Investigation of the effect of heroin on glutathione metabolism at metabolomic level

Çatak, Ş. Investigation of the Effect of Heroin on Glutathione Metabolism at Metabolomic Level, Hacettepe University Graduate School of Health Sciences Pharmacy Department of Pharmaceutical Toxicology Master of Science Thesis, Ankara, 2023. Heroin is a substance that is a synthetic opioid derivative with a high addictive potential. Serious toxic effects may occur due to heroin use. Although many different mechanisms are effective in the emergence of these effects, oxidative stress formation and glutathione (GSH) consumption are also included in the main toxic effect mechanism, causing serious oxidative damage to users. In this thesis study, investigating the effects of heroin on glutathione metabolism in SH-SY5Y neuroblastoma cell line with both targeted and untargeted metabolomic analyzes, revealing the relationship of heroin with enzymes in the GSH pathway with in silico modeling methods, It is aimed to conduct a preliminary study that will contribute to the general health status of addicts by revealing the possible protective effects on this toxicity with N-acetylcysteine (NAC) and N-acetylcysteine amidine (NACA). According to the findings, it was determined that the cytotoxic response due to heroin was prevented by NAC and NACA administration, and the decrease in GSH levels with heroin administration was also prevented by GSH precursors. However, when NAC and NACA were compared, there was no significant difference between them in terms of protection. In addition, in silico molecular modeling studies, a significant binding was determined between glutathione transferase, one of the important enzymes in the GSH pathway, and morphine, the most important metabolite of heroin. Metabolomics studies have also shown that both glutathione and cysteine metabolism pathways are altered by heroin administration and these targets are important in heroin toxicity. In the literature review, no study was found in which the comparative effect of NAC and NACA against heroin toxicity was examined at the metabolomic level, and it is planned to contribute to the development of an alternative approach that can be applied to heroin addicts in the future. Therefore, it will contribute to filling the scientific gap in the development of treatment approaches.