Hepatobiliary excretion of biliverdin isomers and C10-substituted biliverdins in Mrp2-deficient (TR−) rats

McDonagh, Antony F.; Lightner, David A.; Kar, A.; Norona, Wilma S.

doi:10.1016/s0006-291x(02)00325-x

Cited by 13 publications

(11 citation statements)

References 21 publications

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“…However, owing to the low UDPglucuronosyl transferase activity of the fetal liver and the absence of placental biotransformation of unconjugated BR during transplacental transfer, when this compound is administered through the umbilical artery of in situ perfused rat placentas (5), MRP2 is not expected to play an important role in BR transfer across the placenta. Moreover, the excretion of dicarboxylate organic anions related to BV into rat bile is also mediated by MRP2-independent mechanisms (24), suggesting that this export pump is not responsible for the poor release of BV from the trophoblast into the maternal blood across the apical pole of this epithelium.…”

Section: Resultsmentioning

confidence: 99%

Excretion of fetal biliverdin by the rat placenta-maternal liver tandem

Briz

Macı́as

Pérez

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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Fetal liver immaturity is accompanied by active heme catabolism. Thus fetal biliary pigments must be excreted toward the mother by the placenta. To investigate biliverdin handling by the placenta-maternal liver tandem, biliverdin-IXalpha was administered to 21-day pregnant rats through the jugular vein or the umbilical artery of an in situ perfused placenta. Jugular administration resulted in the secretion into maternal bile of both bilirubin and biliverdin (3:1). However, when biliverdin was administered to the placenta, most of it was transformed into bilirubin before being transferred to the maternal blood. Injecting Xenopus laevis oocytes with mRNA from rat liver or placenta enhanced their ability to take up biliverdin, which was inhibited by estradiol 17beta-d-glucuronide. The expression of three OATP isoforms in this system revealed that they have a varying degrees of ability to transport biliverdin (Oatp1/1a1 > Oatp2/1a4 > Oatp4/1b2). The abundance of their mRNA in rat trophoblast was Oatp1/1a1 >> Oatp4/1b2 > Oatp2/1a4. The expression of biliverdin-IXalpha reductase in rat placenta was detected by RT-PCR/sequencing and Western blot analysis. The relative abundance of biliverdin-IXalpha reductase mRNA (determined by real-time quantitative RT-PCR) was fetal liver > placenta > maternal liver. Common bile duct ligation in the last week of pregnancy induced an upregulation of biliverdin-IXalpha reductase in maternal liver but had no effect on fetal liver and placenta. In conclusion, several members of the OATP family may contribute to the uptake of fetal biliverdin by the rat placenta. Before being transferred to the mother, biliverdin is extensively converted into bilirubin by biliverdin-IXalpha reductase, whose expression is maintained even though bilirubin excretion into maternal bile is impaired.

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Section: Resultsmentioning

confidence: 99%

Excretion of fetal biliverdin by the rat placenta-maternal liver tandem

Briz

Macı́as

Pérez

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Unconjugated bilirubin (λmax 450 nm) and its isomers, bilirubin mono and diglucuronides (λmax 450 nm), bilirubin ditaurate (λmax 450 nm) and biliverdin (λmax 375 nm) were detected using a photodiode array (240–650 nm), in a single run. The bile pigments were separated using a reverse phase C18 column (Ultrasphere, 4.6 mm × 250 mm, 5 µm; Beckman Coulter, Fullerton, CA, USA) as described by McDonagh et al . (2002).…”

Section: Methodsmentioning

confidence: 99%

Bile pigment pharmacokinetics and absorption in the rat: therapeutic potential for enteral administration

Bulmer

Coombes

Blanchfield

et al. 2011

British J Pharmacology

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BACKGROUND AND PURPOSEBilirubin and biliverdin possess antioxidant and anti-inflammatory properties and their exogenous administration protects against the effects of inflammation and trauma in experimental models. Despite the therapeutic potential of bile pigments, little is known about their in vivo parenteral or enteral absorption after exogenous administration. This study investigated the absorption and pharmacokinetics of bile pigments after i.v., i.p. and intraduodenal (i.d.) administration in addition to their metabolism and routes of excretion. EXPERIMENTAL APPROACHAnaesthetized Wistar rats had their bile duct, jugular and portal veins cannulated. Bile pigments were infused and their circulating concentrations/biliary excretion were measured over 180 min. KEY RESULTSAfter i.v. administration of unconjugated bilirubin, biliverdin and bilirubin ditaurate, their plasma concentrations decreased exponentially over time. Subsequently, native and metabolized compounds appeared in the bile. When administered i.p., their absolute bioavailabilities equalled 14.0, 16.1 and 33.1%, respectively, and correspondingly 38, 28 and 34% of the same bile pigment doses were excreted in the bile. Administration of unconjugated bilirubin and bilirubin ditaurate i.d. increased their portal and systemic concentrations and their systemic bioavailability equalled 1.0 and 2.0%, respectively. Correspondingly, 2.7 and 4.6%, of the doses were excreted in the bile. Biliverdin was rapidly metabolized and these products were absorbed and excreted via the urine and bile. CONCLUSIONS AND IMPLICATIONSBile pigment absorption from the peritoneal and duodenal cavities demonstrate new routes of administration for the treatment of inflammatory and traumatic pathology. Oral biliverdin administration may lead to the production of active metabolite that protect from inflammation/complement activation.

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“…The efficient hepatic disposition of bilirubin together with severe bilirubin-induced encephalopathy observed in jaundiced newborns [252] have promoted the viewpoint that bilirubin is a toxic, lipophilic, waste compound, and something solely to be eliminated. However, questions remain concerning the survival and fitness advantages of animals expressing biliverdin reductase [118], catalyzing bilirubin production from biliverdin, which is itself a hydrophilic tetrapyrrole that can be eliminated unmodified, in both bile [253] and urine [254]. The discovery of the antioxidant property of bilirubin [255] contributed to challenge the viewpoint of bilirubin as a mere toxic catabolite [256].…”

Section: Bilirubin As An Endogenous Antioxidantmentioning

confidence: 99%

Bioavailability of Flavonoids: A Review of Their Membrane Transport and the Function of Bilitranslocase in Animal and Plant Organisms

Passamonti¹,

Terdoslavich²,

Franca³

et al. 2009

CDM

169

140

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Fruits and vegetables are rich in flavonoids, and ample epidemiological data show that diets rich in fruits and vegetables confer protection against cardiovascular, neurodegenerative and inflammatory diseases, and cancer. However, flavonoid bioavailability is reportedly very low in mammals and the molecular mechanisms of their action are still poorly known. This review focuses on membrane transport of flavonoids, a critical determinant of their bioavailability. Cellular influx and efflux transporters are reviewed for their involvement in the absorption of flavonoids from the gastro-intestinal tract and their subsequent tissue distribution. A focus on the mammalian bilirubin transporter bilitranslocase (TCDB 2.A.65.1.1) provides further insight into flavonoid bioavailability and its relationship with plasma bilirubin (an endogenous antioxidant). The general function of bilitranslocase as a flavonoid membrane transporter is further demonstrated by the occurrence of a plant homologue in organs (petals, berries) where flavonoid biosynthesis is most active. Bilitranslocase appears associated with sub-cellular membrane compartments and operates as a flavonoid membrane transporter.

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Hepatobiliary excretion of biliverdin isomers and C10-substituted biliverdins in Mrp2-deficient (TR−) rats

Cited by 13 publications

References 21 publications

Excretion of fetal biliverdin by the rat placenta-maternal liver tandem

Excretion of fetal biliverdin by the rat placenta-maternal liver tandem

Bile pigment pharmacokinetics and absorption in the rat: therapeutic potential for enteral administration

Bioavailability of Flavonoids: A Review of Their Membrane Transport and the Function of Bilitranslocase in Animal and Plant Organisms

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