Metabolomics/Applications/Health and Pharmaceuticals

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Heath and Pharmaceuticals

Introduction

Milk

Nutritional intake is essential for optimizing sport and exercise performance. Proper nutrition is also crucial for optimizing adaptations to training. The timing of nutritional intake is an important factor for optimizing the adaptations to any form of exercise, as well as having an important role in the recovery period after both resistance and endurance exercise.

Bovine milk products represent substantial sources of proteins, lipids, amino acids, vitamins and minerals. Low-fat milk has a number of characteristics to indicate that it is a significant recovery beverage. It contains carbohydrates in the form of lactose, casein and whey protein in a ratio that allows for slow protein absorption and sustained blood amino acid concentrations and a high concentration of electrolytes that aid in fluid recovery.

There is still developing evidence that supports the advantageous nature of consuming low-fat milk after exercise, especially for athletes who adhere to strength or endurance training regimens. The fat from free milk has proven to be as effective as, and in some cases more effective than, commercially available sports drinks when implemented to promote the recovery process after strength and endurance exercise. Milk also provides additional nutrients and vitamins that aid this recovery process and are not found in commercial sports drinks. It is in support of these details that milk has been proven to be an effective post-exercise beverage and an alternative to commercial sports drinks for lactose tolerant individuals.

Link to article:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18831752

Vitamin C

Polymorphisms are involved with the xenobiotic metabolizing enzyme, GSTP1-1, in vitamin C (C) and urinary C excretion. This highlights the requirement to consider gene polymorphisms when determining the C requirements of individuals.

C intake into the blood and C excretion into the urine both occur rapidly after the oral loading of DAsA. While there may be large individual differences in the levels of C excretion, blood C levels are maintained within a relatively narrow range due to homeostasis.

Enhanced C intake is necessary for individuals that smoke. This allows smokers to maintain an in vivo C storage that is equivalent to non-smokers. This suggests that polymorphisms in enzymes that relate to xenobiotic metabolism might be related to the individual differences in urinary C excretion.

Researchers believe that it is unlikely that individual differences in C metabolism are explained solely by polymorphisms of GSTP1-1. The polymorphisms of other genes and lifestyle factors are necessary to include when considering individual C requirements and deficits. In order to further understand the variations in individual C metabolisms, investigations of the association with other polymorphisms and long-term loading experiments that involve the ingestion of DAsA are currently being performed.

Link to article:

http://www.jstage.jst.go.jp/article/jnsv/54/4/54_315/_article

Cheonggukjang

The cheonggukjang supplement leads to increased mRNA expressions of enzymes and protein that are involved in the fatty acid oxidation that occurs in the liver. As a result, this supplement reduces the accumulation of body fat and improves the serum lipids in high fat diets that have been fed to mice.

High fat diets are known to lead to overall increased body weight, energy intake and efficiency of energy storage. Cheonggukjang supplementation is expected to control the frequency of coronary heart diseases that develop as a result of poor eating habits. In turn, this should encourage the avoidance of diets that are high in fat and low in cholesterol.

Changes in the expression levels of hepatic acyl-CoA synthase (ACS) may modulate metabolic fluctuations of acyl-CoA in tissues that use fatty acids in order to generate and store energy. Cheonggukjang supplementation results in higher levels of hepatic ACS mRNA levels than those who eat normal or high fat diets.

Increased fatty acid availability with cheonggukjang supplementation induces an increased expression of hepatic carnitine palmitoyltransferase-I (CPT-I) mRNA.

Cheonggukjang supplementation up-regulates uncoupling protein 2 (UCP2) mRNA. This action may consist of cellular ATP levels and decreased metabolic efficiency. This would be in support of the resultant decrease in fat accumulation.

Cheonggukjang supplementation has evident beneficial effects on weight gain, epididymal and back fat mass, lipid profiles of serum and liver in high fat diets that are fed to mice. Cheonggukjang supplementation enhances fatty acid beta-oxidation, in the liver. These effects are believed to be attributed to cheonggukjang modulating transcriptional levels of proteins and enzymes that are associated with lipid metabolism.

Link to article:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18850232

Personalized Medicine

Metabolomics: Working Toward Personalized Medicine

http://www.fda.gov/fdac/features/2005/605_metabolomics.html

Summary:

This article is sort of introducing the concept of metabolomics and its possible potentials in modern medicine to the general public. The article goes into a simplified explanation of how metabolomics came about (from the human genome project) and how exactly it relates to proteomics and genomics and details about techniques used by scientists to conduct research in this area. Currently, scientists are monitoring concentrations of metabolites in human fluid samples and are trying to figure out what the changes in metabolic profiles mean so that they can develop pharmaceuticals that are best suited for each individual person. This will save cost (if it prevents the development of an unsuccessful drug) and possibly many people’s health – as studies have shown that people who have negative reactions to certain medicines most often develop liver problems.

Definitions:

Metabolomics – the systematic study of the unique chemical fingerprints that specific cellular processes leave behind

Metabonomics - the quantitative measurement of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification

Toxicology – the study of adverse effects of chemicals on living organisms: symptoms, mechanisms, treatments and poisonings – especially among people

Metabolite – a product of a metabolic process (including intermediates)

NHGRI – National Human Genome Research Institute – a division of the National Institutes of Health, located in Bethesday, Maryland

Metabolome – the complete set of small molecule metabolites to be found within a living organism

Relevance:

This article relates to what we’ve learned up till now by providing a supplemental resource and real world applications. In class we’ve learned a few of the metabolic pathways and are presently learning some ways in which these pathways are regulated, but this article explains how the study of these pathways and specifically their concentrations of products and intermediates is useful in sort of genetically personalizing medicine – reducing the risk of side effects or injury and possibly enhancing the medicine’s effectiveness.

FDA

Resource: http://www.fda.gov/fdac/features/2005/605_metabolomics.html

Summary:

The main purpose of this website it to educate people about metabolomics, its potential benefits, and challenges that may be faced. It also explains the FDA’s role in metabolomics. As new drugs are being produced and tested using metabolomics, the FDA will need a new way of evaluating the data that comes in with the promise of a new drug. There must be a great understanding of this process if a drug, tested using metabolomics, is to be introduced into the general public.

Terms:

Metabolomics - study of all the molecules derived from metabolism in a living organism.

Biomarkers - substances used as indicators of a biologic state

NMR - nuclear magnetic resonance

MS - mass spectrometry

NCTR - National Center for Toxicological Research

Relevance:

In class, we have been learning about several metabolic pathways and the products they produce. Some of these metabolites are excreted from the body in urine, sweat, or pus. The focus of metabolomics is to look at the different metabolites secreted, such as glucose, and use the knowledge of how the pathway works to determine if the body is functioning properly. For example, if there is excess glucose in the urine it could mean that the person is a risk for diabetes.

Selegiline

Selegiline (L-deprenyl) is a mechanism-based inactivator of CYP2A6 inhibiting nicotine metabolism in humans and mice

http://jpet.aspetjournals.org/cgi/reprint/jpet.107.133900v1

Summary:

The other article I used was a study of the effects that Selegiline and its metabolites has on nicotine metabolism. In this article, the researchers took a look at Selegiline (L-deprenyl), which is (as of December 7, 2007) in clinical studies as a potential smoking cessation drug. In mice, Selegiline is found to be a potent nicotine inhibitor in hepatic microsomes, and its several metabolites were also found to inhibit nicotine metabolism. Hepatic microsomes were used because the liver is where nicotine is metabolized in the body, thus the effects in vitro would be similar. The study was also done in vitro with human hepatic microsomes. It appears that Selegiline is even more effective in humans than in rats because it acts both a competitive and mechanism-based inhibitor. When nicotine enters the body it binds to CNS type nicotinic receptors, which then increase dopamine levels. Selegiline in turn works as a dopamine inhibitor.

Terms:

Microsome: a small vesicle that is derived from fragmented smooth endoplasmic reticulum (SER) produced when tissues such as liver are mechanically broken

Metabolite: are the intermediates and products of metabolism, or the everyday chemical reactions that keep an organism alive, in this case the desmethylselegiline and L-methamphetamine that Selegiline is metabolized into.

Dopamine: a hormone and neurotransmitter that raises blood pressure and heart rate, and is also associated with the “pleasure system” of the brain.

Selegiline: a drug known more commonly by its several brand names (l-deprenyl, Eldepryl or Anipryl), that is used to treat early-stage Parkinsons and senile dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor, however in larger doses (>20 mg in a typical adult) it loses its specificity and also inhibits MAO-A.

Competitive Inhibitor: is a form of enzyme inhibition where binding of the inhibitor to the enzyme prevents binding of the substrate and vice versa.

Mechanism-based inhibitor: A competitive inhibitor that is converted to an irreversible inhibitor at the active site of the enzyme. (suicide inhibitor)

Relevance:

This article touches upon the various types of inhibitors that can block enzyme action that we learned about in Biochem: Conformation and Dynamics, as well as looking at how various molecules are metabolized into more useful molecules that the body can use.

Drug Development

Agilent Pharmaceuticals

http://www.chem.agilent.com/cag/Pharmanews/Pharma19/newsletter.asp?page=PN_19_F5_metabolomics.html

Summary:

The main focus of this resource is the use of metabolomics in drug development. Metabolomics can be used to eliminate the drugs that will be toxic to humans. The source also gives analytical tools to use in the identification of metabolites.

Terms:

Metabolomics- To characterize small molecules of any product of metabolism.

Metabolome- In one organism the complete set of small molecules that metabolism will produce.

Nuclear Magnetic resonance- A tool used to distinguish molecules based on their nucleus spin.

Mass Spectrometry- A tool used to measure mass to charge ratio of ions (m/z). It can be used to measure molecular weight, monitor enzyme reactions, amino acid sequencing and protein structure.

Gas Chromatography- Separates chemicals based on their volatility or how easy they evaporate into gas.

Liquid Chromatography- Separates chemical or the interactions between what is being analyzed and the chromatography column.

Relevance:

Knowing the biological and chemical process of glycolysis and gluconeogenesis. This leads to a better and rapid drug development by the characterization of the metabolites that these two pathways create.

Capsacin

In Vitro Hepatic and Skin Metabolism of Capsaicin

http://dmd.aspetjournals.org/cgi/reprint/dmd.107.019240v1

Summary:

The focus of this resource was to determine how and where the body metabolizes pure capsaicin as well as the main metabolites created during the process. The study was conducted in in vitro in human skin cells and liver cells. To compare their results, rat and dog cells were also used. The study contributed to our understanding of why capsaicin is effective as a pain treatment both topically and internally.

Terms:

Microsomes-A microsome is a small vesicle that is derived from fragmented endoplasmic reticulum (ER) produced when tissues such as liver are mechanically broken (homogenized). Microsomes contain the cell's cytochrome P450 (CYP) enzymes, involved in oxidative metabolism.

Metabolite-A substance, by-product, waste product, or endotoxin produced as the result of metabolism.

Biotransformation-The chemical conversion of substances by living organisms or enzyme preparations.

Agonist-Any molecule that improves the activity of a different molecule

Nociceptors-Nerve endings which detect and respond to painful or unpleasant stimuli.

Moiety-When referring to a molecule, a 'moiety' is a part or section of the whole.

Relevance:

This was relevant to class material because it demonstrated how different areas of the body metabolize products differently. It showed the difference between how the skin breaks down capsaicin versus how the liver utilizes the substance. It also determined/confirmed that the liver was more effective at breaking down capsaicin than was the skin.

Metabolomic data and human health

Metabolomics: Building on a Century of Biochemistry to Guide Human Health

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1457093

Summary:

The main focus of this article talks about how medical diagnosis and health issues for people utilizing metabolomic data. There are databases that contain metabolite profiles that are built, stored and indexed in accordance to metabolic and health status.

Terms:

Proteomics- large scale study of proteins with emphasis on their structure and function

Transcriptomics- global study of gene expression at the RNA level

Nuclear Magnetic Resonance- physical phenomenon based upon the quantum mechanical magnetic properties of an atom's nucleus

Macronutrient- a nutrient required or used in large quantities; examples include lipids, amino acids, simple sugars, etc

Genomics- study of an organism's entire genome

Relevance:

Every pathway that we have talked about has enzymes, cofactors, substrates, intermediates, and products. We have studied glycolysis, gluconeogenesis, and the pentose phosphate pathway and we have looked at the factors that activate and inactivate certain enzymes. As a result, since we have an idea and understanding of how the pathways work, we are able to create better foods, drugs, and agricultural chemicals that target improving health. Metabolomics has to do with metabolism so if we understand metabolism we are able to provide and figure out how to improve health sanctions and find cures for diseases. If understand the metabolite data and the metabolites function in the metabolism pathway it is easier to develop remedies to health problems.

Articles and Web Pages for Review and Inclusion

Peer-Reviewed Article #1: Vinnie Snow

Systems biology and functional genomics approaches for the identification of cellular responses to drug toxicity

Expert Opin Drug Metab Toxicol. 2008 November; 4(11): 1379–1389. '"

Main Focus

The main focus is to develop sensitive biomarkers in order to predict drug toxicity using genomic information as well as other types of omics datasets. These datasets can then be used to better understand the toxicity mechanisms of a particular biological system such as toxicity in humans.

New Terms

Toxicogenomics

a field of science that deals with the collection, interpretation, and storage of information about gene and protein activity within a particular cell or tissue in an organism in response to toxic substances. (source: http://en.wikipedia.org/wiki/Toxicogenomics)

Toxicogenetics

The study of genetic influences on the responses of organisms to toxins. (source: http://en.wiktionary.org/wiki/toxicogenetics)

Xenobiotics

a chemical which is found in an organism but which is not normally produced or expected to be present in it. Typically drugs such as antibiotics. (source: http://en.wikipedia.org/wiki/Xenobiotic)

Transcriptomics

The study of the transcriptome, the complete set of RNA transripts produced by the genome at any one time. (source: http://www.medterms.com/script/main/art.asp?articlekey=23518)

Pharmacogenomics

is the branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity. (source: http://en.wikipedia.org/wiki/Pharmacogenomics)

Summary

This paper takes into account that testing toxicity of particular drugs on a human can be complicated. The in vivo systems are typically a rodent vector and the results don't completely correlate with that of the human body. Another method uses is human tissue culture, in vitro, in which you can learn more about specific cells but not the human body as a whole and tissues react differently in an in vitro system than they do in an in vivo system. The purpose of using toxicogenomics is to identify gene expression patterns that indicate an adverse health effect at low doses. The modern technique used to measure functional genomics is to use transcriptomic assays by microarray technology. The microarrays used enable high-throughput screening of chemicals for potential toxicity. The results are analyzed from both in vivo and in vitro systems and are coupled with data-rich output in order to build more life-like results of what would actually happen in a human system. This type of research has successfully led to important regulatory action by the FDA that allows many drugs to remain on the market due to genetic testing. This is important to both the pharmaceutical companies and the potential patients that the drugs can help. The information on genetic polymorphisms which are available through the Human Genome project has led to an major increase in research being done on genetic variation that relates to toxicity and pharmacologic phenotypes. The majority of the current research focuses on the relationship between phenotype(disease) and single nucleotide polymorphisms. So far there have been a number of publications that have shown a significant association between SNPs and disease phenotype(s). There have been few publications that have been validated that refute the original conclusion which suggests that this is a reliable method of testing toxicity.

Relevance to a Traditional Metabolism Course

This article relates to a traditional metabolism course in that the techniques being used evaluate the multiple pathways of metabolism as it relates to a human and in some cases rodent systems. The research uses toxicogenomics as well other omics coupled with microarrays in order to determine if a particular drug has any toxicity on a human system. The gene expression from the microarrays was used in concert with proteomic and metabolomic data which allows us to see the comprehensive picture of cellular responses when a particular drug is administered. The newer technology that is being used is the use of microarrays and the human genome project in order to see the effect on particular genes and pathways.