Transcriptome profile analysis reveals putative molecular mechanisms of 5-aminolevulinic acid toxicity

0571760 - ÚMG 2024 RIV US eng J - Journal Article
Menezes, P. R. - Madureira Trufen, Carlos Eduardo - Lichtenstein, F. - Pellegrina, D. V. d. S. - Reis, E. M. - Onuki, J.
Transcriptome profile analysis reveals putative molecular mechanisms of 5-aminolevulinic acid toxicity.
Archives of Biochemistry and Biophysics. Roč. 738, April (2023), č. článku 109540. ISSN 0003-9861. E-ISSN 1096-0384
Institutional support: RVO:68378050
Keywords : 5-aminolevulinic acid * Bioinformatics * Hepatocellular carcinoma * Porphyrias * Transcriptome
OECD category: Biochemistry and molecular biology
Impact factor: 3.9, year: 2022
Method of publishing: Limited access
https://www.sciencedirect.com/science/article/pii/S0003986123000395?via%3Dihub

5-aminolevulinic acid (5-ALA) is the first precursor of the heme biosynthesis pathway, accumulated in acute intermittent porphyria (AIP), an inherited metabolic disease characterized by porphobilinogen deaminase deficiency. An increased incidence of hepatocellular carcinoma (HCC) has been reported as a long-term mani-festation in symptomatic AIP patients. 5-ALA is an alpha-aminoketone prone to oxidation, yielding reactive oxygen species and 4,5-dioxovaleric acid. A high concentration of 5-ALA presents deleterious pro-oxidant potential. It can induce apoptosis, DNA damage, mitochondrial dysfunction, and altered expression of carcinogenesis-related proteins. Several hypotheses of the increased risk of HCC rely on the harmful effect of elevated 5-ALA in the liver of AIP patients, which could promote a pro-carcinogenic environment. We investigated the global transcriptional changes and perturbed molecular pathways in HepG2 cells following exposure to 5-ALA 25 mM for 2 h and 24 h using DNA microarray. Distinct transcriptome profiles were observed. 5-ALA '25 mM-2h ' upregulated 10 genes associated with oxidative stress response and carcinogenesis. Enrichment analysis of differentially expressed genes by KEGG, Reactome, MetaCoreTM, and Gene Ontology, showed that 5-ALA '25 mM-24h' enriched pathways involved in drug detoxification, oxidative stress, DNA damage, cell death/survival, cell cycle, and mitochondria dysfunction corroborating the pro-oxidant properties of 5-ALA. Furthermore, our results disclosed other possible processes such as senescence, immune responses, endoplasmic reticulum stress, and also some putative effectors, such as sequestosome, osteopontin, and lon peptidase 1. This study provided additional knowledge about mo-lecular mechanisms of 5-ALA toxicity which is essential to a deeper understanding of AIP and HCC patho-physiology. Furthermore, our findings can contribute to improving the efficacy of current therapies and the development of novel biomarkers and targets for diagnosis, prognosis, and therapeutic strategies for AHP/AIP and associated HCC.
Permanent Link: https://hdl.handle.net/11104/0343502