ABSTRACT: Acute hepatic porphyrias (AHPs) are inherited metabolic diseases characterized by decreased activity or reduction in synthesis of the heme biosynthetic pathway enzymes, leading to acute attacks of abdominal pain, hypertension, neuropsychiatric alterations, and a long-term increase in the incidence of hepatocellular carcinoma (HCC). 5-aminolevulinic acid (ALA) seems to be the major pathogenic factor of AHPs. Studies only reported biological effects on specific macromolecules, thus we investigated the global transcriptional changes and perturbed molecular pathways in HepG2 cells following exposure to ALA 2.5 mM or 25 mM for 2 h and 24 h using DNA microarray. The identification and analysis of differentially expressed genes (DEGs) showed distinct transcriptome profiles from each ALA treatment. Molecular pathways and biological processes enrichment analysis of DEGs by KEGG, Reactome, Metacore, and Gene Ontology, showed that ALA ‘2.5 mM-2h’ induced perturbation in the mitochondrial respiratory chain, ion homeostasis, cell proliferation/apoptosis, and UPR/ER stress, which were connected by the network hubs AP1, C/EBP, ATF-6. ALA ‘25 mM-24h’ elicited changes in oxidative stress, cell death/survival, immune response, drug detoxification, and carcinogenesis with AP-1, C/EBP, EGR1, STAT5, Cyclin D1, JAK2, ERK1/2, and RAC1 as the main network hubs and SQSTM1, HMOX1, SPP1, and LONP-1 genes as putative effectors. This study contributes to revealing molecular mechanisms of ALA potentially associated with the pathogenesis of the clinical manifestations of AHPs.
