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British Journal of Anaesthesia Sep 1972
Review
Topics: Bile Acids and Salts; Biliary Tract; Bilirubin; Carbohydrate Metabolism; Cholestasis; Endoplasmic Reticulum; Hepatitis; Humans; Hyperbilirubinemia, Hereditary; Lipid Metabolism; Liver; Liver Diseases; Liver Function Tests; Lysosomes; Mitochondria, Liver; Pharmaceutical Preparations; Protein Biosynthesis
PubMed: 4564263
DOI: 10.1093/bja/44.9.910 -
The Israel Medical Association Journal... Aug 2001
Review
Topics: Adolescent; Adult; Bilirubin; Female; Gilbert Disease; Glucuronosyltransferase; Heme; Humans; Male
PubMed: 11519385
DOI: No ID Found -
Yakugaku Zasshi : Journal of the... 2022ATP-binding cassette (ABC) transporters, which comprise the largest gene-family in humans, are membrane proteins that transport various substrates, depending on ATP... (Review)
Review
ATP-binding cassette (ABC) transporters, which comprise the largest gene-family in humans, are membrane proteins that transport various substrates, depending on ATP hydrolysis. Among these transporters, several include ABCB1 (P-glycoprotein), identified here for the first time in humans, which exports anti-cancer drugs from cancer cells, thus participating in multidrug resistance (MDR). ABC transporters also export drugs, in general, from the human body, therefore affecting overall pharmacokinetics. We have contributed, here, to a better understanding of the role of these exporter proteins in two aspects. First, we have cloned the human ABCC2 gene and identified mutations in hereditary hyperbilirubinemia patients, demonstrating the role of ABCC2 as a xenobiotic export pump. Second, we also found an unexpected role of ABCB1 in cancer, in that it promotes tumor initiation independently of the MDR phenomenon, which was further confirmed by a chemoprevention experiment using verapamil, an ABCB1 inhibitor. In this review, I discuss the role of ABC transporters, both in biodefense against xenobiotics and in cancer development and malignant alterations, based on our results as well as the studies of others.
Topics: Humans; ATP-Binding Cassette Transporters; Drug Resistance, Multiple; Neoplasms; ATP Binding Cassette Transporter, Subfamily B, Member 1; Xenobiotics; Adenosine Triphosphate; Drug Resistance, Neoplasm
PubMed: 36328450
DOI: 10.1248/yakushi.22-00108 -
British Medical Journal May 1968
Topics: Humans; Hyperbilirubinemia, Hereditary
PubMed: 5646534
DOI: No ID Found -
Bulletin of the New York Academy of... Jul 1959
Topics: Gilbert Disease; Humans; Jaundice
PubMed: 13662733
DOI: No ID Found -
The Journal of Clinical Investigation Sep 1965
Topics: Blood; Enzyme Inhibitors; Female; Glucosyltransferases; Glucuronates; Humans; Hyperbilirubinemia; Hyperbilirubinemia, Hereditary; Hyperbilirubinemia, Neonatal; Infant, Newborn; Infant, Newborn, Diseases; Kernicterus; Liver; Pathology; Pharmacology; Phenols; Pregnancy; Progestins; Rats; Research
PubMed: 14332157
DOI: 10.1172/JCI105250 -
Journal of Clinical Laboratory Analysis Jun 2022Uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1), which is the major UGT1 gene product, is located on chromosome 2q37. The expression of UGT1A1 is relatively...
BACKGROUND
Uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1), which is the major UGT1 gene product, is located on chromosome 2q37. The expression of UGT1A1 is relatively managed by a polymorphic dinucleotide repeat inside the promoter TATA box consisting of 5-8 copies of a TA repeat. A (TA) 6TAA is considered as the wild type. The A (TA) 7TAA allele has been identified as the most frequent allele in the Caucasian populations while A (TA) 8TAA allele remains the rarest allele worldwide in North Africa, including the Arab populations.
METHODS
The spectrum of UGT1A1 genetic mutations in seventeen Tunisian children affected by persistent unconjugated hyperbilirubinemias is represented in addition to their relatives, notably parents, sisters, and brothers. Tunisian children, from 16 unrelated families as well as a 17 family without CN1 affected child, were originated from the West Center of Tunisia. The promoter region and coding exons of the UGT1A1 were PCR amplified, subsequently subjected to Sanger sequencing.
RESULTS
The frequencies of genotypes in CN1 patients were as follows (TA) (7/7) (12/17: 70.6%) and (TA) (8/8) (5/17: 29.4%). All patients harbored the c.1070A>G mutation of exon 3 (UGT1A1*16) in the homozygous state. Among relatives of our patients (n = 16), who were all heterozygotes for UGT1A1*16, 13/16 (81.25%) had a heterozygous state for UGT1A1∗1/UGT1A1∗28 or (TA) (6/7) and, 18.75% (3/16) were heterozygous for UGT1A1∗28/UGT1A1∗37 or (TA) (7/8) of the promoter polymorphisms.
CONCLUSION
UGT1A1*16 accompanied with UGT1A1*28 or UGT1A1*37 had a specific geographic and ethnic distribution for CN pathogenesis in this Tunisian cohort.
Topics: Child; Crigler-Najjar Syndrome; Exons; Genotype; Glucuronosyltransferase; Humans; Male; Mutation; Polymorphism, Genetic
PubMed: 35527687
DOI: 10.1002/jcla.24482 -
Journal of Hepatology Aug 2017Biliverdin and bilirubin were previously considered end products of heme catabolism; now, however, there is evidence for further degradation to diverse bioactive...
BACKGROUND & AIMS
Biliverdin and bilirubin were previously considered end products of heme catabolism; now, however, there is evidence for further degradation to diverse bioactive products. Z-BOX A and Z-BOX B arise upon oxidation with unknown implications for hepatocellular function and integrity. We studied the impact of Z-BOX A and B on hepatic functions and explored their alterations in health and cholestatic conditions.
METHODS
Functional implications and mechanisms were investigated in rats, hepatocytic HepG2 and HepaRG cells, human immortalized hepatocytes, and isolated perfused livers. Z-BOX A and B were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in acute and acute-on-chronic liver failure and hereditary unconjugated hyperbilirubinemia.
RESULTS
Z-BOX A and B are found in similar amounts in humans and rodents under physiological conditions. Serum concentrations increased ∼20-fold during cholestatic liver failure in humans (p<0.001) and in hereditary deficiency of bilirubin glucuronidation in rats (p<0.001). Pharmacokinetic studies revealed shorter serum half-life of Z-BOX A compared to its regio-isomer Z-BOX B (p=0.035). While both compounds were taken up by hepatocytes, Z-BOX A was enriched ∼100-fold and excreted in bile. Despite their reported vasoconstrictive properties in the brain vasculature, BOXes did not affect portal hemodynamics. Both Z-BOX A and B showed dose-dependent cytotoxicity, affected the glutathione redox state, and differentially modulated activity of Rev-erbα and Rev-erbβ. Moreover, BOXes-triggered remodeling of the hepatocellular cytoskeleton.
CONCLUSIONS
Our data provide evidence that higher-order heme degradation products, namely Z-BOX A and B, impair hepatocellular integrity and might mediate intra- and extrahepatic cytotoxic effects previously attributed to hyperbilirubinemia.
LAY SUMMARY
Degradation of the blood pigment heme yields the bile pigment bilirubin and the oxidation products Z-BOX A and Z-BOX B. Serum concentrations of these bioactive molecules increase in jaundice and can impair liver function and integrity. Amounts of Z-BOX A and Z-BOX B that are observed during liver failure in humans have profound effects on hepatic function when added to cultured liver cells or infused into healthy rats.
Topics: Acute-On-Chronic Liver Failure; Animals; Bile; Bilirubin; Biliverdine; Cholestasis; Glutathione; Heme; Hemodynamics; Hep G2 Cells; Humans; Hyperbilirubinemia; In Vitro Techniques; Liver; Liver Circulation; Male; Oxidation-Reduction; Pyrroles; Rats; Rats, Wistar
PubMed: 28412296
DOI: 10.1016/j.jhep.2017.03.037 -
BMC Pediatrics Sep 2022ABO blood group incompatibility, neonatal sepsis, G-6-PD deficiency, thyroid dysfunction, and hereditary spherocytosis are all probable causes of neonatal...
BACKGROUND
ABO blood group incompatibility, neonatal sepsis, G-6-PD deficiency, thyroid dysfunction, and hereditary spherocytosis are all probable causes of neonatal hyperbilirubinemia. However, the etiology of some hyperbilirubinemia is extremely complicated, which may be caused by multiple factors, resulting in severe jaundice. We report a case of severe jaundice due to three causes, showing the significance for the investigation of the etiology of neonatal hyperbilirubinemia.
CASE PRESENTATION
At 96 h of life, a full-term and vaginal delivery male infant with yellowish discoloration of body was transferred to our hospital. When he entered neonatal intensive care unit on the fourth day after birth, he developed jaundice and the transcutaneous bilirubin was 28 mg/dl. Total bilirubin was 540.2 μmol/L, while the indirect bilirubin was 516.7 μmol/L. Both parents and the baby's blood types were O Rh(D +), and direct coomb's test was negative. But mother's indirect coomb's test was positive. Investigating for minor blood group revealed that the father's blood type of Rh was CCDee, the mather's was ccDEE, and CcDEe for the baby. After intensive phototherapy and double volume exchange transfusion, the total bilirubin remained at 303 μmol/L. At day 10, the bilirubin level was 303.5 μmol/L, intensive phototherapy was continued, and intravenous immunoglobulin was used again. The test for thyroid hormones at day 10, the TSH was 13.334mIU/L. And the screening for congenital hypothyroidism showed the TSH was 33mIU/L. Because of the palpable abdominal mass, ultrasound and MRI was done, showed a huge mass in the right adrenal gland. Brainstem auditory evoked potential was performed at day 7, which indicated hearing impairment (65db for left ear and 70db for the right). Euthyrox and intermittent phototherapy were given as following treatment. The jaundice did not subside until the 12th day.
CONCLUSION
Even if their parents' ABO blood group and Rh (d) are consistent, a Coomb test is required for newborns with hyperbilirubinemia since they may have minor blood group incompatibilities. When bilirubin rises rapidly or the clinical treatment effect is inadequate, additional causes should be aggressively screened. Adrenal ultrasound should be performed on newborns with palpable abdominal mass, anemia and jaundice to determine whether there is adrenal hemorrhage.
Topics: Bilirubin; Congenital Hypothyroidism; Female; Hematoma; Humans; Hyperbilirubinemia, Neonatal; Infant, Newborn; Jaundice; Male; Thyrotropin
PubMed: 36089589
DOI: 10.1186/s12887-022-03594-7 -
JGH Open : An Open Access Journal of... Oct 2020Crigler-Najjar syndrome (CNs) is a rare hereditary unconjugated hyperbilirubinemia caused by mutations in the bilirubin Uridine (UDP) glucuronosyltransferase family 1...
Crigler-Najjar syndrome (CNs) is a rare hereditary unconjugated hyperbilirubinemia caused by mutations in the bilirubin Uridine (UDP) glucuronosyltransferase family 1 member A1 (UGT1A1, ENSG00000241635) gene. Two patients were clinically diagnosed with Crigler-Najjar Syndrome types II (CNs-II) can be clinically diagnosed which were based on the level of total bilirubin, efficacy of phenobarbital treatment, normal liver architecture and exclusion of hemolysis. Diagnosis was also confirmed by UGT1A1 gene mutations, which by sequencing the coding region for UGT1A1 gene mutations, which were the homozygous mutations c.668G > A/p.Cys223Tyr and which caused less than 10% of activity of the enzyme. No data have been reported about this mutate in the population. These patients have a good prognosis and require no active intervention, indicating that an early accurate diagnosis is necessary for disease management and genetic counseling.
PubMed: 33102778
DOI: 10.1002/jgh3.12355