Opioid use affects antioxidant activity and purine metabolism: preliminary results

Mannelli, Paolo; Patkar, Ashwin A.; Rozen, Steve; Matson, Wayne R.; Krishnan, Ranga; Kaddurah‐Daouk, Rima

doi:10.1002/hup.1068

Cited by 54 publications

(42 citation statements)

References 65 publications

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“…By complementing the more targeted approaches that have looked at one or few biochemical events at a time, it promises to provide a detailed map of the regulation of metabolic pathways as influenced by genome and environment (12, 13). We and others have reported initial metabolomic signatures for several disease states, including motor neuron disease, schizophrenia, depression, addictive disorders, Parkinson's disease, Huntington's disease, cardiovascular disorders and diabetes (15– 24). However, to date, no study has used a systems biochemistry approach to evaluate multiple metabolomic changes in an autopsy confirmed sample of AD and control subjects.…”

Section: Introductionmentioning

confidence: 99%

Metabolomic changes in autopsy‐confirmed Alzheimer's disease

Kaddurah‐Daouk

Rozen

Matson

et al. 2010

Alzheimer's & Dementia

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Metabolomics, the global science of biochemistry, provides powerful tools to map perturbations in the metabolic network and enables simultaneous quantification of a large number of metabolites to identify metabolic perturbances that might provide insights into disease. In this pilot study we take a targeted electrochemistry based metabolomics approach where liquid chromatography followed by coulometric array detection enables quantification of over thirty metabolites within key neurotransmitter pathways (dopamine and serotonin) and pathways involved in oxidative stress.Using samples from post-mortem ventricular cerebrospinal fluid (CSF) (15 AD and 15 nondemented subjects with autopsy confirmed diagnoses) and using regression models, correlations, Wilcoxon rank-sum tests and t-tests we identified alterations in tyrosine, tryptophan, purine, and tocopherol pathways in patients with AD. Reductions in norepinephrine and its related metabolites were also seen, consistent with prior literature. These data support further investigation of metabolomics in larger samples of clinical AD as well as in those with preclinical disease for utility as biomarkers. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Disclosures RKD has patents in this field, stock in Metabolon, and has received funding from pharmaceutical companies for metabolomic studies. KWB has received in the past a research gift/grant from GSK to the Bryan ADRC. She has also served as a paid advisor to several pharmaceutical companies including GSK, Metabolon, and Pfizer. JRB has been advisor to GSK. PMD has received research grants (through Duke) and served as a paid advisor to several companies. He owns stock in Sonexa. XH serves as a consultant for the LipoSpectrum LLC.

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Section: Introductionmentioning

confidence: 99%

Metabolomic changes in autopsy‐confirmed Alzheimer's disease

Kaddurah‐Daouk

Rozen

Matson

et al. 2010

Alzheimer's & Dementia

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141

110

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“…Besides direct/exposure metabolites, methadone can also induce biochemical alterations, which may be of major interest in understanding potential toxic effects (Deng et al, 2012;Dinis-Oliveira, 2014b;Jiang et al, 2003;Mannelli et al, 2009). Indeed, patients undergoing methadone treatment showed altered oxidation-reduction activity confirmed by higher plasma levels of a-and c-tocopherol and increased GSH/GSSG ratio, and altered purine metabolism evidenced by increased concentration of guanine and xanthosine, with decreased guanosine, hypoxanthine and hypoxanthine/xanthine and xanthine/xanthosine ratios (Mannelli et al, 2009).…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

“…Indeed, patients undergoing methadone treatment showed altered oxidation-reduction activity confirmed by higher plasma levels of a-and c-tocopherol and increased GSH/GSSG ratio, and altered purine metabolism evidenced by increased concentration of guanine and xanthosine, with decreased guanosine, hypoxanthine and hypoxanthine/xanthine and xanthine/xanthosine ratios (Mannelli et al, 2009). Nevertheless, these represent preliminary results and further studies are needed in this field to claim them as useful biomarkers of disease or response to methadone treatment.…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

Metabolomics of methadone: clinical and forensic toxicological implications and variability of dose response

Dinis-Oliveira

2016

Drug Metabolism Reviews

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Methadone is a full μ-opioid receptor agonist used in the treatment of heroin addiction. It is commercialized as a racemic mixture with considerable variability in the pharmacokinetics and pharmacodynamics between individuals that can affect dose-response and toxicological profile. This review aims to discuss metabolomics of methadone, namely by presenting all major and minor metabolites and pharmacokinetic drug interactions. The main mechanism for methadone metabolism is hepatic through the cytochrome P450, specifically isoenzymes 2B6, 3A4 and 2D6. Firstly, methadone is N-demethylated and cyclize to form its major 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyraline (EMDP) metabolites. Several alternate minor pathways have been described namely various methadol metabolites, which proved to be active. It is expected that knowing the metabolomics of methadone may provide further insights, attempting a personalized therapy aiming to attain effective blood concentrations. The historical record is therefore especially important when investigating clinical and forensic cases related to methadone administration, since interindividual responses are known to vary considerably.

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“…Different concentrations of purine nucleotide (25 mg/ mL, 75 mg/mL, 125 mg/mL, 175 mg/mL, 225 mg/mL) were used for the experiment. Effects of purine nucleotide administration on purine nucleotide metabolism in brains of heroin-dependent rats 793 decreased GMP concentrations are associated with opioid dependence in humans (Mannelli et al, 2009). It has also been shown that opioid use may have toxic effects on the central and peripheral nervous systems, leading to irreversible, pathological cellular changes.…”

Section: Content Detection Of Purine Nucleotidesmentioning

confidence: 99%

Effects of purine nucleotide administration on purine nucleotide metabolism in brains of heroin-dependent rats

Zhang

Chen

et al. 2016

Braz. J. Pharm. Sci.

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Heroin is known to enhance catabolism and inhibit anabolism of purine nucleotides, leading to purine nucleotide deficiencies in rat brains. Here, we determined the effect of exogenous purine nucleotide administration on purine nucleotide metabolism in the brains of heroin-dependent rats. Heroin was administrated in increasing doses for 9 consecutive days to induce addiction, and the biochemical changes associated with heroin and purine nucleotide administration were compared among the treated groups. HPLC was performed to detect the absolute concentrations of purine nucleotides in the rat brain cortices. The enzymatic activities of adenosine deaminase (ADA) and xanthine oxidase (XO) in the treated rat cortices were analyzed, and qRT-PCR was performed to determine the relative expression of ADA, XO, adenine phosphoribosyl transferase (APRT), hypoxanthine-guaninephosphoribosyl transferase (HGPRT), and adenosine kinase (AK). Heroin increased the enzymatic activity of ADA and XO, and up-regulated the transcription of ADA and XO. Alternatively, heroin decreased the transcription of AK, APRT, and HGPRT in the rat cortices. Furthermore, purine nucleotide administration alleviated the effect of heroin on purine nucleotide content, activity of essential purine nucleotide metabolic enzymes, and transcript levels of these genes. Our findings therefore represent a novel, putative approach to the treatment of heroin addiction. Uniterms:Purine nucleotide/quantitative analysis. Purine nucleotide/effects/brain rats. Heroin analysis. Adenosine deaminase analysis. Xanthine oxidase analysis INTRODUCTIONOpiates, such as morphine and heroin, are illegally used as recreational drugs worldwide, and can significantly impair the user's physical and mental health (Chu et al., 2009;Li et al., 2014). Opioid dependence is a significant public health concern, underscoring the need for effective treatment options (Kresina, Bruce, Mulvey, 2013;Nutt, King, Phillips, 2010). Therefore, the exploration of the effects of repeated exposure to these compounds is important for understanding the mechanisms of drug dependency and developing new treatment options.Properly regulated purine nucleotide (PN) metabolism is necessary for normal brain function (Franke, 2011). Imbalances in purine nucleotide levels lead to a variety of human diseases (Burhans, Weinberger, 2007;El-Hattab, Scaglia, 2013;Kimura et al., 2003). Studies have shown that morphine and heroin can enhance the oxidation of xanthine and hypoxanthine in the lobus temporalis, lobus frontalis, and lobus parietalis of rats (Liu et al., 2007;Yang et al., 2006). Uric acid (UA) is the final oxidation product of purine metabolism in humans and higher primates, and changes in UA levels may reflect the catabolism of purine nucleotides (Liang, Clark, 2004). Furthermore, it has been reported that morphine may increase UA concentrations in the corpus striatum, as well as in serum and extracellularly, in vitro (Enrico et al., 1997;Sumathi, Niranjali Devaraj, 2009). In patients where morphine was administe...

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Opioid use affects antioxidant activity and purine metabolism: preliminary results

Cited by 54 publications

References 65 publications

Metabolomic changes in autopsy‐confirmed Alzheimer's disease

Metabolomic changes in autopsy‐confirmed Alzheimer's disease

Metabolomics of methadone: clinical and forensic toxicological implications and variability of dose response

Effects of purine nucleotide administration on purine nucleotide metabolism in brains of heroin-dependent rats

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