Bilirubin Toxicity to Human Erythrocytes: A More Sanguine View

McDonagh, Antony F.

doi:10.1542/peds.2007-0438

Cited by 14 publications

(7 citation statements)

References 43 publications

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“…Brito (2006), according to the observation of hyperbilirubinemic and normobilirubinemic neonates, presumed toxicity of UCB to erythrocyte's membrane [34]. In contrast to this assumption, McDonagh (2007) claimed that Gunn rats and patients with Crigler-Najjar syndrome have persistent unconjugated hyperbilirubinemia and do not suffer from extensive hemolysis [35]. Of particular interest in our experiment is the observed rise in thrombocytes after UCB administration, both in healthy and the AIA animals (Figure 2c).…”

Section: Discussionmentioning

confidence: 74%

Hyperbilirubinemia Maintained by Chronic Supplementation of Unconjugated Bilirubin Improves the Clinical Course of Experimental Autoimmune Arthritis

Sýkora

Babál

Dráfi

et al. 2021

IJMS

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Rheumatoid arthritis (RA) is a chronic multisystem disease, therapy of which remains a challenge for basic research. The present work examined the effect of unconjugated bilirubin (UCB) administration in adjuvant-induced arthritis (AIA)—an experimental model, in which oxidative stress (OS), inflammation and inadequate immune response are often similar to RA. Male Lewis rats were randomized into groups: CO—control, AIA—untreated adjuvant-induced arthritis, AIA-BIL—adjuvant-induced arthritis administrated UCB, CO-BIL—control with administrated UCB. UCB was administered intraperitoneally 200 mg/kg of body weight daily from 14th day of the experiment, when clinical signs of the disease are fully manifested, to 28th day, the end of the experiment. AIA was induced by a single intradermal immunization at the base of the tail with suspension of Mycobacterium butyricum in incomplete Freund’s adjuvant. Clinical, hematologic, biochemical and histologic examinations were performed. UCB administration to animals with AIA lead to a significant decrease in hind paws volume, plasma levels of C-reactive protein (CRP) and ceruloplasmin, drop of leukocytes, lymphocytes, erythrocytes, hemoglobin and an increase in platelet count. UCB administration caused significantly lowered oxidative damage to DNA in arthritic animals, whereas in healthy controls it induced considerable oxidative damage to DNA. UCB administration also induced atrophy of the spleen and thymus in AIA and CO animals comparing to untreated animals. Histological signs of joint damage assessed by neutrophils infiltration and deposition of fibrin were significantly reduced by UCB administration. The effects of exogenously administered UCB to the animals with adjuvant-induced arthritis might be identified as therapeutic, in contrast to the effects of UCB administration in healthy animals rather classified as toxic.

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Section: Discussionmentioning

confidence: 74%

Hyperbilirubinemia Maintained by Chronic Supplementation of Unconjugated Bilirubin Improves the Clinical Course of Experimental Autoimmune Arthritis

Sýkora

Babál

Dráfi

et al. 2021

IJMS

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“…As shown in Fig. 2, the reduced expression/activity of UGT1A1 may increase the plasma concentrations of unconjugated bilirubin, leading to hyperbilirubinemia 10 from the mild Gilbert׳s syndrome up to kernicterus and the potentially fatal Crigler-Najjar syndrome type I11., 12., 13., 14.. In addition, polymorphic variants of UGT1A1 may lead to drug-induced liver injury.…”

Section: Introductionmentioning

confidence: 99%

Recent progress and challenges in screening and characterization of UGT1A1 inhibitors

Xia

Finel

et al. 2019

Acta Pharmaceutica Sinica B

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Uridine-diphosphate glucuronosyltransferase 1A1 (UGT1A1) is an important conjugative enzyme in mammals that is responsible for the conjugation and detoxification of both endogenous and xenobiotic compounds. Strong inhibition of UGT1A1 may trigger adverse drug/herb–drug interactions, or result in metabolic disorders of endobiotic metabolism. Therefore, both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have recommended assaying the inhibitory potential of drugs under development on the human UGT1A1 prior to approval. This review focuses on the significance, progress and challenges in discovery and characterization of UGT1A1 inhibitors. Recent advances in the development of UGT1A1 probes and their application for screening UGT1A1 inhibitors are summarized and discussed in this review for the first time. Furthermore, a long list of UGT1A1 inhibitors, including information on their inhibition potency, inhibition mode, and affinity, has been prepared and analyzed. Challenges and future directions in this field are highlighted in the final section. The information and knowledge that are presented in this review provide guidance for rational use of drugs/herbs in order to avoid the occurrence of adverse effects via UGT1A1 inhibition, as well as presenting methods for rapid screening and characterization of UGT1A1 inhibitors and for facilitating investigations on UGT1A1—ligand interactions.

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“…Heme, a component of hemoglobin in red blood cells, is broken down by heme oxygenase resulting in bilirubin. 1, 2 Glucuronidation by UDP-glycosyltransferase in hepatocytes 3 is an important step in facilitating the excretion of bilirubin into bile. 4 A very high level of bilirubin, especially in children, is neurotoxic.…”

Section: Introductionmentioning

confidence: 99%

UGT1A1 is a major locus influencing bilirubin levels in African Americans

et al. 2011

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Total serum bilirubin is associated with several clinical outcomes, including cardiovascular disease, diabetes and drug metabolism. We conducted a genome-wide association study in 619 healthy unrelated African Americans in an attempt to replicate reported findings in Europeans and Asians and to identify novel loci influencing total serum bilirubin levels. We analyzed a dense panel of over two million genotyped and imputed SNPs in additive genetic models adjusting for age, sex, and the first two significant principal components from the sample covariance matrix of genotypes. Thirty-nine SNPs spanning a 78 kb region within the UGT1A1 displayed P-values <5 × 10−8. The lowest P-value was 1.7 × 10−22 for SNP rs887829. None of SNPs in the UGT1A1 remained statistically significant in conditional association analyses that adjusted for rs887829. In addition, SNP rs10929302 located in phenobarbital response enhancer module was significantly associated with bilirubin level with a P-value of 1.37 × 10−11; this enhancer module is believed to have a critical role in phenobarbital treatment of hyperbilirubinemia. Interestingly, the lead SNP, rs887829, is in strong linkage disequilibrium (LD) (r2≥0.74) with rs10929302. Taking advantage of the lower LD and shorter haplotypes in African-ancestry populations, we identified rs887829 as a more refined proxy for the causative variant influencing bilirubin levels. Also, we replicated the reported association between variants in SEMA3C and bilirubin levels. In summary, UGT1A1 is a major locus influencing bilirubin levels and the results of this study promise to contribute to understanding of the etiology and treatment of hyperbilirubinaemia in African-ancestry populations.

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Bilirubin Toxicity to Human Erythrocytes: A More Sanguine View

Cited by 14 publications

References 43 publications

Hyperbilirubinemia Maintained by Chronic Supplementation of Unconjugated Bilirubin Improves the Clinical Course of Experimental Autoimmune Arthritis

Hyperbilirubinemia Maintained by Chronic Supplementation of Unconjugated Bilirubin Improves the Clinical Course of Experimental Autoimmune Arthritis

Recent progress and challenges in screening and characterization of UGT1A1 inhibitors

UGT1A1 is a major locus influencing bilirubin levels in African Americans

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