Morphine Induces Redox-Based Changes in Global DNA Methylation and Retrotransposon Transcription by Inhibition of Excitatory Amino Acid Transporter Type 3–Mediated Cysteine Uptake

Trivedi, Malav Suchin; Shah, Jayni; Hodgson, Nathaniel; Byun, Hyang‐Min; Deth, Richard C.

doi:10.1124/mol.114.091728

Cited by 77 publications

(93 citation statements)

References 55 publications

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“…While the mechanism underlying inhibition of cysteine uptake by food-derived opiate peptides is not fully established, we previously found that protein kinase A (PKA) and/or Mitogen activated protein kinase kinase (MEKK) might be involved in mediating the effects of morphine on EAAT3 (50). The inhibitory effects on cysteine uptake are also observed at the levels of redox status and methylation capacity as well as at the DNA methylation status and the transcription levels of genes involved in maintaining the redox methylation homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Food-derived opioid peptides inhibit cysteine uptake with redox and epigenetic consequences

Trivedi

Shah

Al-Mughairy

et al. 2014

The Journal of Nutritional Biochemistry

100

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Dietary interventions like gluten-free and casein-free diets have been reported to improve intestinal, autoimmune and neurological symptoms in patients with a variety of conditions; however, the underlying mechanism of benefit for such diets remains unclear. Epigenetic programming, including CpG methylation and histone modifications, occurring during early postnatal development can influence the risk of disease in later life, and such programming may be modulated by nutritional factors such as milk and wheat, especially during the transition from a solely milk-based diet to one that includes other forms of nutrition. The hydrolytic digestion of casein (a major milk protein) and gliadin (a wheat-derived protein) releases peptides with opioid activity, and in the present study, we demonstrate that these food-derived proline-rich opioid peptides modulate cysteine uptake in cultured human neuronal and gastrointestinal (GI) epithelial cells via activation of opioid receptors. Decreases in cysteine uptake were associated with changes in the intracellular antioxidant glutathione and the methyl donor S-adenosylmethionine. Bovine and human casein-derived opioid peptides increased genome-wide DNA methylation in the transcription start site region with a potency order similar to their inhibition of cysteine uptake. Altered expression of genes involved in redox and methylation homeostasis was also observed. These results illustrate the potential of milk- and wheat-derived peptides to exert antioxidant and epigenetic changes which may be particularly important during the postnatal transition from placental to GI nutrition. Differences between peptides derived from human and bovine milk may contribute to developmental differences between breastfed and formula-fed infants. Restricted antioxidant capacity, caused by wheat- and milk-derived opioid peptides, may predispose susceptible individuals to inflammation and systemic oxidation, partly explaining the benefits of gluten-free or casein-free diets.

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Section: Discussionmentioning

confidence: 99%

Food-derived opioid peptides inhibit cysteine uptake with redox and epigenetic consequences

Trivedi

Shah

Al-Mughairy

et al. 2014

The Journal of Nutritional Biochemistry

100

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“…In addition to methylation and acetylation modifications of histones, morphine exposure induces methylation changes on DNA directly (Nielsen et al, 2008; Chorbov et al, 2011; Doehring et al, 2013; Trivedi et al, 2014). Morphine modulates cellular oxidative stress and methyl group donation through the antioxidant glutathione and the methyl donor SAM, respectively (Trivedi et al, 2014).…”

Section: Inheritance Of Drug Exposurementioning

confidence: 99%

“…Morphine modulates cellular oxidative stress and methyl group donation through the antioxidant glutathione and the methyl donor SAM, respectively (Trivedi et al, 2014). Consequently, as the redox state of the cell impacts methylation events, DNA methylation changes can occur following morphine exposure.…”

Section: Inheritance Of Drug Exposurementioning

confidence: 99%

“…Just as LINE-1 seems to be vulnerable to histone methylation changes following morphine exposure, the transposable element exhibits decreases in methylation after morphine administration. Hypomethylation at LINE-1 retrotransposons has been identified in leukocytes of chronic heroin users (Doehring et al, 2013) and in neuronal cell lines (Trivedi et al, 2014); consequently, LINE-1 mRNA expression increases (Trivedi et al, 2014). In contrast, increased CpG methylation has been reported in lymphocytes, blood, and sperm of chronic heroin users in the promoter region of the OPRM1 gene (Chorbov et al, 2011; Nielsen et al, 2008).…”

Section: Inheritance Of Drug Exposurementioning

confidence: 99%

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Multigenerational and transgenerational inheritance of drug exposure: The effects of alcohol, opiates, cocaine, marijuana, and nicotine

Yohn

Bartolomei

Blendy

2015

Progress in Biophysics and Molecular Biology

127

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Familial inheritance of drug abuse is composed of both genetic and environmental factors. Additionally, epigenetic transgenerational inheritance may provide a means by which parental drug use can influence several generations of offspring. Recent evidence suggests that parental drug exposure produces behavioral, biochemical, and neuroanatomical changes in future generations. The focus of this review is to discuss these multigenerational and transgenerational phenotypes in the offspring of animals exposed to drugs of abuse. Specifically, changes found following the administration of alcohol, opioids, cocaine, marijuana, and nicotine will be discussed. In addition, epigenetic modifications to the genome following administration of these drugs will be detailed as well as their potential for transmission to the next generation.

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“…It was observed that increasing the concentration of L1 RNA increased its inhibitory effect on PSF/DNA binding affinity. L1 RNA is transcribed from endogenous genomic retrotransposons and the level varies depending on the cell type and the level of global hypomethylation (25). Thus, the key parameters that determine whether GAGE6 expression is repressed by PSF or induced by L1 RNA are the type of cell and the global hypomethylation status.…”

Section: Discussionmentioning

confidence: 99%

Binding of LINE-1 RNA to PSF transcriptionally promotes GAGE6 and regulates cell proliferation and tumor formation in vitro

Zhao

2017

Experimental and Therapeutic Medicine

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Abstract. Hepatocellular carcinoma (HCC) has one of the highest mortality rates among numerous types of cancer. It has been demonstrated that in hepatitis B (HBV)-associated HCC, the expression of chimeric fusion transcript HBx-long interspersed nuclear element-1 (LINE-1) initiated by HBV integration is correlated with hepatocarcinogenesis and poor patient survival rates. Furthermore, increased rates of LINE-1 hypomethylation have been detected in HCC tissues compared with adjacent tissues. This suggests that individual LINE-1 RNA (L1 RNA) serves an important role in the processes of hepatocarcinogenesis. The present study assessed the epigenic interaction between L1 RNA and polypyrimidine tract-binding protein-associated splicing factor (PSF) in the A549 human alveolar epithelial and 16HBE human bronchial epithelial cell lines. In addition, changes in the transcriptional regulatory activity of PSF on its target gene, proto-oncogene G antigen 6 (GAGE6), were investigated following overexpression of L1 RNA, as well as its impact on cell-proliferative capacity, carried out by plotting cell growth curves and 5-ethynyl-2'-deoxyuridine assay. It was observed that L1 RNA specifically bound to the RNA binding domain of PSF and released the GAGE6 promoter region from the DNA-binding domain of PSF. This increased the transcription of GAGE6 and led to the promotion of cell proliferation as well as colony formation. Furthermore, at least two binding sites specific for PSF were identified on L1 RNA. In conclusion, the transcriptional regulatory activity of L1 RNA may partially result in cell transformation, and endogenous L1 RNA may function as an important regulatory factor in the process of tumorigenesis.

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Morphine Induces Redox-Based Changes in Global DNA Methylation and Retrotransposon Transcription by Inhibition of Excitatory Amino Acid Transporter Type 3–Mediated Cysteine Uptake

Cited by 77 publications

References 55 publications

Food-derived opioid peptides inhibit cysteine uptake with redox and epigenetic consequences

Food-derived opioid peptides inhibit cysteine uptake with redox and epigenetic consequences

Multigenerational and transgenerational inheritance of drug exposure: The effects of alcohol, opiates, cocaine, marijuana, and nicotine

Binding of LINE-1 RNA to PSF transcriptionally promotes GAGE6 and regulates cell proliferation and tumor formation in vitro

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