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- W4377029167 abstract "<b>Abstract ID 21867</b> <b>Poster Board 578</b> Ketoconazole, an imidazole derivative, is one of the treatment options used to treat Cushing’s syndrome in adults and adolescents (>12-year-old) by suppressing steroidogenesis through its inhibition of CYP17A1 (Cyp17a1 in rodents), while Cushing’s syndrome is a rare but life-threatening disease caused by cortisol hypersecretion. It is well known that microRNAs (miRNAs) influence drug metabolism by regulating the expression of CYP enzymes. Our previous liver toxicity study has shown that miRNA expressions are altered and contributed to liver toxicity by ketoconazole exposure in rats. However, it is unclear if/how miRNAs may affect Cyp17a1 levels under the treatment of ketoconazole. To that end, we used miRWalk to identify miRNA candidates that may target Cyp17a1. miRNAs with a binding probability larger than 0.95 were considered as miRNA candidates, resulting in that135 miRNAs with a high confidence for targeting Cyp17a were selected. Next, we analyzed differentially expressed miRNAs (DEMs) from rats that were treated with ketoconazole for 3, 7, and 14 days, at the middle and high doses, by which we identified 11 common DEMs with log2FoldChange > 2 or < -1 across all treatment conditions. Furthermore, we overlapped the 11 common DEMs with the predicted miRNAs targeting Cyp17a1, and found that mir-22-5p, miR-671, miR-28-3p, and miR-92b-3p were significantly upregulated by ketoconazole treatment and could target Cyp17a1. Our conservation analysis based on miRNA sequences revealed that all these four miRNAs were 100% identical between rats and humans. Taken together, our work suggests that ketoconazole may upregulate mir-22-5p, miR-671, miR-28-3p, and miR-92b-3p to inhibit Cyp17A1 expression to suppress steroidogenesis in Cushing’s syndrome. Wet-lab experiments that validate the molecular mechanisms are currently ongoing and will be discussed. Support/Funding Information: FDA funded study." @default.
- W4377029167 created "2023-05-19" @default.
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- W4377029167 date "2023-05-18" @default.
- W4377029167 modified "2023-09-29" @default.
- W4377029167 title "Pharmacological Effects of Ketoconazole in the Treatment of Steroidogenesis Suppression via CYP17A1 Inhibition May Involve MicroRNA Regulation" @default.
- W4377029167 doi "https://doi.org/10.1124/jpet.122.218670" @default.
- W4377029167 hasPublicationYear "2023" @default.
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