investigation into fatty acid ethyl esters in mouse brains after ethanol treatment: detection, quantification, and potential toxicity

• Online Access: http://hdl.handle.net/2047/D20284522

Background: Mankind's oldest drug, ethanol (alcohol) is largely cleared by oxidation in the liver. The proximal metabolite is acetaldehyde, but this reactive and volatile chemical is swiftly further oxidized to acetate which is incorporated into normal metabolic pathways. A small fraction of the acetaldehyde is well-known to be converted into alkaloid-like chemicals whose actions may contribute to the overall effects of alcohol intoxication. Importantly, however, small amounts of non-oxidative metabolites are also formed in numerous tissues including the liver, pancreas, and brain. For example, ethyl glucuronide and ethyl sulfate formed by classical phase II drug metabolizing pathways have been used as markers of ethanol consumption. One of the most prominent non-oxidative metabolic pathways involves condensation of ethanol with endogenous fatty acids, generating fatty acid ethyl esters (FAEEs). These compounds have previously been shown to be pharmacologically active and potentially toxic using both in vitro and in vivo animal models of ethanol use primarily in the liver and pancreas. The potential role that these non-oxidative metabolites play in the brain, a tissue isolated from systemic circulation with limited oxidative metabolism of ethanol, has not yet been thoroughly explored. The brain is a known target for ethanol and fatty acid toxicity. One of the most abundant fatty acids in the brain is arachidonic acid, and the ethyl ester of arachidonic acid is ethyl arachidonate (AAEE). In studies of post mortem brain tissue from intoxicated accident victims the most prominent FAEE found is AAEE. However, AAEE has not been documented in brains from mice after ethanol administration, so that studies with this common model species were not available to explore the likely relevance of AAEE neurotoxicity in humans.