Granzyme B and miR-378a Interaction in Acetaminophen Toxicity in Children

(E-pub Ahead of Print)

Author(s): Sandra McCullough, Harsh Dweep, Mitchell R McGill, Sudeepa Bhattacharyya, Laura James, Sara Frankowski, Aaron Woodall, Gregory Kearns, Pritmohinder Gill*.

Journal Name: MicroRNA

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Abstract:

BACKGROUND AND AIM: Hepatic phase I drug metabolizing enzymes CYP2E1, CYP1A2 and CYP3A4 catalyze the biotransformation of acetaminophen (APAP) and are important in the mediation of toxicity. The potential role of other hepatic and non-hepatic Phase I enzymes in APAP toxicity has not been established.

METHODS: PCR array containing 84 genes involved in phase I drug metabolism was examined in subgroups of hospitalized children for APAP overdose, categorized as no toxicity (ALT ≤ 45 IU/L, n=5) and moderate toxicity (ALT ≥ 500 IU/L, n=5).

RESULTS: Significant downregulation was observed for ALDH6A1, CYP4F12 and GZMB in the no toxicity subgroup and ALDH1A1, CYP27A1 and GZMB in the moderate toxicity subgroup. qRT-PCR confirmed significant downregulation for ALDH1A1, CYP4F12, and GZMB. In-silico analysis identified GZMB 3’UTR to be a target of miR-378a-5p. Overexpression of miR-378a-5p reduced the luciferase activity of GZMB 3’UTR reporter plasmid reportedly by 50%. NK-92 cells transfected with the miR-378a-5p mimic extended the effect of APAP on GZMB protein expression compared to mimic controls. In addition, miR-378a-5p was significantly upregulated in blood samples of children with APAP overdose undergoing NAC treatment.

CONCLUSION: Overall, our study suggests the presence of a novel signaling pathway, whereby miR-378a-5p inhibits GZMB expression in children with APAP overdose.

Keywords: Acetaminophen (APAP), Cytochrome P450, Granzyme B, miR-378a, APAP-induced liver injury (AILI), overdose

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(E-pub Ahead of Print)
DOI: 10.2174/2211536608666190808144456

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