Identification of Molecular Targets Associated with Ethanol Toxicity and Implications in Drug Development

Lin-Lin      Wang; An-Kui      Yang; Shu-Ming      He; Jun      Liang; Zhi-Wei      Zhou; Yong      Li; Shu-Feng      Zhou

doi:10.2174/138161210791034030

Abstract

Alcohol dependence is a major disease burden of adults in modern society worldwide. There is no cure for alcohol dependence. In this study, we have examined the molecular targets of ethanol-induced toxicity in humans based on a systematic review of literature data and then discussed current and potential therapeutic targets for alcohol abuse and dependence. Using human samples with ethanol exposure, microarray analyses of gene expression have shown that numerous genes are up- and/or down-regulated by alcohol exposure. The ethanol-responsive genes mainly encode functional proteins such as proteins involved in nucleic acid binding, transcription factors, selected regulatory molecules, and receptors. These genes are also correlated with important biological pathways, such as angiogenesis, integrin signaling pathway, inflammation, wnt signaling pathway, platelet-derived growth factor signaling pathway, p53 pathway, epidermal growth factor receptor signaling pathway and apoptosis signaling pathway. Currently, only three medications were approved by the U.S. Food and Drug Administration (FDA) for the treatment of alcohol abuse and alcohol dependence, including the aldehyde dehydrogenase inhibitor disulfiram, the μ-opioid receptor antagonist naltrexone, and the N-methyl-D-aspartate (NMDA) receptor inhibitor acamprosate (oral and injectable extended-release formulations). In addition, a number of agents are being investigated as novel treatments for alcohol abuse and dependence. These include selective 5-HT reuptake inhibitors (e.g. fluoxetine), 5-HT1 receptor agonists (e.g. buspirone), 5-HT2 receptor antagonists (e.g. ritanserin), 5-HT3 receptor antagonists (e.g. ondansetron), dopamine receptor antagonists (e.g. aripiprazole and quetiapine), dopamine receptor agonists (e.g. bromocriptine), GABAB receptor agonists (e.g. baclofen), and cannabinoid-1 (CB1) receptor antagonists. Some of these agents have shown promising efficacy in initial clinical studies. However, further randomized studies with larger samples are warranted to establish their efficacy and safety profiles in the treatment of alcohol dependence.

Keywords: Ethanol, toxicity, molecular target, biological pathway, drug development, disulfiram, acamprosate, naltrexone