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Metabolomics in Alcohol Research and Drug Development

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Metabolomics in Alcohol Research and Drug Development Metabolomics in Alcohol Research and Drug Development George G. Harrigan, Ph.D.; Greg Maguire, Ph.D.; and Laszlo Boros, M.D. Developers of new medications need to describe and predict the functional attributes of test compounds administered to cells, animals, and humans. Today, researchers increasingly appreciate the role that intermediary products (i.e., metabolites) generated in the course of various metabolic pathways play in both health and disease states and how their analysis can support development of new medications. Advances in analytical and computational techniques have facilitated the rise of new and powerful tools for measuring metabolic and biochemical pathways in such complex systems. Metabolomics—a systems biology approach to characterizing metabolites produced in biochemical pathways—is contributing to many studies of disease progression and treatment, although it has not yet been extensively applied in research on metabolic perturbations associated with alcohol abuse. However, numerous metabolomic approaches may contribute to alcohol-related research, as illustrated by studies on alcohol-related metabolic dysfunctions such as (1) alterations in fat metabolism and (2) thiamine deficiency. By further increasing the number and types of metabolites that can be measured in a given biological sample, metabolomic approaches may be able to help define the role of the many different metabolic pathways affected by alcohol abuse and support discovery and development of novel medications for the treatment of alcoholism and related conditions. KEY WORDS: Alcohol abuse and dependence; alcoholism; alcohol- related disorders; systems biology; metabolomics; metabolome; metabolic networks; metabolic pathways; metabolites; metabolic process; metabolic profiling; lipid dysfunction; thiamine deficiency; disease etiology; drug design ttempts to develop new and/or and computational methodologies to ronmental changes. Identification of improved medications for the describe the effects of medication can- induced changes in the concentration A treatment of illnesses affecting didates within the complex biochemi- of these metabolites, or altered flux1 millions of people around the world cal pathways of intact, fully assembled rates through metabolic pathways are characterized by an ever-increasing living networks (Goodacre et al. 2004; disparity between research expenditure Joyce and Palsson 2007; Maguire et al. 1 For a definition of this and other technical terms, see (both in terms of time and money) in 2006, 2007; Mo et al. 2007). A most the glossary on p. 84. the pharmaceutical industry and return promising approach to studying such networks is metabolomics. on investment (Di Masi et al. 2003). GEORGE G. HARRIGAN, PH.D, currently Therefore, strategies that can rapidly Metabolomics is a systems biology is a study director in the Product Safety identify novel candidate medications (or approach to measuring changes in Center at Monsanto Company, St. Louis, potential targets of new medications), small-molecule intermediary products Missouri. which are likely to demonstrate effective- (i.e., metabolites)—such as sugars ness in clinical trials, will be valuable to (e.g., glucose), amino acids, and organic GREG MAGUIRE, PH.D., currently is both patients and the pharmaceutical acids—in any given biological system based in San Diego, California. industry. One means to achieve this exposed to genetic modification, drugs goal—the adoption of screening or medications, or any other environ- LASZLO BOROS, M.D., is associate professor approaches that can be performed in mental perturbation. The levels of these of Pediatrics at the University of Cali- isolated cells and tissues (i.e., in vitro) small-molecule metabolites within a fornia Los Angeles, co-director of the or using computer models (i.e., in cell, tissue, or an organism largely reflect Stable Isotope Research Laboratory at silico)—continues apace. Another impor- the endogenous activity of biochemical Harbor-UCLA Medical Center, and tant prerequisite for effective screening pathways; moreover, they also are chief scientific advisor at SiDMAP, Los tools is the development of analytical highly responsive to external or envi- Angeles, California. 26 Alcohol Research & Health Metabolomics, Alcohol Research, and Drug Development (e.g., Maguire et al. 2006; 2007), may metabolomics are to probe the mecha­ NMR and MS, as well as other provide insights into the activities, nisms that contribute to changes in techniques, can be employed in two interactions, and regulatory roles of all metabolite levels and fluxes in cells, tis­ different (but not necessarily mutual­ biochemical processes of interest. sues, and organisms and to understand ly exclusive) conceptual approaches Although metabolomic approaches the implications of such changes on that can broadly be defined as “non­ to date have been used primarily for disease, response to drugs and medica­ targeted” and “targeted” (Goodacre other physiological processes and dis­ tions, and nutritional intervention. To et al. 2004). Nontargeted approaches eases, they are equally applicable to achieve these goals, numerous technical provide a hypothesis-free global over­ studies on the impact of alcohol on approaches to data acquisition are avail­ view of readily detectable metabolites metabolism as well as the effect of able. The main technologies utilized in in a sample (e.g., lipid or sugar meta­ medications developed to treat the metabolomics are nuclear magnetic res­ bolites in plasma). Many experiments effects of alcohol abuse and depen­ onance (NMR) spectroscopy and mass have successfully used such nontargeted dence. The costs associated with alco­ spectrometry (MS) (for a review, see approaches, although some investiga­ holism, at both the personal and more Dunn and Ellis 2005). Briefly, NMR tors are increasingly concerned about global level, are well understood. From spectroscopy is a technique that exploits current statistical treatments and meth­ a medical standpoint, it is important the magnetic properties of the nuclei of odological practices in such experiments both to understand the psychological certain atoms (e.g., protons [1H] or a (Broadhurst and Kell 2006; Lay et and emotional factors that contribute variant [i.e., isotope] of carbon known al. 2006). It has been suggested, for to alcohol dependence and to amelio­ as 13C). In a typical metabolomics example, that the results of a study rate the physiological devastation that experiment, a solvent extract of the bio­ claiming that nontargeted NMR this dependence can cause. Because logical sample (or in the case of urine analysis of plasma could accurately excessive alcohol use can induce pro­ or plasma, the sample itself) is placed predict the risk of coronary heart found metabolic perturbations, there in a magnetic field and then exposed to disease actually were confounded by radiowaves covering a given frequency gender and drug use (Kirschenlohr et should be numerous opportunities 2 for using metabolomic approaches. range. The way in which the biological al. 2006). Indeed, the first attempts at such sample absorbs that energy is depen­ Targeted approaches, in contrast, metabolic profiling research date back dent on the relative proportion of dif­ focus on identified and preselected to at least the 1980s, when researchers ferent metabolites in that sample. This metabolic pathways, which may offer measured the levels of various metabo­ allows investigators to obtain an NMR particular advantages in studies on lites in the urine of ethanol-exposed spectrum that represents the metabolite metabolic dysregulation. These tar­ humans and rats (Axelson et al. 1981; composition of the sample and that geted approaches typically employ Weiner et al. 1984). More recently, can be compared with the NMR spec­ optimized measurement techniques however, metabolomic strategies rarely tra of other biological samples. that specifically detect certain classes of metabolites or pathways. This have been applied systematically in MS is another analytical technique approach recognizes the wide differ­ the alcohol field. that can be used to assess the metabo­ ences in physiochemical structure, This article briefly describes the lite composition of a biological sample. For these assays, samples are injected stability, and abundance of different concepts behind metabolomic research. metabolites in a given sample— It highlights examples of how meta­ into a mass spectrometer that can separate compounds according to factors that present challenges in bolomic approaches have been used accurately measuring a wide range of to study metabolic perturbations, such their molecular mass, and a list of the molecular masses of the compounds metabolites in a single measurement. as altered fat (i.e., lipid) metabolism Targeted approaches also recognize and thiamine deficiency, that also are in the sample is generated. The meta­ bolites corresponding to a given that evaluation of low-abundance observed in alcohol-dependent patients. metabolites, such as signaling lipids, It also considers the role that meta­ molecular mass can then be identified and their relative abundance in a hormones, and neurotransmitters, may bolomics can play in further elucidating require specialized methods. Finally, the causes and effects of these changes sample determined. The specific data acquisition tech­ targeted metabolomic approaches and supporting the discovery and emphasizing biological expertise in development of new medications to nology
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