Inhibition of UDP-glucose dehydrogenase by 6-thiopurine and its oxidative metabolites: Possible mechanism for its interaction within the bilirubin excretion pathway and 6TP associated liver toxicity

Weeramange, Chamitha; Binns, Cassie M.; Chen, Chixiang; Rafferty, Ryan J.

doi:10.1016/j.jpba.2017.12.058

Cited by 6 publications

(4 citation statements)

References 25 publications

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“…In the smooth ER, bilirubin and UDP-glucuronic acid are esterified under the action of glucuronosyltransferase to generate glucuronosyl bilirubin, which is then excluded from the liver together with bile under the action of Golgi bodies and lysosomes. However, bilirubin metabolism disorder leads to jaundice, and the typical clinical symptom of swine HE is jaundice ( 61 – 63 ). Therefore, swine HEV ORF3 might affect the pentose and glucuronate interconversions of the above top 20 pathways and mediate the occurrence of jaundice.…”

Section: Discussionmentioning

confidence: 99%

Deep Insight Into Long Non-coding RNA and mRNA Transcriptome Profiling in HepG2 Cells Expressing Genotype IV Swine Hepatitis E Virus ORF3

Shuai

Luo

et al. 2021

Front. Vet. Sci.

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Swine hepatitis E (swine HE) is a new type of zoonotic infectious disease caused by the swine hepatitis E virus (swine HEV). Open reading frame 3 (ORF3) is an important virulent protein of swine HEV, but its function still is mainly unclear. In this study, we generated adenoviruses ADV4-ORF3 and ADV4 negative control (ADV4-NC), which successfully mediated overexpression of enhanced green fluorescent protein (EGFP)-ORF3 and EGFP, respectively, in HepG2 cells. High-throughput sequencing was used to screen for differentially expressed long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs). The cis-target genes of lncRNAs were predicted, functional enrichment (Gene Ontology [GO] and Kyoto Encyclopedia of Genes and Genomes [KEGG]) was performed, and 12 lncRNAs with statistically significant different expressions (p ≤ 0.05 and q ≤ 1) were selected for further quantitative real-time reverse transcription (qRT-PCR) validation. In HepG2 cells, we identified 62 significantly differentially expressed genes (DEGs) (6,564 transcripts) and 319 lncRNAs (124 known lncRNAs and 195 novel lncRNAs) that were affected by ORF3, which were involved in systemic lupus erythematosus, Staphylococcus aureus infection, signaling pathways pluripotency regulation of stem cells, the peroxisome proliferator-activated receptor (PPAR) signaling pathway, and platinum drug resistance pathways. Cis-target gene prediction identified 45 lncRNAs corresponding to candidate mRNAs, among which eight were validated by qRT-PCR: LINC02476 (two transcripts), RAP2C-AS1, AC016526, AL139099, and ZNF337-AS1 (3 transcripts). Our results revealed that the lncRNA profile in host cells affected by ORF3, swine HEV ORF3, might affect the pentose and glucuronate interconversions and mediate the formation of obstructive jaundice by influencing bile secretion, which will help to determine the function of ORF3 and the infection mechanism and treatment of swine HE.

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Section: Discussionmentioning

confidence: 99%

Deep Insight Into Long Non-coding RNA and mRNA Transcriptome Profiling in HepG2 Cells Expressing Genotype IV Swine Hepatitis E Virus ORF3

Shuai

Luo

et al. 2021

Front. Vet. Sci.

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show abstract

“…In the smooth endoplasmic reticulum (ER), bilirubin and UDP-glucuronic acid are esteri ed under the action of glucuronosyl transferase to generate glucuronosyl bilirubin, which is then excluded from the liver together with bile under the action of Golgi bodies and lysosomes. However, bilirubin metabolism disorder leads to jaundice, and the typical clinical symptom of SHE is jaundice [57][58][59]. Therefore, SHEV-ORF3 might affect the pentose and glucuronate interconversions of the above top 20 pathways and mediate the occurrence of jaundice.…”

Section: Discussionmentioning

confidence: 99%

Deep Insight Into Long Non-Coding RNA and mRNA Transcriptome Profiling in HepG2 Cells Expressing Genotype IV Swine Hepatitis E Virus ORF3

Jiao

Shuai

Luo

et al. 2020

Preprint

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Background: Swine hepatitis E (SHE) is a new type of zoonotic infectious disease caused by swine hepatitis E virus (SHEV). Open reading frame 3 (ORF3) is an important virulent protein of SHEV but its function still is mainly unclear.Methods: In this study we generated adenoviruses ADV4-ORF3 and ADV4-NC which successfully mediated overexpression of EGFP-ORF3 and EGFP, respectively, in HepG2 cells. High throughput sequencing was used to screen for differentially expressed long non‑coding RNAs (lncRNAs) and mRNAs. The cis-target genes of lncRNAs were predicted, functional enrichment (Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG)) was performed, and 12 lncRNAs with statistically significant different expression (p value ≤ 0.05 and q value ≤ 1) were selected for further quantitative real-time reverse transcription (qRT-PCR) validation.Results: In HepG2 cells, we identified 62 significantly differential expression genes (DEGs) (6,564 transcripts), and 319 lncRNAs (124 known lncRNAs and 195 novel lncRNAs) that were affected by ORF3, which were involved in systemic lupus erythematosus, staphylococcus aureus infection, signaling pathways regulating pluripotency of stem cells, the PPAR signaling pathway, and platinum drug resistance pathways. Cis-target gene prediction identified 45 lncRNAs corresponding to candidate mRNAs, among which 8 were validated by qRT-PCR: LINC02476 (two transcripts), RAP2C-AS1, AC016526, AL139099, and ZNF337-AS1 (3 transcripts). Conclusions: Our results revealed the lncRNA profile in host cells affected by ORF3, which will help to determine the function of ORF3, and the infection mechanism and treatment of SHE.

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“…TG interferes with bilirubin excretion pathway and failure to excrete bilirubin leads to jaundice and liver toxicity. Oxidative metabolites of TG are potent inhibitors of UDP-glucose dehydrogenase, an enzyme that is responsible for the formation of UDPglucuronic acid, an essential substrate used in the liver detoxification processes [61]. In contrast to TG, MP showed specific angiogenetic and angioprotective properties, favoring endothelial integrity and attenuating monocytes attraction/adhesion/activation on vascular cells [62,63].…”

Section: Tpmt Polymorphism and Thioguanine-induced Sinusoidal Obstruc...mentioning

confidence: 99%

Understanding thiopurine methyltransferase polymorphisms for the targeted treatment of hematologic malignancies

Franca

Braidotti

Stocco

et al. 2021

Expert Opinion on Drug Metabolism & Toxicology

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IntroductionThiopurine methyltransferase (TPMT) catalyses the S-methylation of thiopurines, such as mercaptopurine and tioguanine (TG), fundamental chemotherapeutic agents used in the treatment of acute lymphoblastic leukemia (ALL). Polymorphisms in TPMT gene encode diminished activity enzyme, thus enhancing accumulation of active metabolites, and partially explaining the inter-individual differences in patients' clinical response. Areas coveredThis review gives an overview on TPMT gene and function, and discusses the well-established pharmacogenomic implications of TPMT variants in the prevention of severe thiopurine-induced hematological toxicities and the less known implication on TG-induced sinusoidal obstruction syndrome. Additional genetic and non-genetic factors impairing TPMT activity are considered. Literature search was done in PubMed for English articles published between 1990 and June 2021, and on PharmGKB for thiopurine drugs. Expert opinionIn order to titrate thiopurines safely and effectively, achieve the right degree of lymphotoxic effect and avoid excessive myelosuppression, the optimal management will combine a pre-emptive TPMT genotyping to establish a safe initial dose to a close phenotypic monitoring of the TPMT activity and/or of the active metabolites during the long-term treatment. Compared to current ALL protocols, replacement of TG by MP during reinduction phase in TPMT heterozygotes as well as novel individualized TG regimens in maintenance for TPMT wild type subjects could be investigated to further improve outcomes while avoiding the risk of severe hepatotoxicity.

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Inhibition of UDP-glucose dehydrogenase by 6-thiopurine and its oxidative metabolites: Possible mechanism for its interaction within the bilirubin excretion pathway and 6TP associated liver toxicity

Cited by 6 publications

References 25 publications

Deep Insight Into Long Non-coding RNA and mRNA Transcriptome Profiling in HepG2 Cells Expressing Genotype IV Swine Hepatitis E Virus ORF3

Deep Insight Into Long Non-coding RNA and mRNA Transcriptome Profiling in HepG2 Cells Expressing Genotype IV Swine Hepatitis E Virus ORF3

Deep Insight Into Long Non-Coding RNA and mRNA Transcriptome Profiling in HepG2 Cells Expressing Genotype IV Swine Hepatitis E Virus ORF3

Understanding thiopurine methyltransferase polymorphisms for the targeted treatment of hematologic malignancies

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Inhibition of UDP-glucose dehydrogenase by 6-thiopurine and its oxidative metabolites: Possible mechanism for its interaction within the bilirubin excretion pathway and 6TP associated liver toxicity

Cited by 6 publications

References 25 publications

Deep Insight Into Long Non-coding RNA and mRNA Transcriptome Profiling in HepG2 Cells Expressing Genotype IV Swine Hepatitis E Virus ORF3

Deep Insight Into Long Non-coding RNA and mRNA Transcriptome Profiling in HepG2 Cells Expressing Genotype IV Swine Hepatitis E Virus ORF3

Deep Insight&nbsp;Into Long Non-Coding RNA and mRNA Transcriptome Profiling in HepG2 Cells Expressing Genotype IV Swine Hepatitis E Virus ORF3

Understanding thiopurine methyltransferase polymorphisms for the targeted treatment of hematologic malignancies

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Deep Insight Into Long Non-Coding RNA and mRNA Transcriptome Profiling in HepG2 Cells Expressing Genotype IV Swine Hepatitis E Virus ORF3