scholarly journals Transient liver enzyme derangement following Remdesivir use: a case series

2021 ◽  
Vol 2 (3) ◽  
pp. 31-34
Author(s):  
HARSH PATEL ◽  
Harsha Makwana ◽  
Karan Shah ◽  
Supriya Malhotra
Keyword(s):  
Liver Injury ◽  
Rna Polymerase ◽  
Liver Enzyme ◽  
Case Series ◽  
Mitochondrial Rna ◽  
Drug Induced ◽  
Serum Aminotransferase ◽  
Mitochondrial Rna Polymerase ◽  
Grade 3

Remdesivir, a nucleotide analog RNA polymerase inhibitor, which was originally evaluated in clinical trials to thwart the Ebola outbreak in 2014, has shown in vitro efficacy against SARS-CoV-2. Experience on its efficacy and safety in COVID-19 is accumulating. In COVID-19, Remdesivir therapy is given intravenously for 5 to 10 days and is frequently accompanied by transient, reversible mild-to-moderate elevations in serum aminotransferase levels but has been only rarely linked to instances of clinically apparent liver injury as a drug-induced liver injury (DILI). It may be caused by direct toxicity possibly due to inhibition of mitochondrial RNA polymerase. Here, we have discussed two cases where liver enzyme levels increased dramatically on the day next after initiating Remdesivir. Case one and two showed grade 4 and grade 3 hepatotoxicity respectively. In both cases, a positive de-challenge was observed and concomitant drugs were not considered to be confounders.  Hence, Remdesivir has a causal relationship with the occurrence of this adverse drug reaction.

Direct in vitro action of thyroid hormones on mitochondrial RNA-polymerase

1986 ◽  
Vol 11 (4) ◽  
pp. 205-211 ◽  
Author(s):  
G. Martino ◽  
C. Covello ◽  
R. De Giovanni ◽  
R. Filippelli ◽  
G. Pitrelli
Keyword(s):  
Thyroid Hormones ◽  
Rna Polymerase ◽  
Mitochondrial Rna ◽  
Mitochondrial Rna Polymerase

scholarly journals Distinct roles for two purified factors in transcription of Xenopus mitochondrial DNA.

1995 ◽  
Vol 15 (12) ◽  
pp. 7032-7042 ◽  
Author(s):  
I Antoshechkin ◽  
D F Bogenhagen
Keyword(s):  
Mitochondrial Dna ◽  
Rna Polymerase ◽  
Sequence Similarity ◽  
Protein A ◽  
Mitochondrial Rna ◽  
Basal Transcription ◽  
Hmg Box ◽  
Mitochondrial Rna Polymerase ◽  
Dnase I Footprinting

Transcription of Xenopus laevis mitochondrial DNA (xl-mtDNA) by the mitochondrial RNA polymerase requires a dissociable factor. This factor was purified to near homogeneity and identified as a 40-kDa protein. A second protein implicated in the transcription of mtDNA, the Xenopus homolog of the HMG box protein mtTFA, was also purified to homogeneity and partially sequenced. The sequence of a cDNA clone encoding xl-mtTFA revealed a high degree of sequence similarity to human and Saccharomyces cerevisiae mtTFA. xl-mtTFA was not required for basal transcription from a minimal mtDNA promoter, and this HMG box factor could not substitute for the basal factor, which is therefore designated xl-mtTFB. An antibody directed against the N terminus of xl-mtTFA did not cross-react with xl-mtTFB. xl-mtTFA is an abundant protein that appears to have at least two functions in mitochondria. First, it plays a major role in packaging mtDNA within the organelle. Second, DNase I footprinting experiments identified preferred binding sites for xl-mtTFA within the control region of mtDNA next to major mitochondrial promoters. We show that binding of xl-mtTFA to a site separating the two clusters of bidirectional promoters selectively stimulates specific transcription in vitro by the basal transcription machinery, comprising mitochondrial RNA polymerase and xl-mtTFB.

scholarly journals Non-DNA-Templated Addition of Nucleotides to the 3′ End of RNAs by the Mitochondrial RNA Polymerase of Physarum polycephalum

2008 ◽  
Vol 28 (18) ◽  
pp. 5795-5802 ◽  
Author(s):  
Mara L. Miller ◽  
Dennis L. Miller
Keyword(s):  
Mitochondrial Dna ◽  
Rna Polymerase ◽  
Rna Editing ◽  
Physarum Polycephalum ◽  
Mitochondrial Gene ◽  
In Vitro Transcription ◽  
Open Reading Frames ◽  
Mitochondrial Rna ◽  
Mitochondrial Rna Polymerase

ABSTRACT Mitochondrial gene expression is necessary for proper mitochondrial biogenesis. Genes on the mitochondrial DNA are transcribed by a dedicated mitochondrial RNA polymerase (mtRNAP) that is encoded in the nucleus and imported into mitochondria. In the myxomycete Physarum polycephalum, nucleotides that are not specified by the mitochondrial DNA templates are inserted into some RNAs, a process called RNA editing. This is an essential step in the expression of these RNAs, as the insertion of the nontemplated nucleotides creates open reading frames for the production of proteins from mRNAs or produces required secondary structure in rRNAs and tRNAs. The nontemplated nucleotide is added to the 3′ end of the RNA as the RNA is being synthesized during mitochondrial transcription. Because RNA editing is cotranscriptional, the mtRNAP is implicated in RNA editing as well as transcription. We have cloned the cDNA for the mtRNAP of Physarum and have expressed the mtRNAP in Escherichia coli. We have used in vitro transcription assays based on the Physarum mtRNAP to identify a novel activity associated with the mtRNAP in which non-DNA-templated nucleotides are added to the 3′ end of RNAs. Any of the four ribonucleoside triphosphates (rNTPs) can act as precursors for this process, and this novel activity is observed when only one rNTP is supplied, a condition under which transcription does not occur. The implications of this activity for the mechanism of RNA editing are discussed.

Use of yeast nuclear DNA sequences to define the mitochondrial RNA polymerase promoter in vitro

1989 ◽  
Vol 9 (8) ◽  
pp. 3193-3202
Author(s):  
G T Marczynski ◽  
P W Schultz ◽  
J A Jaehning
Keyword(s):  
Rna Polymerase ◽  
Dna Sequences ◽  
Nuclear Dna ◽  
In Vitro Transcription ◽  
Catalytic Rna ◽  
Mitochondrial Rna ◽  
Promoter Sequences ◽  
Sequence Recognition ◽  
Mitochondrial Rna Polymerase

We have extended an earlier observation that the TATA box for the nuclear GAL10 gene serves as a promoter for the mitochondrial RNA polymerase in in vitro transcription reactions (C. S. Winkley, M. J. Keller, and J. A. Jaehning, J. Biol. Chem. 260:14214-14223, 1985). In this work, we demonstrate that other nuclear genes also have upstream sequences that function in vitro as mitochondrial RNA polymerase promoters. These genes include the GAL7 and MEL1 genes, which are regulated in concert with the GAL10 gene, the sigma repetitive element, and the 2 microns plasmid origin of replication. We used in vitro transcription reactions to test a large number of nuclear DNA sequences that contain critical mitochondrial promoter sequences as defined by Biswas et al. (T. K. Biswas, J. C. Edwards, M. Rabinowitz, and G. S. Getz, J. Biol. Chem. 262:13690-13696, 1987). The results of these experiments allowed us to extend the definition of essential promoter elements. This extended sequence, -ACTATAAACGatcATAG-, was frequently found in the upstream regulatory regions of nuclear genes. On the basis of these observations, we hypothesized that either (i) a catalytic RNA polymerase related to the mitochondrial enzyme functions in the nucleus of the yeast cell or (ii) a DNA sequence recognition factor is shared by the two genetic compartments. By using cells deficient in the catalytic core of the mitochondrial RNA polymerase (rpo41-) and sensitive assays for transcripts initiating from the nuclear promoter sequences, we have conclusively ruled out a role for the catalytic RNA polymerase in synthesizing transcripts from all of the nuclear sequences analyzed. The possibility that a DNA sequence recognition factor functions in both the nucleus and the mitochondria remains to be tested.

Marked Increase of Gamma-Glutamyltransferase as an Indicator of Drug-Induced Liver Injury in Patients without Conventional Diagnostic Criteria of Acute Liver Injury

2021 ◽  
pp. 1-6
Author(s):  
Sabine Weber ◽  
Julian Allgeier ◽  
Gerald Denk ◽  
Alexander L. Gerbes
Keyword(s):  
Liver Injury ◽  
Case Series ◽  
Assessment Method ◽  
Close Monitoring ◽  
In Vitro Test ◽  
Drug Induced ◽  
Gamma Glutamyltransferase ◽  
Drug Induced Liver Injury ◽  
Full Remission

<b><i>Introduction:</i></b> Clinically significant drug-induced liver injury (DILI) is defined by elevations of alanine aminotransferase (ALT) ≥5 times the upper limit of normal (ULN), alkaline phosphatase (ALP) ≥2 × ULN, or ALT ≥3 × ULN and total bilirubin TBIL &#x3e;2 × ULN. However, DILI might also occur in patients who do not reach those thresholds and still may benefit from discontinuation of medication. <b><i>Methods:</i></b> Fifteen patients recruited for our prospective study on potentially hepatotoxic drugs were included. DILI diagnosis was based on RUCAM (Roussel Uclaf Causality Assessment Method) score and expert opinion and was supported by an in vitro test using monocyte-derived hepatocyte-like (MH) cells. <b><i>Results:</i></b> Median RUCAM score was 6 (range 4–8), indicating that DILI was possible or probable in all cases. The predominant types of liver injury were mixed (60%) and cholestatic (40%). While no elevation above 2 × ULN of ALP and TBIL was observed, gamma-glutamyltransferase (GGT) above 2 × ULN was identified in 8 of the patients. Six of the 15 patients did not achieve full remission and showed persistent elevation of GGT, which was significantly associated with peak GGT elevation above 2 × ULN (<i>p</i> = 0.005). <b><i>Conclusion:</i></b> Here we present a case series of patients with liver enzyme elevation below the conventional thresholds who developed DILI with a predominant GGT elevation leading to drug withdrawal and/or chronic elevation of liver parameters, in particular of GGT. Thus, we propose that DILI should be considered in particular in cases with marked increase of GGT even if conventional DILI threshold levels are not reached, resulting in discontinuation of the causative drug and/or close monitoring of the patients.

scholarly journals Nucleotide Substrate Specificity of Anti-Hepatitis C Virus Nucleoside Analogs for Human Mitochondrial RNA Polymerase

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Maryam Ehteshami ◽  
Longhu Zhou ◽  
Sheida Amiralaei ◽  
Jadd R. Shelton ◽  
Jong Hyun Cho ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Substrate Specificity ◽  
Rna Polymerase ◽  
Rna Virus ◽  
Antiviral Agents ◽  
Nucleoside Analogs ◽  
Mitochondrial Rna ◽  
Mitochondrial Rna Polymerase

ABSTRACT Nucleoside analog inhibitors (NAIs) are an important class of antiviral agents. Although highly effective, some NAIs with activity against hepatitis C virus (HCV) can cause toxicity, presumably due to off-target inhibition of host mitochondrial RNA polymerase (POLRMT). The in vitro nucleotide substrate specificity of POLRMT was studied in order to explore structure-activity relationships that can facilitate the identification of nontoxic NAIs. These findings have important implications for the development of all anti-RNA virus NAIs.

scholarly journals Anti-viral nucleotide incorporation by recombinant human mitochondrial RNA polymerase is predictive for increased in vivo mitochondrial toxicity risk

2016 ◽  
pp. AAC.01253-16 ◽  
Author(s):  
Martijn Fenaux ◽  
Xiaodong Lin ◽  
Fumiaki Yokokawa ◽  
Zachary Sweeney ◽  
Oliver Saunders ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Mitochondrial Dysfunction ◽  
Elevated Serum ◽  
Nucleoside Analogs ◽  
Hepatic Function ◽  
Gene Signature ◽  
Mitochondrial Rna ◽  
Mitochondrial Rna Polymerase

Nucleoside or nucleotide inhibitors are a highly successful class of antivirals due to selectivity, potency, broad coverage, and high barrier to resistance. Nucleosides are the backbone of combination treatments for HIV, hepatitis B and - since the FDA approval of sofosbuvir in 2013 - also for hepatitis C (HCV). However, many promising nucleotides have advanced to clinical trials only to be terminated due to unexpected toxicity. Here we describe the in vitro pharmacology of1, a monophosphate prodrug of a 2’ -ethynyluridine developed for the treatment of HCV.1inhibits multiple HCV genotypes in vitro (EC50= 0.05-0.1 μM) with a selectivity index of >300 (CC50= 30 μM in MT-4 cells). The active triphosphate metabolite of1,2, does not inhibit human α, β or γ DNA polymerases, but was a substrate for incorporation by the human mitochondrial RNA polymerase (POLRMT). In dog, the oral administration of1resulted in elevated serum liver enzymes and microscopic changes in the liver. Transmission electron microscopy showed significant mitochondrial swelling and lipid accumulation in hepatocytes. Gene expression analysis revealed dose-proportional gene signature changes linked to loss of hepatic function and increased mitochondrial dysfunction. The potential of in vivo toxicity through mitochondrial polymerase incorporation by nucleoside analogs has been previously shown. This study shows that even moderate levels of nucleotide analog incorporation by POLRMT increase the risk of in vivo mitochondrial dysfunction. Based on these results, further development of1as an anti-HCV compound was terminated.

scholarly journals Use of yeast nuclear DNA sequences to define the mitochondrial RNA polymerase promoter in vitro.

1989 ◽  
Vol 9 (8) ◽  
pp. 3193-3202 ◽  
Author(s):  
G T Marczynski ◽  
P W Schultz ◽  
J A Jaehning
Keyword(s):  
Rna Polymerase ◽  
Dna Sequences ◽  
Nuclear Dna ◽  
In Vitro Transcription ◽  
Catalytic Rna ◽  
Mitochondrial Rna ◽  
Promoter Sequences ◽  
Sequence Recognition ◽  
Mitochondrial Rna Polymerase

We have extended an earlier observation that the TATA box for the nuclear GAL10 gene serves as a promoter for the mitochondrial RNA polymerase in in vitro transcription reactions (C. S. Winkley, M. J. Keller, and J. A. Jaehning, J. Biol. Chem. 260:14214-14223, 1985). In this work, we demonstrate that other nuclear genes also have upstream sequences that function in vitro as mitochondrial RNA polymerase promoters. These genes include the GAL7 and MEL1 genes, which are regulated in concert with the GAL10 gene, the sigma repetitive element, and the 2 microns plasmid origin of replication. We used in vitro transcription reactions to test a large number of nuclear DNA sequences that contain critical mitochondrial promoter sequences as defined by Biswas et al. (T. K. Biswas, J. C. Edwards, M. Rabinowitz, and G. S. Getz, J. Biol. Chem. 262:13690-13696, 1987). The results of these experiments allowed us to extend the definition of essential promoter elements. This extended sequence, -ACTATAAACGatcATAG-, was frequently found in the upstream regulatory regions of nuclear genes. On the basis of these observations, we hypothesized that either (i) a catalytic RNA polymerase related to the mitochondrial enzyme functions in the nucleus of the yeast cell or (ii) a DNA sequence recognition factor is shared by the two genetic compartments. By using cells deficient in the catalytic core of the mitochondrial RNA polymerase (rpo41-) and sensitive assays for transcripts initiating from the nuclear promoter sequences, we have conclusively ruled out a role for the catalytic RNA polymerase in synthesizing transcripts from all of the nuclear sequences analyzed. The possibility that a DNA sequence recognition factor functions in both the nucleus and the mitochondria remains to be tested.

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