Rotor's syndrome

Wolkoff, Allan W.; Wolpert, Ellen B.; Pascasio, Flora N.; Arias, Irwin M.

doi:10.1016/0002-9343(76)90426-5

Cited by 92 publications

(9 citation statements)

References 25 publications

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“…There was no change in plasma levels of conjugated bile acids, consistent with the observations noted above in Oatp1a1 and Oatp1a4 knockout mice (49). The elevation of conjugated bilirubin levels is similar to what has been described in patients with the rare disorder known as Rotor syndrome, in which there is chronic elevation of conjugated bilirubin in plasma with otherwise normal routine liver function tests (212). In recent studies, these individuals have been found to have simultaneous null mutations in the genes encoding OATP1B1 and OATP1B3 (175).…”

Section: Clearance Of Organic Anions From the Circulationsupporting

confidence: 72%

Organic Anion Uptake by Hepatocytes

Wolkoff

2014

Comprehensive Physiology

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Many of the compounds taken up by the liver are organic anions that circulate tightly bound to protein carriers such as albumin. The fenestrated sinusoidal endothelium of the liver permits these compounds to have access to hepatocytes. Studies to characterize hepatic uptake of organic anions through kinetic analyses, suggested that it was carrier-mediated. Attempts to identify specific transporters by biochemical approaches were largely unsuccessful and were replaced by studies that utilized expression cloning. These studies led to identification of the organic anion transport proteins (oatps), a family of 12 transmembrane domain glycoproteins that have broad and often overlapping substrate specificities. The oatps mediate Na+-independent organic anion uptake. Other studies identified a seven transmembrane domain glycoprotein, Na+/taurocholate transporting protein (ntcp) as mediating Na+-dependent uptake of bile acids as well as other organic anions. Although mutations or deficiencies of specific members of the oatp family have been associated with transport abnormalities, there have been no such reports for ntcp, and its physiologic role remains to be determined, although expression of ntcp in vitro recapitulates the characteristics of Na+-dependent bile acid transport that is seen in vivo. Both ntcp and oatps traffic between the cell surface and intracellular vesicular pools. These vesicles move through the cell on microtubules, using the microtubule based motors dynein and kinesins. Factors that regulate this motility are under study and may provide a unique mechanism that can alter the plasma membrane content of these transporters and consequently their accessibility to circulating ligands.

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Section: Clearance Of Organic Anions From the Circulationsupporting

confidence: 72%

Organic Anion Uptake by Hepatocytes

Wolkoff

2014

Comprehensive Physiology

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“…We also find that OATP2B1 more efficiently transports CPIII than CPI (Figure 2). Genetic mutations that cause combined deficiencies in OATP1B1/OATP1B3 (Rotor Syndrome), result in redirection of CPI and CPIII elimination from bile to urine and an increase in CPI/CPIII urinary ratio (Wolkoff et al, 1976;van de Steeg et al, 2012). Unlike CPI, basal CPIII concentrations in the blood do not appear to be associated with the reduced function SLCO1B1 c.521T>C allele (Yee et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Organic Anion Transporting Polypeptide 2B1 (OATP2B1) Genetic Variants: In Vitro Functional Characterization and Association With Circulating Concentrations of Endogenous Substrates

et al. 2021

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Organic anion transporting polypeptide 2B1 (OATP2B1, gene SLCO2B1) is an uptake transporter that is thought to determine drug disposition and in particular, the oral absorption of medications. At present, the clinical relevance of SLCO2B1 genetic variation on pharmacokinetics is poorly understood. We sought to determine the functional activity of 5 of the most common missense OATP2B1 variants (c.76_84del, c.601G>A, c.917G>A, c.935G>A, and c.1457C>T) and a predicted dysfunctional variant (c.332G>A) in vitro. Furthermore, we measured the basal plasma concentrations of endogenous OATP2B1 substrates, namely estrone sulfate, dehydroepiandrosterone sulfate (DHEAS), pregnenolone sulfate, coproporphyrin I (CPI), and CPIII, and assessed their relationships with SLCO2B1 genotypes in 93 healthy participants. Compared to reference OATP2B1, the transport activities of the c.332G>A, c.601G>A and c.1457C>T variants were reduced among the substrates examined (estrone sulfate, DHEAS, CPI, CPIII and rosuvastatin), although there were substrate-dependent effects. Lower transport function of OATP2B1 variants could be explained by diminished cell surface expression. Other OATP2B1 variants (c.76-84del, c.917G>A and c.935G>A) had similar activity to the reference transporter. In the clinical cohort, the SLCO2B1 c.935G>A allele was associated with both higher plasma CPI (42%) and CPIII (31%) concentrations, while SLCO2B1 c.917G>A was linked to lower plasma CPIII by 28% after accounting for the effects of age, sex, and SLCO1B1 genotypes. No association was observed between SLCO2B1 variant alleles and estrone sulfate or DHEAS plasma concentrations, however 45% higher plasma pregnenolone sulfate level was associated with SLCO2B1 c.1457C>T. Taken together, we found that the impacts of OATP2B1 variants on transport activities in vitro were not fully aligned with their associations to plasma concentrations of endogenous substrates in vivo. Additional studies are required to determine whether circulating endogenous substrates reflect OATP2B1 activity.

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“…The separation and determination of coproporphyrin I and III isomers is clinically important. It has been used for the differential diagnosis of the porphyrias (Doss & Schermuly, 1976) and for distinguishing the Dubin-Johnson Syndrome from the Rotor Syndrome (Ben-Ezzer et al., 1971;Wolkoff et al, 1976). In addition the analysis and preparative isolation of pure isomers is important in the fields of porphyrin chemistry and biochemistry.…”

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confidence: 99%