enzyme has low residual activity (õ5%). Accumulacium phosphate in vitro. Orally ingested amorphous caltion of unconjugated bilirubin (UCB) is potentially toxic and, cium phosphate may act as a trapping agent for bilirubin if not treated, can lead to mental retardation and death. [4][5][6] in the intestine, thereby preventing back-diffusion Besides liver transplantation, the only therapy known so far across the intestinal wall. In this study, we tested whether feeding calcium phosphate leads to enhanced is phototherapy. Light in the blue range (wavelength range, excretion of unconjugated bilirubin in Gunn rats. When 400-500 nm) induces formation of photoproducts of bilirubin. a purified control diet was substituted by a high calcium These photoproducts can be excreted in bile.7-9 Type II paphosphate diet, a decrease in bilirubin levels of 30% to tients can be treated with phenobarbital, an agent that is 50% in male Gunn rats and of 23% in female rats was thought to induce the residual activity of bilirubin-uridine observed. The fecal output of bilirubin was more than diphosphate-glucuronosyltransferase. Both therapies have doubled in Gunn rats in the first 3 days after the normal disadvantages, and phototherapy becomes less effective with diet had been replaced by the high calcium-phosphate age.10-13 Therefore, the goal of our research was to find possidiet. The biological half-life of 3 H-labeled bilirubin in ble new therapies for this disease. Gunn rats have the same blood was 89.8 { 17.2 hours in rats fed the purified con-enzyme deficiency as Crigler-Najjar patients and were used trol diet and 50.9 { 1.4 hours in rats fed the high calcium as a model for the disease. phosphate diet (P Å .004). After 30 weeks, plasma biliruIn Gunn rats and in Crigler-Najjar patients, the plasma bin levels were still significantly lower in Gunn rats fed bilirubin level is constant. This indicates that an equilibrium a high calcium phosphate diet. No differences were exists between bilirubin production and excretion. The bilirufound in plasma concentrations of calcium, magnesium, bin production rate in Crigler-Najjar patients is equal to that phosphate, urea, and creatinine in both Gunn rats and in normal healthy individuals.14 Thus, the amount of biliruWistar rats on control or high calcium phosphate diets. bin and bilirubin breakdown products excreted pe...

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Metabolism and Disposition of C14-Bilirubin in Congenital Nonhemolytic Jaundice*

Cited by 223 publications

References 35 publications

Bilirubin accumulation and Cyp mRNA expression in selected brain regions of jaundiced Gunn rat pups

Bilirubin accumulation and Cyp mRNA expression in selected brain regions of jaundiced Gunn rat pups

Effective oral treatment of unconjugated hyperbilirubinemia in Gunn rats

Influence of dietary calcium phosphate on the disposition of bilirubin in rats with unconjugated hyperbilirubinemia

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