Chemical Education Today
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Research Advances by Angela G. King
Onions Battle Osteoporosis Besides adding flavor to food, onions also may be good for your bones. Researchers at the University of Bern in Switzerland have identified a compound in the popular vegetable that appears to decrease bone loss in laboratory studies using rat bone cells. Although further studies are needed, the current study suggests that eating onions might help prevent bone loss and osteoporosis, a disease which predominately affects older women. The disease results in an estimated $17 billion in medical costs. Nutritional supplements offer a cost-effective way to prevent the loss of bone mass associated with osteoporosis, but current options have limited effectiveness. For instance, calcium in milk reduces the risk of hip fracture in only the 10% of women with the lowest daily intake of calcium. In earlier work, researchers looking for new nutritional approaches to preventing bone loss noted that rats fed a diet that included dried onion bulbs displayed increases in bone mineral content and decreases of bone resorption. Ethanol extracts of onion prevented bone loss in an osteoporosis model and inhibited osteoclast resorption activity in vitro. This launched a search for the compound responsible for the onion’s bioactivity. While onions are packed with flavonoids, fractionation of the ethanol extract showed that the activity was not in the flavonoid fraction, but in a fraction containing more polar compounds. The researchers analyzed the active chemical components of white onions using bioassay-guided fractionation. Medium-pressure liquid chromatography was used to separate successive fractions and each fraction was tested in vivo using the urinary [3H]tetracycline excretion rat model and in vitro using the osteoclast pit assay. The final active fraction contained a compound fully characterized through HPLC– ESI–MS–MS and NMR experiments. The structure of the active compound, ␥-L-glutamyl-trans-S-1-propenyl-L-cys-
teine sulfoxide (GPCS) was confirmed by spectroscopic comparison with a reference sample of GPCS. GPCS accounts for 1.73% of the mass of dried onions. To confirm its effectiveness at preventing bone loss, the research team exposed the cells to parathyroid hormone to stimulate bone loss, and then exposed some of the treated cells to GPCS. Treatment with GPCS significantly inhibited the loss of bone minerals, including calcium, when compared to cells that were not exposed to GPCS, according to the researchers. Additional studies are needed to determine whether GPCS will have a similar effect in people, how much onion or GPCS is needed for a positive effect on bone health, and to determine the mechanism of action of GPCS on bone cells, the researchers say. More work is also needed to determine whether GPCS is a unique active compound or represents a new class of bioactive compounds with similar activity.
More Information 1. Wetli, Herbert A.; Brenneisen, Rudolf; Tschudi, Ingrid; Langos, Manuela; Bigler, Peter; Sprang, Thomas; Schuerch, Stefan; Muehlbauer, Roman C. A ␥-Glutamyl Peptide Isolated from Onion (Allium cepa L.) by Bioassay-Guided Fractionation Inhibits Resorption Activity of Osteoclasts. J. Ag. Food Chem. 2005, 53, 3408–3414. 2. The National Onion Association includes historical medicinal uses and a report on phytochemical and health properties of onions on its web page. See http://www.onions-usa.org/about/ history.asp and http://www.onions-usa.org/pdf_files/ phytochemical.pdf#search=’medicinal%20use%20of%20onions’, respectively (sites accessed Jun 2005). 3. A lab where students can relate mineral levels in bones with diet has been published in this Journal. Rheingold, Arnold L.; Hues, Steven; Cohen, Mark N. Strontium and Zinc Content in Bones as an Indication of Diet: An Undergraduate Project in Quantitative Analysis with Interdisciplinary Interest. J. Chem. Educ. 1983, 60, 233.
Figure 1. The structure of ␥-L-glutamyl-trans-S-1-propenyl-L-cysteine sulfoxide (GPCS), a compound isolated from onions that may help prevent bone loss.
O S
HN
OH O
NH2
OH
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Structure by A. King
O
O
Structure by A. King
Chemical Education Today
Figure 2. The absolute configuration of anti-TB compound R207910.
Br N
O
OH N
New Weapon in War on TB Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis, which usually attacks the lung and is spread through the air from one person to another. TB was once targeted for elimination but it has proved resilient and now infects more people than at any other time in history. TB currently infects one third of the world’s population and every 15 seconds someone dies from TB. Tuberculosis is one of the world’s most deadly infectious diseases, killing 2–3 million people each year, with an annual global economic impact of $12 billion. Drug resistance and lengthy treatments of up to twelve months hamper anti-TB efforts and the Global Alliance for TB Drug Development is seeking to improve the TB control program with new drugs. There have been no new treatments developed for TB in over 30 years, but recent breakthroughs by an international team of scientists may change that. Researchers from Johnson & Johnson Pharmaceutical Research and Development, the Swedish Institute for Infectious Disease Control and The Pitié-Salpêtrière School of Medicine began their search for new anti-TB compounds by testing prototypes of different chemical series in a whole cell assay against Mycobacterium smegmatis. A promising compound, R207910, led to 20 different diarylquinolines (DARQs) with minimum inhibitory concentrations (MIC) against M. tuberculosis H37Rv below 0.5 g/mL. DARQs differ from other quinolone and quinoline classes in having a functionalized lateral (3⬘) chain. In vivo testing confirmed antimycobacterial activity in three of the DARQs. The compound, R207910, has two stereocenters. It was prepared in five synthetic steps as a mixture of diastereomers, which were then separated by HPLC. The individual stereoisomers were assayed for activity and the absolute configuration of the active isomer was determined by circular dichroism and X-ray crystallography. R207910 has a potent early bactericidal activity in the nonestablished infection murine TB model. It attacks a different target from existing anti-TB drugs, inhibiting ATP synthase. Shutting down ATP synthase may result in ATP depletion and imbalance in pH homeostasis. Both of these factors lead to decreased survival for the target microorganism. The specificity of R207910 against mycobacteria is due to differences in ATP synthase sequences in eukaryotes and bacteria. Since existing anti-TB drugs do not target ATP synthase, there is no cross-resistance when R207910 is used. Sciwww.JCE.DivCHED.org
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entists have observed a long plasma half-life, long tissue halflife and high tissue penetration for R207910. These factors all contribute to the extended effect of a single dose of R207910 and may increase its value in treating a chronic infection such as TB. Human studies have shown high tolerance and good oral absorption and scientists are now in the process of conducting clinical development in patients with active pulmonary TB.
More Information 1. Andries, Koen; Verhasselt, Peter; Guillemont, Jerome; Goehlmann, Hinrich W. H.; Neefs, Jean-Marc; Winkler, Hans; Van Gestel, Jef; Timmerman, Philip; Zhu, Min; Lee, Ennis; Williams, Peter; de Chaffoy, Didier; Huitric, Emma; Hoffner, Sven; Cambau, Emmanuelle; Truffot-Pernot, Chantal; Lounis, Nacer; Jarlier, Vincent. A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis. Science 2005, 307, 223–227. 2. The Center for Disease Control offers many educational resources on TB. See http://www.cdc.gov/nchstp/tb/faqs/qa.htm (accessed Jun 2005). 3. More information on efforts by the Global Alliance for TB Drug Development may be found at http://www.tballiance.org (accessed Jun 2005). 4. An undergraduate lab measuring isoniazid levels has been developed. See Sottofattori, Enzo; Raggio, Riccardo; Bruno, Olga. Milk as a Drug Analysis Medium: HPLC Determination of Isoniazid. J. Chem. Educ. 2003, 80, 547. 5. The development of current TB treatment is described in this Journal. Kauffman, George B. Isoniazid—Destroyer of the White Plague. J. Chem. Educ. 1978, 55, 448.
Smokers Beware: Study Shows Increased Cadmium Levels in the Brain May Cause Severe Neurological Disorders Every day, people come in contact with cadmium through the air, water and food from contaminated crops. One crop that specifically accumulates cadmium is tobacco, which makes smokers susceptible to significantly higher levels of the metal in their bodies compared to non-smokers. Previous work has shown that cadmium exposure does not alter basal locomotor activity but decreases cocaine’s ability to induce hyperactivity. Other data suggest that cadmium decreases the effect of cocaine by influencing dopamine levels. Now, a University of Missouri–Columbia research team
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Figure 3. Dietary cadmium exposure attenuates methamphetamineinduced hyperactivity. Rats receiving CdCl2 in their diet or on a control diet were administered methamphetamine or saline and placed in an automated activity monitor. Data represent distance traveled in intervals after administration. Reprinted from Miller, Dennis K.;
Dopheide, Marsha M.; Smith, Shawn M.; Casteel, Stan W. Dietary cadmium exposure attenuates—amphetamine-evoked [3H]dopamine release from striatal slices and methamphetamine-induced hyperactivity.Pharmacology, Biochemistry and Behavior 2005, 80, 557–566. Copyright 2005, with permission from Elsevier.
has found that low levels of cadmium in the brain also affect the behavioral effects of amphetamines, a class of drugs that, like cocaine, cause hyperactivity, although through a different mechanism. “The study shows that even low-level exposure to a heavy metal like cadmium can cause a change in the functions of neurons in the brain and the behavioral response to drugs of abuse,” said Dennis Miller, assistant professor of psychology at the University of Missouri. “The implication is that toxicants may encourage drug users to increase their drug intake or increase the odds of developing some neurological disorders such as schizophrenia and Parkinson’s disease.” Miller and Stan Casteel of Missouri’s Veterinary Diagnostic Laboratory tested rats that received cadmium chloride in their diet for 30 days along with rats that received regular food. Miller said the level of cadmium being fed to the rats increased the levels of cadmium in the bloodstream to levels that approximated pack-a-day tobacco smokers. The rats were tested for their behavior and neurochemical responses to amphetamines, which increase the activity of dopamine, a neurotransmitter in the brain. Miller found the brains of rats exposed to the cadmium diet were less sensitive to the amphetamine than those that received regular food. Researchers observed a concentration dependent decrease in the ability of D-amphetamine to cause radio-labeled dopamine release from the striatum. Interestingly, the same result was not observed if the cadmium chloride was applied directly to brain tissue samples. Dietary cadmium exposure also attenuates methamphetamine-induced hyperactivity, as measured by an automated activity monitor for an hour. These results, Miller said, suggest that dietary cadmium exposure produces a subtle neurotoxic effect on neurons in the brain. Miller believes this indicates that dietary cadmium exposure could diminish the reinforcing properties of amphetamines,
which means drug users might need more of the drug to achieve a “high.” This should be a cause for concern for tobacco and drug users, Miller said. “Tobacco smoking produces a long-lasting increase in the body burden of cadmium, and therefore this population might administer higher doses of amphetamine than non-smokers to achieve comparable reinforcing effects,” Miller said. “Selfadministration of higher amphetamine doses would increase the risk of drug toxicity or mortality.” Another implication of the study, Miller said, is the possible role cadmium exposure might have in the development of neurological and psychological disorders. “A number of behavioral and psychiatric disorders are associated with a change in the number and function of dopamine neurons. As such, those exposed to cadmium via tobacco smoke or industrial pollution may be at a greater risk for the development of dopamine-related disorders or may display a decreased sensitivity to anti-psychotic medications or drugs used in schizophrenia and Parkinson’s,” Miller said.
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More Information 1. Miller, Dennis K.; Dopheide, Marsha M.; Smith, Shawn M.; Casteel, Stan W. Dietary Cadmium Exposure Attenuates— D-Amphetamine-evoked [3H]Dopamine Release from Striatal Slices and Methamphetamine-induced Hyperactivity. Pharmacol., Biochem. Behav. 2005, 80, 557–566. 2. Nation J. R.; Grover C. A.; Salinas J. A.; Pugh, C. K.; Peltier R.; Horger, B. A.; Bratton, G. D. Effects of Cadmium on Cocaine-induced Changes in Activity. Behavioral Neuroscience 1991, 105, 998–1003.
Angela G. King is Senior Lecturer in Chemistry at Wake Forest University, P.O. Box 7486, Winston-Salem, NC 27109;
[email protected].
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