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Alaei Faradonbeh F, Lastuvkova H, Cermanova J, Hroch M, Nova Z, Uher M, Hirsova P, Pavek P, Micuda S. Multidrug Resistance-Associated Protein 2 Deficiency Aggravates Estrogen-Induced Impairment of Bile Acid Metabolomics in Rats. Front Physiol 2022; 13:859294. [PMID: 35388287 PMCID: PMC8979289 DOI: 10.3389/fphys.2022.859294] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 02/21/2022] [Indexed: 12/23/2022] Open
Abstract
Multidrug resistance-associated protein 2 (Mrp2) mediates biliary secretion of anionic endobiotics and xenobiotics. Genetic alteration of Mrp2 leads to conjugated hyperbilirubinemia and predisposes to the development of intrahepatic cholestasis of pregnancy (ICP), characterized by increased plasma bile acids (BAs) due to mechanisms that are incompletely understood. Therefore, this study aimed to characterize BA metabolomics during experimental Mrp2 deficiency and ICP. ICP was modeled by ethinylestradiol (EE) administration to Mrp2-deficient (TR) rats and their wild-type (WT) controls. Spectra of BAs were analyzed in plasma, bile, and stool using an advanced liquid chromatography–mass spectrometry (LC–MS) method. Changes in BA-related genes and proteins were analyzed in the liver and intestine. Vehicle-administered TR rats demonstrated higher plasma BA concentrations consistent with reduced BA biliary secretion and increased BA efflux from hepatocytes to blood via upregulated multidrug resistance-associated protein 3 (Mrp3) and multidrug resistance-associated protein 4 (Mrp4) transporters. TR rats also showed a decrease in intestinal BA reabsorption due to reduced ileal sodium/bile acid cotransporter (Asbt) expression. Analysis of regulatory mechanisms indicated that activation of the hepatic constitutive androstane receptor (CAR)-Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by accumulating bilirubin may be responsible for changes in BA metabolomics in TR rats. Ethinylestradiol administration to TR rats further increased plasma BA concentrations as a result of reduced BA uptake and increased efflux via reduced Slco1a1 and upregulated Mrp4 transporters. These results demonstrate that Mrp2-deficient organism is more sensitive to estrogen-induced cholestasis. Inherited deficiency in Mrp2 is associated with activation of Mrp3 and Mrp4 proteins, which is further accentuated by increased estrogen. Bile acid monitoring is therefore highly desirable in pregnant women with conjugated hyperbilirubinemia for early detection of intrahepatic cholestasis.
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Affiliation(s)
- Fatemeh Alaei Faradonbeh
- Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Hana Lastuvkova
- Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Jolana Cermanova
- Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Milos Hroch
- Department of Medical Biochemistry, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Zuzana Nova
- Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Martin Uher
- Department of Medical Biochemistry, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Petra Hirsova
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Petr Pavek
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Stanislav Micuda
- Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czechia
- *Correspondence: Stanislav Micuda,
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Wu H, Zhao XK, Zhu JJ. Clinical characteristics and ABCC2 genotype in Dubin-Johnson syndrome: A case report and review of the literature. World J Clin Cases 2021; 9:878-885. [PMID: 33585635 PMCID: PMC7852649 DOI: 10.12998/wjcc.v9.i4.878] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 11/20/2020] [Accepted: 12/06/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Dubin-Johnson syndrome (DJS) is a benign autosomal recessive liver disease involving mutations of the ABCC2 gene. It is characterized by chronic or intermittent conjugated hyperbilirubinemia, with chronic idiopathic jaundice as the main clinical manifestation. Genetic alterations of the ABCC2 gene are commonly used for diagnosing DJS; however, the causative ABCC2 point mutation in Chinese patients remains unknown. Research on ABCC2 mutations in Chinese DJS patients is extremely rare, and the diagnosis of DJS remains limited. The routine analysis of ABCC2 mutations is helpful for the diagnosis of DJS. Here, we report the clinical characteristics and ABCC2 genotype of an adult female DJS patient. This article is to expound the discovery of more potentially pathogenic ABCC2 variants will that contribute to DJS identification.
CASE SUMMARY This study investigated a woman referred for DJS and involved clinical and genetic analyses. ABCC2 mutations were identified by next-generation sequencing (NGS). The patient showed intermittent jaundice and conjugated hyper-bilirubinemia. Histopathological examinations were consistent with the typical phenotype of DJS. Genetic diagnostic analysis revealed an ABCC2 genotype exhibiting a pathogenic variant, namely c.2443C>T (p.Arg815*), which has not been reported previously in the domestic or foreign literature.
CONCLUSION Pathogenic ABCC2 mutations play an important role in the diagnosis of DJS, especially in patients with atypical presentations. Currently, NGS is used in the routine analysis of DJS cases and such tests of further cases will better illuminate the relationship between various genotypes and phenotypes of DJS.
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Affiliation(s)
- Huan Wu
- Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, Guiyang 550001, Guizhou Province, China
| | - Xue-Ke Zhao
- Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, Guiyang 550001, Guizhou Province, China
| | - Juan-Juan Zhu
- Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, Guiyang 550001, Guizhou Province, China
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Ruan J, Duan MF, Liu D, Wei Q. Dubin-Johnson Syndrome in Pregnancy: Case Report and Literature Review. MATERNAL-FETAL MEDICINE 2020. [DOI: 10.1097/fm9.0000000000000031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Corpechot C, Barbu V, Chazouillères O, Broué P, Girard M, Roquelaure B, Chrétien Y, Dong C, Lascols O, Housset C, Jéru I. Genetic contribution of ABCC2 to Dubin-Johnson syndrome and inherited cholestatic disorders. Liver Int 2020; 40:163-174. [PMID: 31544333 DOI: 10.1111/liv.14260] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 08/27/2019] [Accepted: 09/10/2019] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND AIMS The ABCC2 gene is implicated in Dubin-Johnson syndrome (DJS), a rare autosomal recessive liver disorder. The primary aim of this study was to determine the diagnostic value of ABCC2 genetic testing in the largest cohort of DJS reported to date. The high number of patients with cholestatic manifestations in this series prompted us to evaluate the genetic contribution of rare, potentially pathogenic ABCC2 variants to other inherited cholestatic disorders. METHODS The cohort study included 32 patients with clinical DJS diagnosis, and 372 patients referred for the following disorders: low phospholipid-associated cholelithiasis (LPAC) syndrome, intrahepatic cholestasis of pregnancy (ICP) and benign recurrent intrahepatic cholestasis (BRIC). ABCC2 was screened by next-generation sequencing. RESULTS Most patients with clinical DJS had positive genetic diagnosis (n = 30; 94%), with a great diversity of point mutations and copy number variations in ABCC2. Strikingly, eight (27%) of these patients showed transient cholestatic features at presentation: four neonatal cholestasis, two ICP, one contraceptive-induced cholestasis and one sporadic cholestasis. Conversely, the frequency of rare, heterozygous, potentially pathogenic ABCC2 variants in patients with LPAC, ICP or BRIC did not differ significantly from that of the general population. CONCLUSIONS This large series reveals that DJS is a highly homogeneous Mendelian disorder involving a large spectrum of ABCC2 variants. Genetic testing is crucial to establish early DJS diagnosis in patients with atypical presentations, such as neonatal cholestasis. This study also provides no evidence for the contribution of rare, potentially pathogenic ABCC2 variants to other inherited cholestatic disorders.
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Affiliation(s)
- Christophe Corpechot
- Centre de Référence des Maladies Inflammatoires des Voies Biliaires et des Hépatites Auto-Immunes (MIVB-H), Filière de Santé des Maladies Rares du Foie de l'enfant et de l'adulte (FILFOIE), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France.,INSERM, Centre de Recherche Saint-Antoine (CRSA), Institut Hospitalo-Universitaire de Cardio-métabolisme et Nutrition (ICAN), Sorbonne Université, Paris, France
| | - Véronique Barbu
- INSERM, Centre de Recherche Saint-Antoine (CRSA), Institut Hospitalo-Universitaire de Cardio-métabolisme et Nutrition (ICAN), Sorbonne Université, Paris, France.,Laboratoire Commun de Biologie et Génétique Moléculaires, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France
| | - Olivier Chazouillères
- Centre de Référence des Maladies Inflammatoires des Voies Biliaires et des Hépatites Auto-Immunes (MIVB-H), Filière de Santé des Maladies Rares du Foie de l'enfant et de l'adulte (FILFOIE), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France.,INSERM, Centre de Recherche Saint-Antoine (CRSA), Institut Hospitalo-Universitaire de Cardio-métabolisme et Nutrition (ICAN), Sorbonne Université, Paris, France
| | - Pierre Broué
- Centres de compétences maladies rares du foie de l'enfant et Centre de référence constitutif maladies héréditaires du métabolisme, Hépatologie Pédiatrique et Maladies Héréditaires du Métabolisme, Hôpitaux de Toulouse, Hôpital des Enfants, Toulouse, France
| | - Muriel Girard
- Service d'Hépato-Gastroentérologie et Nutrition Pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France.,INSERM U1151, Institut Necker Enfants-Malades, Université Paris Descartes, Paris, France
| | - Bertrand Roquelaure
- Service d'Hépato-Gastroentérologie et Nutrition Pédiatrique, Assistance Publique-Hôpitaux de Marseille, Hôpital de la Timone Enfants, Marseille, France
| | - Yves Chrétien
- Centre de Référence des Maladies Inflammatoires des Voies Biliaires et des Hépatites Auto-Immunes (MIVB-H), Filière de Santé des Maladies Rares du Foie de l'enfant et de l'adulte (FILFOIE), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France
| | - Catherine Dong
- Centre de Référence des Maladies Inflammatoires des Voies Biliaires et des Hépatites Auto-Immunes (MIVB-H), Filière de Santé des Maladies Rares du Foie de l'enfant et de l'adulte (FILFOIE), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France
| | - Olivier Lascols
- INSERM, Centre de Recherche Saint-Antoine (CRSA), Institut Hospitalo-Universitaire de Cardio-métabolisme et Nutrition (ICAN), Sorbonne Université, Paris, France.,Laboratoire Commun de Biologie et Génétique Moléculaires, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France
| | - Chantal Housset
- Centre de Référence des Maladies Inflammatoires des Voies Biliaires et des Hépatites Auto-Immunes (MIVB-H), Filière de Santé des Maladies Rares du Foie de l'enfant et de l'adulte (FILFOIE), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France.,INSERM, Centre de Recherche Saint-Antoine (CRSA), Institut Hospitalo-Universitaire de Cardio-métabolisme et Nutrition (ICAN), Sorbonne Université, Paris, France
| | - Isabelle Jéru
- INSERM, Centre de Recherche Saint-Antoine (CRSA), Institut Hospitalo-Universitaire de Cardio-métabolisme et Nutrition (ICAN), Sorbonne Université, Paris, France.,Laboratoire Commun de Biologie et Génétique Moléculaires, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France
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Pennell EN, Shiels R, Vidimce J, Wagner KH, Shibeeb S, Bulmer AC. The impact of bilirubin ditaurate on platelet quality during storage. Platelets 2019; 31:884-896. [PMID: 31747815 DOI: 10.1080/09537104.2019.1693038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Bilirubin ditaurate (BRT), a conjugated bilirubin analogue, has demonstrated anti-platelet characteristics following acute ex vivo exposure. Scavenging of mitochondrial superoxide and attenuation of granule exocytosis suggested a potential benefit for including BRT for storage. With no reports of cytotoxicity following acute exposure, the impact of 35µM BRT on platelet function was investigated, in clinically suppled units, for up to seven days. Exposure to 35µM BRT significantly reduced mitochondrial membrane potential and increased glucose consumption until exhaustion after 72 hours. Platelet aggregation and activation was significantly impaired by BRT. Mitochondrial superoxide production and phosphatidylserine expression were significantly elevated following glucose exhaustion, with decreased viability observed from day five onwards. Lactate accumulation and loss of bicarbonate, support a metabolic disturbance, leading to a decline of quality following BRT inclusion. Although acute ex vivo BRT exposure reported potentially beneficial effects, translation from acute to chronic exposure failed to combat declining platelet function during storage. BRT exposure resulted in perturbations of platelet quality, with the utility of BRT during storage therefore limited. However, these are the first data of prolonged platelet exposure to analogues of conjugated bilirubin and may improve our understanding of platelet function in the context of conjugated hyperbilirubinemia.
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Affiliation(s)
- Evan Noel Pennell
- School of Medical Science, Griffith University , Gold Coast, Australia
| | - Ryan Shiels
- School of Medical Science, Griffith University , Gold Coast, Australia
| | - Josif Vidimce
- School of Medical Science, Griffith University , Gold Coast, Australia
| | - Karl-Heinz Wagner
- Research Platform Active Aging, Department of Nutritional Science, University of Vienna , Vienna Austria
| | - Sapha Shibeeb
- School of Medical Science, Griffith University , Gold Coast, Australia.,Endeavour College of Natural Health , Melbourne, Australia
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Abstract
Dubin-Johnson syndrome is an autosomal recessive condition characterized by recurrent episodes of jaundice and conjugated hyperbilirubinemia. It exacerbates during pregnancy and needs to be differentiated from other causes of jaundice. A 30-year-old patient presented to us with jaundice in her fourth pregnancy. She had intermittent episodes of jaundice earlier, with exacerbation in each pregnancy during the second trimester. The diagnosis of Dubin-Johnson syndrome was made on detailed evaluation along with histopathological confirmation on liver biopsy tissue. The patient was managed conservatively and had a good perinatal outcome.
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Affiliation(s)
- Avantika Gupta
- Obstetrics & Gynecology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, IND
| | - Purnima Tiwari
- Obstetrics & Gynecology, Maulana Azad Medical College, New Delhi, IND
| | - Poonam Sachdeva
- Obstetrics & Gynecology, Maulana Azad Medical College, New Delhi, IND
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Kularatnam GAM, Warawitage HD, Vidanapathirana DM, Jayasena S, Jasinge E, de Silva GNN, Liyanarachchi KLAMS, Wickramasinghe P, Devgun MS, Barbu V, Lascols O. Correction to: Dubin-Johnson syndrome and intrahepatic cholestasis of pregnancy in a Sri Lankan family: a case report. BMC Res Notes 2017; 10:492. [PMID: 28982379 PMCID: PMC5629802 DOI: 10.1186/s13104-017-2815-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Accepted: 09/26/2017] [Indexed: 11/19/2022] Open
Affiliation(s)
| | | | | | - Subashini Jayasena
- Department of Chemical Pathology, Lady Ridgeway Hospital for Children, Colombo, Sri Lanka
| | - Eresha Jasinge
- Department of Chemical Pathology, Lady Ridgeway Hospital for Children, Colombo, Sri Lanka
| | | | | | - Pujitha Wickramasinghe
- Department of Paediatrics, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | - Manjit Singh Devgun
- Clinical Laboratories, Department of Biochemistry, Wishaw General Hospital, Wishaw, Lanarkshire, ML2 0DP, UK
| | - Veronique Barbu
- Laboratoire Commun de Biologie et de Génétique Moléculaires, Hôpital Saint-Antoine, 184, rue du Faubourg Saint-Antoine, 75012, Paris, France
| | - Olivier Lascols
- Laboratoire Commun de Biologie et de Génétique Moléculaires, Hôpital Saint-Antoine, 184, rue du Faubourg Saint-Antoine, 75012, Paris, France
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