Upregulation in the expression of multidrug resistance protein Mrp1 mRNA and protein by increased bilirubin production in rat

Cekic, Dean; Bellarosa, Cristina; García‐Mediavilla, María Victoria; Rigato, Igino; Pascolo, Lorella; Ostrow, J. Donald; Tiribelli, Claudio

doi:10.1016/j.bbrc.2003.10.081

Cited by 20 publications

(11 citation statements)

References 22 publications

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“…This is in line with previous evidence in yeast (20) and placental trophoblasts (21,37) suggesting that Mrp1 may be involved in the ATP-dependent transport of UCB. It is supported further by our recent demonstration that rats rendered hyperbilirubinemic by hemolysis induced with phenylhydrazine exhibit up-regulation of Mrp1 mRNA and protein in the liver and spleen, and that this response is blunted by decreasing UCB formation with the heme oxygenase inhibitor, tin mesoporphyrin (38).…”

Section: Discussionsupporting

confidence: 62%

Bilirubin protects astrocytes from its own toxicity by inducing up-regulation and translocation of multidrug resistance-associated protein 1 (Mrp1)

Gennuso

Fernetti

Tirolo

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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144

128

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Unconjugated bilirubin (UCB) causes encephalopathy in severely jaundiced neonates by damaging astrocytes and neurons. Astrocytes, which help defend the brain against cytotoxic insults, express the ATP-dependent transporter, multidrug resistance-associated protein 1 (Mrp1), which mediates export of organic anions, probably including UCB. We therefore studied whether exposure to UCB affects the expression and intracellular localization of Mrp1 in cultured mouse astroglial cells (>95% astrocytes). Mrp1 was localized and quantitated by confocal laser scanning microscopy and double immunofluorescence labeling by using specific antibodies against Mrp1 and the astrocyte marker glial fibrillary acidic protein, plus the Golgi marker wheat germ agglutinin (WGA). In unexposed astrocytes, Mrp1 colocalized with WGA in the Golgi apparatus. Exposure to UCB at a low unbound concentration (B f) of 40 nM caused rapid redistribution of Mrp1 from the Golgi throughout the cytoplasm to the plasma membrane, with a peak 5-fold increase in Mrp1 immunofluorescence intensity from 30 to 120 min. B f above aqueous saturation produced a similar but aborted response. Exposure to this higher B f for 16 h markedly decreased Trypan blue exclusion and methylthiazoletetrazoilum activity and increased apoptosis 5-fold by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay. These toxic effects were modestly increased by inhibition of Mrp1 activity with 3-([3-(2-[7-chloro-2-quinolinyl]ethenyl)phenyl-(3-dimethylamino-3-oxopropyl)-thio-methyl]thio)propanoic acid (MK571). By contrast, B f ‫؍‬ 40 nM caused injury only if Mrp1 activity was inhibited by MK571, which also blocked translocation of Mrp1. Our conclusion is that in astrocytes, UCB up-regulates expression of Mrp1 and promotes its trafficking from the Golgi to the plasma membrane, thus moderating cytotoxicity from UCB, presumably by limiting its intracellular accumulation.

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Section: Discussionsupporting

confidence: 62%

Bilirubin protects astrocytes from its own toxicity by inducing up-regulation and translocation of multidrug resistance-associated protein 1 (Mrp1)

Gennuso

Fernetti

Tirolo

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

144

128

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“…5,25) I th a sa l s ob e e nr e p o r t e d that human organic anion transporting polypeptide (OATP2) mediates the highanity transport of bilirubin. 25) Furthermore, Cekic et al 26) reported that Mrp1 is upregulated when the load of unconjugated bilirubin is increased. In the present study, the serum total and direct bilirubin concentrations in the fatfree TPN group were markedly higher than those in the other groups (i.e., the oral diet and fatcontaining TPN groups) ( Table 4).…”

Section: Discussionmentioning

confidence: 97%

Role of Soybean Oil Pat Emulsion in the Prevention of Hepatic Xenobiotic Transporter mRNA Up- and Down-Regulation Induced by Overdose of Pat-free Total Parenteral Nutrition in Infant Rats

Nishimura

Yamaguchi

Yamauchi

et al. 2005

Drug Metabolism and Pharmacokinetics

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Total parenteral nutrition (TPN) is associated with cholestasis and hepatic steatosis in human infants. The present study focused on the changes in hepatic xenobiotic transporters associated with overdose of fat-free or fat-containing TPN in infant rats. Three-week-old male Sprague-Dawley rats were divided into three groups: group 1 received an oral diet, group 2 received TPN without fat, and group 3 received TPN with 20% of its calories from fat (soybean oil emulsion). After TPN administration for 4 days, both serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, which are indicators of hepatic dysfunction, in group 2 were significantly higher (p<0.001) than those in the other groups, whereas there were no differences between groups 1 and 3 in either serum AST or ALT levels. The serum bilirubin concentration in group 2 was also markedly higher than that in the other groups. Mdr2, Bsep, Mrp2, Mrp6, Oct1, and Oat2 mRNA levels were decreased in group 2 (fat-free TPN) compared with those in group 1 (oral diet), whereas Mdr1b, Mrp1, and Mrp5 mRNA levels were increased. Specifically, the level of Mdr1b mRNA in group 2 was 16 times higher (p<0.001) than that in group 1. On the other hand, the changes in these mRNA expression levels in group 3 (fat-containing TPN) were smaller than those in group 2, and specifically, the expression levels of Mdr1b, Mrp1, Mrp5, Mrp6, and Oat2 mRNA in group 3 were not significantly different from those in group 1. The results of the present study indicate that including fat in the TPN regimen is very important in preventing the mRNA up- and down-regulation of xenobiotic transporters, which is considered to be the main factor responsible for the abnormal hepatic changes such as cholestasis associated with the excessive administration of fat-free TPN.

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“…43,52) It has also been reported that human organic anion transporting polypeptide (OATP2) mediates the high-affinity transport of bilirubin. 52) Furthermore, Cekic et al 53) reported that Mrp1 is up-regulated when the unconjugated bilirubin load is increased. In our study, the serum total and direct bilirubin concentrations in the fat-free TPN group were markedly higher than those in the other groups (i.e., the oral diet and fat-containing TPN groups).…”

Section: Soybean Oil In Tpn Regimen Prevents Hepatic Transporter Mrnamentioning

confidence: 99%

Soybean Oil Fat Emulsion to Prevent TPN-Induced Liver Damage: Possible Molecular Mechanisms and Clinical Implications

Nishimura

Yamaguchi

Naito

et al. 2006

Biological & Pharmaceutical Bulletin

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INTRODUCTIONTotal parenteral nutrition (TPN), which is recognized as one method for parenteral hyperalimentation, has been found to be an effective and relatively safe method for supplying energy and nutrients to surgical patients. Following improvements in parenteral regimens including vitamins and trace elements and in catheter techniques to reduce the septic complications associated with TPN, TPN has been widely employed to provide complete nutritional support and therapeutic benefits in a variety of pathophysiological settings in which patients are unable to eat. However, TPN-induced hepatobiliary dysfunction, which was first described by Peden et al.,1) has been recognized as a cause of severe morbidity and a life-threatening complication of TPN, especially in neonates and infants. Hepatic dysfunction with steatosis is the most common complication associated with fat-free TPN in adults, and cholestasis is more common in infants.2,3) Recently, the 3-component infusion solution containing amino acids, glucose, and soybean oil emulsion, GA-1080 (MIXID ® , Otsuka Pharmaceutical Factory, Inc.; Tokushima, Japan), has been demonstrated to be effective in overcoming such hepatic morbidity in clinical studies.4) Intravenous fat emulsions, especially soybean oil, are now available as a source of essential fatty acids in patients receiving TPN, and the "three-in-one" solution GA-1080 has been found to be clinically safe, stable, and economical. However, the multifactorial pathogenesis of TPN-induced hepatic dysfunction remains unclear, and the molecular mechanisms by which GA-1080 prevents hepatic dysfunction have not yet been identified.We have recently developed an infant rat model of hepatobiliary dysfunction.5) Using this animal model, we have clearly demonstrated the metabolic complications in the liver that may occur due to the excessive administration of fat-free TPN in infant rats. Furthermore, we have shown that including fat in the TPN regimen is very important in preventing TPN-induced hepatic dysfunction. In this review, we describe the molecular mechanisms and the clinical implications of soybean oil in TPN solutions in avoiding the hepatic complications associated with parenteral nutrition. INFANT RAT TPN MODEL WITH HEPATOBILIARY DYSFUNCTIONSince the first studies of TPN in animal models conducted in 1968 by Dudrick et al.,6) it has been known that only a limited number of species (such as the dog, cat, rabbit, and guinea pig) can tolerate the surgical procedures required for TPN, and few studies have employed rats as an animal model for TPN. In 1981, Tashiro and Meng 7) were the first to report a technique for long-term TPN in unrestrained weanling or infant (3-week-old) rats, thus establishing an animal model for pediatric TPN. Numerous studies have focused on the optimal TPN composition in mature rats, but few have addressed this issue in infant rats.We have recently developed an infant rat model with hepatic dysfunction and steatosis induced by overdose of fatfree TPN. 5) After 30 infant (3-week-ol...

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Upregulation in the expression of multidrug resistance protein Mrp1 mRNA and protein by increased bilirubin production in rat

Cited by 20 publications

References 22 publications

Bilirubin protects astrocytes from its own toxicity by inducing up-regulation and translocation of multidrug resistance-associated protein 1 (Mrp1)

Bilirubin protects astrocytes from its own toxicity by inducing up-regulation and translocation of multidrug resistance-associated protein 1 (Mrp1)

Role of Soybean Oil Pat Emulsion in the Prevention of Hepatic Xenobiotic Transporter mRNA Up- and Down-Regulation Induced by Overdose of Pat-free Total Parenteral Nutrition in Infant Rats

Soybean Oil Fat Emulsion to Prevent TPN-Induced Liver Damage: Possible Molecular Mechanisms and Clinical Implications

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