Age-Related Changes in miRNA Expression Influence GSTZ1 and Other Drug Metabolizing Enzymes

Abstract

Previous work has shown that hepatic levels of human glutathione transferase zeta 1 (GSTZ1) protein, involved in tyrosine catabolism and responsible for metabolism of the investigational drug dichloroacetate, increase in cytosol after birth before reaching a plateau around age 7. However, the mechanism regulating this change of expression is still unknown, and previous studies showed that GSTZ1 mRNA levels did not correlate with GSTZ1 protein expression. In this study, we addressed the hypothesis that microRNAs (miRNAs) could regulate expression of GSTZ1. We obtained liver samples from donors aged less than 1 year or older than 13 years and isolated total RNA for use in a microarray to identify miRNAs that were downregulated in the livers of adults compared with children. From a total of 2578 human miRNAs tested, 63 miRNAs were more than 2-fold down-regulated in adults, of which miR-376c-3p was predicted to bind to the 39 untranslated region of GSTZ1 mRNA. There was an inverse correlation of miR-376c-3p and GSTZ1 protein expression in the liver samples. Using cell culture, we confirmed that miR-376c-3p could downregulate GSTZ1 protein expression. Our findings suggest that miR-376c-3p prevents production of GSTZ1 through inhibition of translation. These experiments further our understanding of GSTZ1 regulation. Furthermore, our array results provide a database resource for future studies on mechanisms regulating human hepatic developmental expression. SIGNIFICANCE STATEMENTHepatic glutathione transferase zeta 1 (GSTZ1) is responsible for metabolism of the tyrosine catabolite maleylacetoacetate as well as the investigational drug dichloroacetate. Through examination of microRNA (miRNA) expression in liver from infants and adults and studies in cells, we showed that expression of GSTZ1 is controlled by miRNA. This finding has application to the dosing regimen of the drug dichloroacetate. The miRNA expression profiles are provided and will prove useful for future studies of drug-metabolizing enzymes in infants and adults.

Characterization of the microRNA Expression Profiles in the Goat Kid Liver

“…The miRNAs overexpress or under-express affecting the expression of the gene, and likewise, the expression of the related pathways causing lesions. MiRNA is a potential biomarker for treatment response monitoring and diagnosis, and an imminent new treatment target ( Jahn et al, 2020 ). From clinical trials to laboratory tests, doctors should expect stable miRNA formulas.…”

Neuroprotective Effects and Therapeutic Potential of Dichloroacetate: Targeting Metabolic Disorders in Nervous System Diseases

“…169 In addition, Jahn et al showed that miR-376c-3p prevents the expression of GSTZ1 by repressing translation, and the expression of this miRNA is lower in adults than in children, which provides new ideas for studying the factors that influence GSTZ1. 170 GSTZ1 genotypes are also important in influencing the metabolism of DCA. 171 There are five common haplotypes based on the three common asynchronous single-nucleotide polymorphisms (rs7975, rs7972, rs1046428) in the GSTZ1 gene coding region, which, in order of population frequency, are EGT (GSTZ1C, 50%), KGT (GSTZ1B, 28%), EGM (GSTZ1D, 15%), KRT (GSTZ1A, 7%), and KGM (GSTZ1F, 0.4%).…”

“… 169 In addition, Jahn et al showed that miR-376c-3p prevents the expression of GSTZ1 by repressing translation, and the expression of this miRNA is lower in adults than in children, which provides new ideas for studying the factors that influence GSTZ1. 170 …”

Epigenetic Mechanisms Contribute to Intraindividual Variations of Drug Metabolism Mediated by Cytochrome P450 Enzymes

“…The data support the role of the age-dependent miRNAs in regulating drug-metabolizing enzyme genes, including several CYP genes. Age-related changes in miRNA expression also influence ontogeny of a phase II enzyme of glutathione transferase zeta 1 (GSTZ1) in human liver (Jahn et al, 2020). miRNAs as a major epigenetic mechanism in posttranscriptional regulation of drug metabolizing enzymes has been referred as miRNA pharmacoepigenetics, which may serve as a new strategy for development of more effective therapy (Yu et al, 2016).…”