Title: Identification of Environmental Quaternary Ammonium Compounds as Direct Inhibitors of Cholesterol Biosynthesis.
Authors: Herron, Josi; Reese, Rosalyn C; Tallman, Keri A; Narayanaswamy, Rohini; Porter, Ned A; Xu, Libin
Published In Toxicol Sci, (2016 06)
Abstract: In this study, we aim to identify environmental molecules that can inhibit cholesterol biosynthesis, potentially leading to the same biochemical defects as observed in cholesterol biosynthesis disorders, which are often characterized by congenital malformations and developmental delay. Using the Distributed Structure-Searchable Toxicity (DSSTox) Database Network developed by EPA, we first carried out in silico screening of environmental molecules that display structures similar to AY9944, a known potent inhibitor of 3β-hydroxysterol-Δ(7)-reductase (DHCR7)-the last step of cholesterol biosynthesis. Molecules that display high similarity to AY9944 were subjected to test in mouse and human neuroblastoma cells for their effectiveness in inhibiting cholesterol biosynthesis by analyzing cholesterol and its precursor using gas chromatography-mass spectrometry. We found that a common disinfectant mixture, benzalkonium chlorides (BACs), exhibits high potency in inhibiting DHCR7, as suggested by greatly elevated levels of the cholesterol precursor, 7-dehydrocholesterol (7-DHC). Subsequent structure-activity studies suggested that the potency of BACs as Dhcr7 inhibitors decrease with the length of their hydrocarbon chain: C10 > C12 ≫ C14 > C16. Real-time qPCR analysis revealed upregulation of the genes related to cholesterol biosynthesis and downregulation of the genes related to cholesterol efflux, suggesting a feedback response to the inhibition. Furthermore, an oxidative metabolite of 7-DHC that was previously identified as a biomarker in vivo was also found in cells exposed to BACs by liquid chromatography-mass spectrometry. Our findings suggest that certain environmental molecules could potently inhibit cholesterol biosynthesis, which could be a new link between environment and developmental disorders.
PubMed ID: 26919959
MeSH Terms: Animals; Anti-Infective Agents, Local/chemistry; Anti-Infective Agents, Local/toxicity*; Benzalkonium Compounds/chemistry; Benzalkonium Compounds/toxicity*; Cell Line, Tumor; Cholesterol/biosynthesis*; Databases, Factual; Dose-Response Relationship, Drug; Environmental Pollutants/chemistry; Environmental Pollutants/toxicity*; Enzyme Inhibitors/pharmacology; Humans; Lipid Metabolism/drug effects*; Mice; Molecular Structure; Neurons/drug effects*; Neurons/metabolism; Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors; Oxidoreductases Acting on CH-CH Group Donors/metabolism; Risk Assessment; Structure-Activity Relationship; trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride/metabolism; trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride/pharmacology