PT  - JOURNAL ARTICLE
AU  - Stephan Jahn
AU  - Lauren Gay
AU  - Claire Weaver
AU  - Rolf Renne
AU  - Taimour Y Langaee
AU  - Peter W Stacpoole
AU  - Margaret O. James
TI  - Age-Related Changes in miRNA Expression Influence GSTZ1 and Other Drug Metabolizing Enzymes
AID  - 10.1124/dmd.120.090639
DP  - 2020 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.120.090639
4099  - http://dmd.aspetjournals.org/content/early/2020/04/30/dmd.120.090639.short
4100  - http://dmd.aspetjournals.org/content/early/2020/04/30/dmd.120.090639.full
AB  - 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 seven. 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 could regulate expression of GSTZ1. We obtained liver samples from donors aged less than one year or older than thirteen years and isolated total RNA for use in a microarray to identify miRNAs that were downregulated in the livers of adults compared to children. From a total of 2,578 human miRNAs tested, 63 miRNAs were more than two-fold down-regulated in adults, of which miR-376c-3p was predicted to bind to the 3'-UTR 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 STATEMENT Hepatic GSTZ1 is responsible for metabolism of the tyrosine catabolite maleylacetoacetate as well as the investigational drug dichloroacetate. Through examination of 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.