Citrus Fruit Intake Is Associated with Lower Serum Bilirubin Concentration among Women with the UGT1A1*28 Polymorphism

UDP-glucuronosyltransferase (UGT) 1A1 glucuronidates bilirubin, estrogens, and xenobiotic compounds. The UGT1A1*28 polymorphism results in lower promoter activity due to 7 thymine-adenine (TA) repeats rather than the more common 6 TA repeats. Previously, we showed that serum bilirubin, a marker of UGT1A1 activity, was lower among individuals homozygous for the UGT1A1*28 polymorphism (7/7) when randomized to a high fruit and vegetable (F&V) diet, whereas there was no effect in individuals with the wild-type (6/6) and heterozygous (6/7) genotypes. Our objective here was to determine if we could detect genotype x diet interactions on bilirubin concentrations in an observational study. Healthy nonsmoking men (n = 146) and women (n = 147), recruited from the Seattle area, provided blood samples for genotyping and bilirubin measurements. We used multiple linear regression to assess the relationships among UGT1A1 genotype, bilirubin concentrations, and consumption of specific F&V [cruciferous vegetables, citrus fruits, and soy foods (n = 268)] based on FFQ and F&V from 6 botanical families [Cruciferae, Rosaceae, Rutaceae, Umbelliferae, Solanaceae, and Leguminosae (n = 261)] based on 3-d food records. We observed a significant interaction of UGT1A1 genotype and citrus consumption among women. Women with the 7/7 genotype who consumed 0.5 daily servings of citrus fruit or foods from the Rutaceae botanical family had 30% lower serum bilirubin than those with the same genotype who consumed less, whereas 6/6 and 6/7 genotypes did not differ by consumption (P for interaction = 0.006 and 0.03, respectively). These results suggest that citrus consumption may increase UGT1A1 activity among women with the 7/7 genotype.

Misty R. Saracino4,5, Jeannette Bigler4, Yvonne Schwarz4, Jyh-Lurn Chang4, Shiuying Li4, Lin Li4, Emily White4,5, John D. Potter4 and Johanna W. Lampe4,5,* 4 Fred Hutchinson Cancer Research Center, Seattle, WA, 98109 and 5 Department of Epidemiology, University of Washington, Seattle, WA 98195

Unbound (Free) Bilirubin (Bf): Improving the Paradigm for Evaluating Neonatal Jaundice

BACKGROUND: The serum or plasma total bilirubin concentration (BT) has long been the standard clinical laboratory test for evaluating neonatal jaundice, despite studies showing that BT correlates poorly with acute bilirubin encephalopathy (ABE) and its sequelae including death, classical kernicterus, or bilirubin-induced neurological dysfunction (BIND). The poor correlation between BT and ABE is commonly attributed to the confounding effects of comorbidities such as hemolytic diseases, prematurity, asphyxia, or infection. Mounting evidence suggests, however, that BT inherently performs poorly because it is the plasma non-protein-bound (unbound or free) bilirubin concentration (Bf), rather than BT, that is more closely associated with central nervous system bilirubin concentrations and therefore ABE and its sequelae.

CONTENT: This article reviews (1) the complex relationship between serum or plasma bilirubin measurements and ABE, (2) the history underlying the limited use of Bf in the clinical setting, (3) the peroxidase method for measuring Bf and technical and other issues involved in adapting the measurement to routine clinical use, (4) clinical experience using Bf in the management of newborn jaundice, and (5) the value of Bf measurements in research investigating bilirubin pathochemistry.

SUMMARY: Increasing evidence from clinical studies, clinical experience, and basic research investigating bilirubin neurotoxicity supports efforts to incorporate Bf expeditiously into the routine evaluation of newborn jaundice.

Division of Neonatology, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA

Granulocytic sarcoma of Core-binding Factor (CBF) acute myeloid leukemia mimicking pancreatic cancer

Granulocytic sarcoma mimicking a synchronous second primary neoplasm (SPN) constitutes a diagnostic and therapeutic challenge particularly in elderly patients. We report on a 75-year-old female presenting with a Core-binding Factor (CBF) AML of M4eo subtype. The patient also had jaundice, highly elevated bilirubin, lipase, alkaline phosphatase (AP), CA 19-9, and a pancreatic mass highly suspicious of infiltrating pancreatic carcinoma. However, a biopsy demonstrated granulocytic sarcoma. Since the patient had no comorbidities and had been in excellent performance status until the diagnosis of AML, induction chemotherapy was initiated, with subsequent normalization of bilirubin, CA 19-9, lipase and AP. Complete hematologic remission of AML was attained and the pancreatic mass could not be detected anymore. Retrospective analysis of the c-kit protooncogene did not disclose activating mutations of exons 8 or 17. Following one consolidation treatment, the patient remained in excellent health until relapse occurred 7 months later and she succumbed to AML. In conclusion, AML can rarely mimic the clinical picture of pancreatic cancer. The initially good response of this CBF leukemia highlights the principal usefulness of aggressive induction chemotherapy also in older AML patients, if they are carefully selected not only according to biological risk factors such as cytogenetics, but also to “host factors” (good performance status, lack of comorbidities, etc.).

Leukemia Research Volume 32, Issue 9, Pages 1472-1475 (September 2008)

Granulocytic sarcoma of Core-binding Factor (CBF) acute myeloid leukemia mimicking pancreatic cancer

Henning Sebastian Schäfera, Heiko Beckera, Annette Schmitt-Gräffb, Michael Lübberta

Bilirubin adsorption property of sol–gel-derived titania particles for blood purification therapy

Titania (anatase) gel powders were prepared by peptizing commercially available titania sols and heating them at temperatures up to 700 °C, as candidates for bilirubin adsorbents for blood purification therapy. Those titania particles were in contact with a protein solution containing bilirubin and bovine serum albumin that mimics the blood of bilirubinemia patients. The amount of free or direct bilirubin in the solution insignificant. Indirect bilirubin or a bilirubin complex with albumin was adsorbed on the anatase powders, the primary particle size of which was as large as or larger than the size of an albumin molecule. The surface charge and surface charge density were only minor factors in controlling the indirect bilirubin adsorption. The present results indicated that the size of primary particles and hydrophobicity were significant for the sol-derived anatase in terms of bilirubin adsorption, and both were controllable by the heating temperature and the time period.


ARTICLE

Determining binding sites of drugs on human serum albumin using FIA-QCM

A simple and effective method was developed for determining binding sites of drugs on human serum albumin (HSA) by independent binding or competitive displacement of bilirubin using flow injection analysis-quartz crystal microbalance (FIA-QCM) system. Both independent and competitive bindings were entirely monitored in real time. Bilirubin as a site I-binding ligand was pre-bound to human serum albumin (HSA) sensor so as to occupy the drug-binding site I. When the model site II-binding drugs (ibuprofen, ketoprofen and flurbiprofen) were injected into the bilirubin pre-bound HSA system, the frequency continuously decreased by 6 Hz, 4 Hz and 5 Hz, respectively, which was the same as that of their individual binding to HSA sensor. It indicated that the drug binding to site II was independent and did not interfere with bilirubin binding. However, when the model site I-binding drugs (iodipamide and magnesium salicylate) were introduced into the system, the frequency remained unchanged in the initial several minutes and then rapidly decreased by 4 Hz for iodipamide and increased by 4 Hz for magnesium salicylate. This phenomenon revealed site I-binding drugs competitively bound to HSA against bilirubin and displaced the pre-bound bilirubin. The results demonstrate FIA-QCM can be a valid approach for monitoring the dynamic interaction between drugs and HSA in real time further identifying drug-binding sites without the need of labels.

ARTICLE

Serum Bilirubin and Ferritin Levels Link Between Heme Oxygenase-1 Gene Promoter Polymorphism and Susceptibility to Coronary Artery Disease in Diabetic

Objective: Heme oxygenase (HO) leads to the generation of free iron, carbon monoxide, and bilirubin. A length polymorphism of GT repeat in the promoter of human HO-1 gene has been shown to modulate gene transcription. This study aims to assess the association of the length of (GT)n repeats in HO-1 gene promoter with serum bilirubin, markers of iron status, and the development of coronary artery disease (CAD).

Research design and methods: We screened the allelic frequencies of (GT)n repeats in the HO-1 gene promoter in 986 unrelated individuals that underwent coronary angiography. Serum bilirubin. and markers of iron status were evaluated.

Results: The distribution of numbers of (GT)n repeats was divided into 2 subclasses: class S included shorter (<27) repeats, and class L included longer (27) repeats. Among those with diabetes, subjects with L/L genotype had significantly lower bilirubin levels than those with S/S and S/L genotypes (0.70±0.22 vs. 0.81±0.24 mg/dL, P=0.001) and higher serum ferritin values (4.76±0.72 vs. 4.28±1.05 µg/L for log-ferritin, P=0.001). Compared with those carrying S allele, diabetic subjects with L/L genotype had an almost three-fold increase in CAD risk after controlling for conventional risk factors (odds ratio 2.81, 95% confidence interval [CI] 1.22 to 6.47, P=0.015). Adjusting for both serum bilirubin and ferritin, the effect of HO-1 promoter polymorphism on susceptibility to CAD disappeared.

Conclusions: Length polymorphism in the HO-1 gene promoter is correlated with susceptibility to CAD in diabetic patients and such effect might be conveyed through its influence on serum bilirubin and ferritin.