New concepts in bilirubin and jaundice: Report of the Third International Bilirubin Workshop, April 6-8, 1995, Trieste, Italy

Tiribelli, Claudio; Ostrow, J. Donald

doi:10.1002/hep.510240551

Cited by 40 publications

(18 citation statements)

References 204 publications

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“…Indeed, over a decade ago, the use of metalloporphyrins as therapeutic agents against hyperbilirubinemia was recommended (Drummond and Kappas 1981;Galbraith et al 1992;Martinez et al 2001). Despite this potential clinical application of the metalloporphyrins, the mainstay of managing hyperbilirubinemia has been phototherapy and exchange blood transfusion (Tiribelli and Ostrow 1996;Dennery 2005). This may be due to the lack of selectivity associated with metalloporphyrins as therapeutic drug candidates ( Table 2).…”

Section: Adverse Effects Of Bilirubinmentioning

confidence: 96%

Inhibitors of the heme oxygenase – carbon monoxide system: on the doorstep of the clinic?

Kinobe

Dercho

Nakatsu

2008

Can. J. Physiol. Pharmacol.

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The past decade has seen substantial developments in our understanding of the physiology, pathology, and pharmacology of heme oxygenases (HO), to the point that investigators in the field are beginning to contemplate therapies based on administration of HO agonists or HO inhibitors. A significant amount of our current knowledge is based on the judicious application of metalloporphyrin inhibitors of HO, despite their limitations of selectivity. Recently, imidazole-based compounds have been identified as potent and more selective HO inhibitors. This 'next generation' of HO inhibitors offers a number of desirable characteristics, including isozyme selectivity, negligible effects on HO protein expression, and physicochemical properties favourable for in vivo distribution. Some of the applications of HO inhibitors that have been suggested are treatment of hyperbilirubinemia, neurodegenerative disorders, certain types of cancer, and bacterial and fungal infections. In this review, we address various approaches to altering HO activity with a focus on the potential applications of second-generation inhibitors of HO.

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Section: Adverse Effects Of Bilirubinmentioning

confidence: 96%

Inhibitors of the heme oxygenase – carbon monoxide system: on the doorstep of the clinic?

Kinobe

Dercho

Nakatsu

2008

Can. J. Physiol. Pharmacol.

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“…Subsequent biochemical studies progressively delineated which UGT isoforms were present and active [128,132] culminating in the first isoform-specific studies from Strassburg et al who showed that although fetal levels of mRNA and protein for UGT isoforms did not differ from adults, activities were lower for up to 2 years of age [36]. Subsequently, the pediatric ontogeny of several hepatic UGT1A and UGT2B isoforms has been described [36][37][38][39][121][122][123][124][125][126] although the development of UGT enzymes in other neonatal tissues is not well understood. The liver studies have demonstrated that although mRNA and protein are present, glucuronidation does not mature for several months after birth, with maturation of individual UGT enzymes each under separate developmental controls [37][38][39]121,126].…”

Section: Ontogenetic Regulation Of Ugtmentioning

confidence: 98%

“…While this is not always true, the UGT enzymes are an example of a critical drug elimination pathway that does not mature until after birth [36][37][38][39][121][122][123][124][125][126]. Although UGTs can be detected as early as the blastocyst stage in mammalian development (indicating a possible role in embryology) [127] in fetal red blood cells and in the fetal liver [128][129][130], glucuronidation activity has not been detected until 30 --40 weeks of gestation [122,123].…”

Section: Ontogenetic Regulation Of Ugtmentioning

confidence: 99%

Posttranscriptional regulation of uridine diphosphate glucuronosyltransferases

Riches¹,

Collier²

2015

Expert Opinion on Drug Metabolism & Toxicology

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Posttranscriptional regulation of UGTs has traditionally received less attention than nuclear regulation, in part because mechanisms involving ribosomes and endoplasmic reticula are challenging to investigate. Most promising of the posttranscriptional mechanisms reviewed are likely to be effects on co-substrate (UDP-glucuronic acid) transport and availability and structure-function changes to UGT proteins through, for example, glycosylation and phosphorylation. Although classical biochemistry continues to illuminate many aspects of UGT function, advances in proteomics and structural biology are beginning to assist in the determination of posttranscriptional regulation mechanisms for UGTs.

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“…Together, these data indicate that drug-induced bilirubin elevation might initially result from a decrease in hepatocellular ATP. Bilirubin processing includes several steps that are likely ATP-dependent, e.g., bilirubin conjugation and export from the hepatocyte (Tiribelli and Ostrow, 1996; Paulusma et al, 1997; Borst et al, 2007). Using the DILIsym™ model, APAP was simulated in the presence or absence of an ATP contribution to bilirubin generation.…”

Section: Liver Modeling Case Studiesmentioning

confidence: 99%

Modeling Drug- and Chemical-Induced Hepatotoxicity with Systems Biology Approaches

Bhattacharya¹,

Shoda²,

Zhang³

et al. 2012

Front. Physio.

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We provide an overview of computational systems biology approaches as applied to the study of chemical- and drug-induced toxicity. The concept of “toxicity pathways” is described in the context of the 2007 US National Academies of Science report, “Toxicity testing in the 21st Century: A Vision and A Strategy.” Pathway mapping and modeling based on network biology concepts are a key component of the vision laid out in this report for a more biologically based analysis of dose-response behavior and the safety of chemicals and drugs. We focus on toxicity of the liver (hepatotoxicity) – a complex phenotypic response with contributions from a number of different cell types and biological processes. We describe three case studies of complementary multi-scale computational modeling approaches to understand perturbation of toxicity pathways in the human liver as a result of exposure to environmental contaminants and specific drugs. One approach involves development of a spatial, multicellular “virtual tissue” model of the liver lobule that combines molecular circuits in individual hepatocytes with cell–cell interactions and blood-mediated transport of toxicants through hepatic sinusoids, to enable quantitative, mechanistic prediction of hepatic dose-response for activation of the aryl hydrocarbon receptor toxicity pathway. Simultaneously, methods are being developing to extract quantitative maps of intracellular signaling and transcriptional regulatory networks perturbed by environmental contaminants, using a combination of gene expression and genome-wide protein-DNA interaction data. A predictive physiological model (DILIsym™) to understand drug-induced liver injury (DILI), the most common adverse event leading to termination of clinical development programs and regulatory actions on drugs, is also described. The model initially focuses on reactive metabolite-induced DILI in response to administration of acetaminophen, and spans multiple biological scales.

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New concepts in bilirubin and jaundice: Report of the Third International Bilirubin Workshop, April 6-8, 1995, Trieste, Italy

Cited by 40 publications

References 204 publications

Inhibitors of the heme oxygenase – carbon monoxide system: on the doorstep of the clinic?

Inhibitors of the heme oxygenase – carbon monoxide system: on the doorstep of the clinic?

Posttranscriptional regulation of uridine diphosphate glucuronosyltransferases

Modeling Drug- and Chemical-Induced Hepatotoxicity with Systems Biology Approaches

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