Scientific Publications by FDA Staff

Mol Pharmacol 2020 Aug;98(2):120-9

Multiple birds with one stone: microRNA hsa-miR-1301-3p regulates human ADH6, ALDH5A1 and ALDH8A1 in the ethanol-acetaldehyde-acetate metabolic pathway.

Wang X, Zhao Y, Luo J, Xu L, Li X, Jin Y, Li C, Feng M, Wang Y, Chen J, Hou Y, Zhao Q, Zhao J, Ning B, Zheng Y, Yu D

Alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs) are vital enzymes involved in the metabolism of a variety of alcohols. Differences in the expression and enzymatic activity of human ADHs and ALDHs correlate with individual variability in metabolizing alcohols and drugs and in the susceptibility to alcoholic liver disease (ALD). MicroRNAs (miRNAs) function as epigenetic modulators to regulate the expression of drug metabolizing enzymes (DMEs). To characterize miRNAs that target ADHs and ALDHs in human liver cells, we carried out a systematic bioinformatics analysis to analyze free energies of the interaction between miRNAs and their cognate sequences in ADH and ALDH transcripts, and then calculated expression correlations between miRNAs and their targeting ADH and ALDH genes using a public database. Candidate miRNAs were selected to evaluate bioinformatic predictions using a series of biochemical assays. Our results showed that 11 miRNAs have the potential to modulate the expression of 2 ADH and 7 ALDH genes in the human liver. We found that hsa-miR-1301-3p suppressed the expression of ADH6, ALDH5A1, and ALDH8A1 in liver cells and blocked their induction by ethanol. In summary, our results revealed that hsa-miR-1301-3p plays an important role in ethanol metabolism by regulating ADH and ALDH gene expression. SIGNIFICANCE STATEMENT: We showed that 11 miRNAs might play regulatory roles in the expression of 2 ADH and 7 ALDH genes in human liver via systematic bioinformatics analysis. Experimental evidences proved that hsa-miR-1301-3p suppressed the expression of ADH6, ALDH5A1, and ALDH8A1 in liver cells and blocked their induction by ethanol.