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Title: Small Molecule Antipsychotic Aripiprazole Potentiates Ozone-Induced Inflammation in Airway Epithelium.

Authors: Speen, Adam M; Hoffman, Jessica R; Kim, Hye-Young H; Escobar, Yael N; Nipp, Grace E; Rebuli, Meghan E; Porter, Ned A; Jaspers, Ilona

Published In Chem Res Toxicol, (2019 10 21)

Abstract: Inhaled ground level ozone (O3) has well described adverse health effects, which may be augmented in susceptible populations. While conditions, such as pre-existing respiratory disease, have been identified as factors enhancing susceptibility to O3-induced health effects, the potential for chemical interactions in the lung to sensitize populations to pollutant-induced responses has not yet been studied. In the airways, inhaled O3 reacts with lipids, such as cholesterol, to generate reactive and electrophilic oxysterol species, capable of causing cellular dysfunction and inflammation. The enzyme regulating the final step of cholesterol biosynthesis, 7-dehydrocholesterol reductase (DHCR7), converts 7-dehydrocholesterol (7-DHC) to cholesterol. Inhibition of DHCR7 increases the levels of 7-DHC, which is much more susceptible to oxidation than cholesterol. Chemical analysis established the capacity for a variety of small molecule antipsychotic drugs, like Aripiprazole (APZ), to inhibit DHCR7 and elevate circulating 7-DHC. Our results show that APZ and the known DHCR7 inhibitor, AY9944, increase 7-DHC levels in airway epithelial cells and potentiate O3-induced IL-6 and IL-8 expression and cytokine release. Targeted immune-related gene array analysis demonstrates that APZ significantly modified O3-induced expression of 16 genes, causing dysregulation in expression of genes associated with leukocyte recruitment and inflammatory response. Additionally, we find that APZ increases O3-induced IL-6 and IL-8 expression in human nasal epithelial cells from male but not female donors. Overall, the evidence we provide describes a novel molecular mechanism by which chemicals, such as APZ, that perturb cholesterol biosynthesis affect O3-induced biological responses.

PubMed ID: 31476115 Exiting the NIEHS site

MeSH Terms: Antipsychotic Agents/chemistry; Antipsychotic Agents/toxicity*; Aripiprazole/chemistry; Aripiprazole/toxicity*; Cells, Cultured; Epithelial Cells/drug effects*; Epithelial Cells/metabolism; Humans; Inflammation/chemically induced*; Inflammation/metabolism; Molecular Structure; Ozone/toxicity*; Respiratory Mucosa/drug effects*; Respiratory Mucosa/metabolism; Small Molecule Libraries/chemistry; Small Molecule Libraries/toxicity*; trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride/chemistry; trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride/toxicity

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