Identification of Environmental Quaternary Ammonium Compounds as Direct Inhibitors of Cholesterol Biosynthesis

In this study, the authors aimed 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 characterised by congenital malformations and developmental delay. Using the Distributed Structure-Searchable Toxicity (DSSTox) Database Network developed by EPA, the authors first carried out in silico screening of environmental molecules that display structures similar to AY9944, a known potent inhibitor of 3?-hydroxysterol-?(7)-reductase (DHCR7) – the last step of cholesterol biosynthesis. Molecules that display high similarity to AY9944 were subjected to test in Neuro2a and human neuroblastoma cells for their effectiveness in inhibiting cholesterol biosynthesis by analysing cholesterol and its precursor using gas chromatography-mass spectrometry. A common disinfectant mixture, benzalkonium chlorides (BACs), was found to exhibit 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. The authors concluded that the finding from the present study suggest that certain environmental molecules could potently inhibit cholesterol biosynthesis, which could be a new link between environment and developmental disorders.

Authors: Herron J, Reese R, Tallman KA, Narayanaswamy R, Porter NA, Xu L. ;Full Source: Toxicology Science. 2016 Feb 26. pii: kfw041. [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][Epub ahead of print] ;[/fusion_builder_column][/fusion_builder_row][/fusion_builder_container]