Bilirubin Metabolism and its Disorders

Roy‐Chowdhury, Jayanta; Roy‐Chowdhury, Namita; Jansen, Petér L. M.

doi:10.1016/b978-1-4160-3258-8.50079-6

Cited by 7 publications

(3 citation statements)

References 361 publications

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“…A major reason for this limitation is that each component to the multivariate scoring system only provides a categoric variable and there is no continuous variable that spans a range of function. A further disadvantage of this strategy is the number of underlying factors that contribute to each variable 49 , 50 , 51 …”

Section: Discussionmentioning

confidence: 99%

Liver disease selectively modulates cytochrome P450–mediated metabolism

Frye

Zgheib

Matzke

et al. 2006

Clinical Pharmacology & Therapeutics

212

162

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Section: Discussionmentioning

confidence: 99%

Liver disease selectively modulates cytochrome P450–mediated metabolism

Frye

Zgheib

Matzke

et al. 2006

Clinical Pharmacology & Therapeutics

212

162

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“…Rotor syndrome (RS; OMIM %237450) is a rare, benign hereditary conjugated hyperbilirubinemia, also featuring coproporphyrinuria and strongly reduced liver uptake of many diagnostic compounds, including cholescintigraphic tracers (1)(2)(3)(4)(5)(6). RS is an autosomal recessive disorder that clinically resembles another conjugated hyperbilirubinemia, the Dubin-Johnson syndrome (DJS; OMIM #237500) (7,8).…”

Section: Introductionmentioning

confidence: 99%

Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver

Stránecký²,

et al. 2012

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Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotorsyndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic reuptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.

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“…Rotor syndrome (MIM #237450) is a benign condition presenting with conjugated hyperbilirubinemia [Rotor et al., ; Chowdhury et al., ]. This rare disease was first described in the Philippines [Rotor et al., ].…”

Section: Introductionmentioning

confidence: 99%

Recessive Inheritance of Population-Specific Intronic LINE-1 Insertion Causes a Rotor Syndrome Phenotype

et al. 2015

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Sequences of long-interspersed elements (LINE-1, L1) make up ∼17% of the human genome. De novo insertions of retrotransposition-active L1s can result in genetic diseases. It has been recently shown that the homozygous inactivation of two adjacent genes SLCO1B1 and SLCO1B3 encoding organic anion transporting polypeptides OATP1B1 and OATP1B3 causes a benign recessive disease presenting with conjugated hyperbilirubinemia, Rotor syndrome. Here, we examined SLCO1B1 and SLCO1B3 genes in six Japanese diagnosed with Rotor syndrome on the basis of laboratory data and laparoscopy. All six Japanese patients were homozygous for the c.1738C>T nonsense mutation in SLCO1B1 and homozygous for the insertion of a ∼6.1-kbp L1 retrotransposon in intron 5 of SLCO1B3, which altogether make up a Japanese-specific haplotype. RNA analysis revealed that the L1 insertion induced deleterious splicing resulting in SLCO1B3 transcripts lacking exon 5 or exons 5-7 and containing premature stop codons. The expression of OATP1B1 and OATP1B3 proteins was not detected in liver tissues. This is the first documented case of a population-specific polymorphic intronic L1 transposon insertion contributing to molecular etiology of recessive genetic disease. Since L1 activity in human genomes is currently seen as a major source of individual genetic variation, further investigations are warranted to determine whether this phenomenon results in other autosomal-recessive diseases.

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Bilirubin Metabolism and its Disorders

Cited by 7 publications

References 361 publications

Liver disease selectively modulates cytochrome P450–mediated metabolism

Liver disease selectively modulates cytochrome P450–mediated metabolism

Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver

Recessive Inheritance of Population-Specific Intronic LINE-1 Insertion Causes a Rotor Syndrome Phenotype

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