Multidrug resistance associated protein 1 protects against bilirubin‐induced cytotoxicity

Calligaris, Sebastiàn; Cekic, Dean; Roca-Burgos, Leslye; Gerin, Fabio; Mazzone, Graciela L.; Ostrow, J. Donald; Tiribelli, Claudio

doi:10.1016/j.febslet.2006.01.056

Cited by 30 publications

(21 citation statements)

References 28 publications

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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%

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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%

“…Export of UCB by two ATP-binding cassette transporters (ABCc1 and ABCb1) has a role in protecting cultured central nervous system cells from UCB toxicity (15)(16)(17)(18)(19). Therefore, the mRNA expression of the three Cyps and two ABC transporters was assessed in selected brain regions by quantitative PCR (qPCR).…”

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confidence: 99%

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

et al. 2012

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“…We compared the susceptibility of four cell lines to bilirubin toxicity: HeLa cells (20) and mouse embryo fibroblasts (21), previously used for bilirubin studies in our laboratory, and two neuronal cell lines, SHSY5Y neuroblastoma cells and striatal precursor 2a1 cells.…”

Section: Methodsmentioning

confidence: 99%

Cytotoxicity Is Predicted by Unbound and Not Total Bilirubin Concentration

et al. 2007

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ABSTRACT:Although it has been suggested that the unbound, free, (B f ) rather than total (B T ) bilirubin level correlates with cell toxicity, direct experimental evidence supporting this conclusion is limited. In addition, previous studies never included a direct measurement of B f , using newer, accurate methods. To test "the free bilirubin hypothesis", in vitro cytotoxicity was assessed in four cell lines exposed to different B f concentrations obtained by varying B T /Albumin ratio, using serum albumins with different binding affinities, and/or displacing unconjugated bilirubin (UCB) from albumin with a sulphonamide. B f was assessed by the modified, minimally diluted peroxidase method. Cytotoxicity varied among cell lines but was invariably related to B f and not B T . Light exposure decreased toxicity parallel to a decrease in B f . In the absence of albumin, no cytotoxicity was found at a B f of 150 nM whereas in the presence of albumin a similar B f resulted in a 40% reduction of viability indicating the importance of total cellular uptake of UCB in eliciting toxic effect. In the presence of albumin-bound UCB, bilirubin-induced cytotoxicity in a given cell line is accurately predicted by B f irrespective of the source and concentration of albumin, or total bilirubin level. (Pediatr Res 62: 576-580, 2007) P lasma levels of unconjugated bilirubin (UCB) are elevated in almost all newborn infants. In some infants with markedly elevated plasma UCB levels, bilirubin causes neurotoxicity, sometimes resulting in permanent neurologic dysfunction (1). Management guidelines for jaundiced term and near-term infants, published by the American Academy of Pediatrics (AAP), are based on the premise that total serum bilirubin concentration (B T ) is the best available predictor of risk for bilirubin-induced neurologic damage (BIND) (2). Clinical evidence has indicated, however, that B T , beyond a threshold value of 20 mg/dL, is a poor discriminator of individual risk for BIND (3,4). Since over 99.9% of total plasma UCB (B T ) is bound to albumin or apolipoprotein D (5) and only unbound bilirubin can enter the brain across an intact blood-brain barrier, the level of unbound "free" bilirubin (B f ) should theoretically provide a more accurate indication of the risk of kernicterus.Published studies of UCB toxicity in cell cultures, conducted with different types of albumin at varied molar ratios of bilirubin/albumin (6 -9) reported an increase in cell damage depending on B T . The hypothesis that cell injury is correlated better with B f was first suggested by Nelson et al. (10) in an in vitro study. Moreover, Ostrow et al. (11) reported a meta analysis of in vitro studies that suggested cytotoxicity was better correlated with B f (11). This conclusion was however based on B f calculations using published binding constants, rather than direct measurement in the culture medium, and was thus limited by unknown variations in binding associated with differences in the composition of the incubation media.In jaundiced newborns...

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“…FLVCR-null and littermate control mouse embryonic fibroblasts (MEFs) isolated from day 12.5 embryos (2) were cultured in DMEM with 10% FBS as described above. The MTT assay (American Type Culture Collection, Manassas, VA) was performed as described previously (22).…”

Section: Methodsmentioning

confidence: 99%

Kinetics and Specificity of Feline Leukemia Virus Subgroup C Receptor (FLVCR) Export Function and Its Dependence on Hemopexin

Yang

Philips

Doty

et al. 2010

Journal of Biological Chemistry

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The feline leukemia virus subgroup C receptor (FLVCR) is a heme export protein that is required for proerythroblast survival and facilitates macrophage heme iron recycling. However, its mechanism of heme export and substrate specificity are uncharacterized. Using [55 Fe]heme and the fluorescent heme analog zinc mesoporphyrin, we investigated whether export by FLVCR depends on the availability and avidity of extracellular heme-binding proteins. Export was 100-fold more efficient when the medium contained hemopexin (K d < 1 pM) compared with albumin (K d ‫؍‬ 5 nM) at the same concentration and was not detectable when the medium lacked heme-binding proteins. Besides heme, FLVCR could export other cyclic planar porphyrins, such as protoporphyrin IX and coproporphyrin. However, FLVCR has a narrow substrate range because unconjugated bilirubin, the primary breakdown product of heme, was not transported. As neither protoporphyrin IX nor coproporphyrin export improved with extracellular hemopexin (versus albumin), our observations further suggest that hemopexin, an abundant protein with a serum concentration (6.7-25 M) equivalent to that of the iron transport protein transferrin (22-31 M), by accepting heme from FLVCR and targeting it to the liver, might regulate macrophage heme export and heme iron recycling in vivo. Final studies show that hemopexin directly interacts with FLVCR, which also helps explain why FLVCR, in contrast to some major facilitator superfamily members, does not function as a bidirectional gradient-dependent transporter. Together, these data argue that hemopexin has a role in assuring systemic iron balance during homeostasis in addition to its established role as a scavenger during internal bleeding or hemolysis.The biological roles of heme are diverse and encompass most areas of cell metabolism and gene regulation. Heme serves as a prosthetic group in the hemeproteins, which are involved in crucial biological functions, including oxygen binding (hemoglobin and myoglobin), oxygen metabolism (oxidases, peroxidases, catalases, and hydroxylases), electron transfer (cytochromes) (4), and signal transduction (nitric-oxide synthases) (5). In addition, heme serves as a signaling molecule in erythropoiesis and other physiological systems. Because heme generally signals by binding and inactivating a transcriptional repressor (e.g. Bach1) or translational inhibitor (e.g. heme-regulated inhibitor and thus eIF␣2 kinase), its impact is immediate (6 -8). Perhaps for this reason, heme is utilized in time-sensitive processes, such as the regulation of circadian rhythm (9), N-end rule pathway/protein ubiquitination (10), and globin synthesis. Heme is also required for microRNA processing (11). However, excess free or non-protein-bound heme damages lipid, protein, and DNA through the generation of reactive oxygen species, resulting in cellular injury and death (12). Therefore, free cellular heme levels must be tightly regulated to provide an adequate supply yet avoid heme toxicities (4,(13)(14)(15).Most studies of h...

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Multidrug resistance associated protein 1 protects against bilirubin‐induced cytotoxicity

Cited by 30 publications

References 28 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

Cytotoxicity Is Predicted by Unbound and Not Total Bilirubin Concentration

Kinetics and Specificity of Feline Leukemia Virus Subgroup C Receptor (FLVCR) Export Function and Its Dependence on Hemopexin

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