January 2003 Blog with Durk and Sandy

Noradrenaline Metabolite a Powerful Antioxidant

We read years ago that vitamin C is the most important antioxidant in the brain and that after vitamin C is depleted, noradrenaline becomes the most important antioxidant. A new paper¹ suggests a possible mechanism to explain the importance of noradrenaline in antioxidative systems. The oxidatively deaminated noradrenaline metabolite 3,4-dihydroxymandelic acid (DHMA) is found in different mammalian tissues, and in especially large amounts in the heart. Researchers performed a number of tests to determine the antioxidative and radical-scavenging ability of DHMA.

In one test (the 2,2-diphenyl-1-picrylhydrazyl assay), DHMA had a 4-fold higher radical-scavenging activity compared to ascorbic acid, alpha-tocopherol, and butylated hydroxytoluene (BHT). DHMA was shown to be a powerful superoxide radical scavenger with a 5-fold smaller IC50 value (the amount required to inhibit a reaction by 50%) compared to ascorbic acid. DHMA at 0.001% and 0.0005% levels protected human primary fibroblasts against hydrogen peroxide-induced oxidative stress.

The authors concluded that DHMA in a concentration below 0.001% is not cytotoxic, supports intracellular antioxidative status, and therefore may be important for the defense system of cells against oxidative stress. D&S Note: Noradrenaline is converted to DHMA by the enzyme MAO (monoamine oxidase). People taking an MAO inhibitor antidepressant may, therefore, be at greater risk for free radical damage.

1. Ley et al. 3,4-Dihydroxymandelic acid, a noradrenalin metabolite with powerful antioxidative potential. J Agri Food Chem 50:5897-902 (2002)

Folic Acid Against Cardiovascular Disease

It took a prolonged legal and political struggle to force the FDA to permit a health claim that folic acid reduces the risk of neural-tube-defect births. The two of us and coplaintiffs, represented by attorney Jonathan Emord, recently won a federal district court ruling that forces the FDA to permit a claim that folic acid, along with vitamins B12and B6, may reduce the risk of cardiovascular disease. Nevertheless, there is considerable evidence that folic acid in adequate amounts may also reduce the risk of various cancers. It will no doubt take years of litigation* before this claim will be permitted. In the meantime, however, scientific data on the benefits of folic acid continue to be published.

*Make a blow against the empire by donating to our litigation fund. Even small amounts help. Send donations to: Pearson & Shaw Litigation Fund, c/o Emord & Associates, 5282 Lyngate Court, Burke, VA 22015. Thanks!

There was a recent publication¹ of the results of a randomized, controlled trial of 553 patients who had had successful angioplasty of at least one significant coronary stenosis (equal to or greater than 50% reduction in lumen area) and who were then treated with either placebo or a combination of 1 mg/d of folic acid, 400 mcg/d of vitamin B12 (cyanocobalamin), and 10 mg/d of vitamin B6 (pyridoxine hydrochloride). The patients were evaluated at 6 months and 1 year for major adverse events (death, myocardial infarction, or need for repeated revascularization).

After a mean follow-up of 11 months, the risk of major adverse events was significantly lower in patients treated with the folic acid, B12, and B6 (15.4% vs. 22.8%), primarily owing to a reduced rate of target-lesion regrowth (9.9% vs. 16.0%). There was a nonsignificant trend toward fewer deaths and nonfatal myocardial infarctions with the vitamins.

Another recent paper² suggests possible mechanisms that may be involved in the effects of folate supplementation. Fifty-seven volunteers (30 males, 27 females, mean age 61.2 years) with high risk of coronary events or established atherosclerotic disease and homocysteine concentration of at least 20 micromol/l participated in an open, prospective study. There was 1 month of placebo followed by 2 months of treatment with 10 mg daily of folate. Results showed that folate treatment caused a significant decrease of homocysteine and fibrinogen (a blood factor involved in clotting), while plasminogen (which, when activated by tissue plasminogen activator, dissolves clots) and antithrombin III were significantly increased. In addition, the antioxidant enzymes glutathione peroxidase and superoxide dismutase, as well as glutathione, significantly increased after folate treatment. Malonyldialdehyde (a breakdown product of peroxidized lipids) and von Willebrand factor decreased. Hence, the researchers reported, folate treatment resulted not only in homocysteine decrease, but also in an improvement in hypercoagulation, oxidative stress, and endothelial dysfunction.

1. Schnyder et al. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention. JAMA 288(8):973-9 (2002).
2. Mayer et al. The effects of folate supplementation on some coagulation parameters and oxidative status surrogates. Eur J Clin Pharmacol 58:1-5 (2002).

Isomer of Conjugated Linoleic Acid (CLA) Induces Hyperinsulinemia and Fatty Liver in the Mouse

Dose determines differential effects of bioactive substances such as CLA. CLA is widely used for its potential fat-reducing effects. It is known to have powerful anticarcinogenic effects.¹ The mechanisms for these effects are still not entirely clear, though much has been published on this subject.

The anticarcinogenic effects have been reported to appear in animals when they are fed much lower amounts of CLA than what is needed to affect weight.² Mammary cancer development in rats treated with the carcinogen DMBA was reduced in a dose-dependent manner, with total mammary tumor yield reduced by 22, 36, 50, and 58% in the 0.05, 0.1, 0.25, and 0.5% CLA diets, respectively. The researchers report that intergroup comparison showed that as little as 0.1% CLA was sufficient to cause a significant reduction in the number of tumors.² Another study noted that there appeared to be a dose-dependent protection of synthetically prepared CLA against dimethylbenz(a)anthracene-induced mammary tumors in rats at levels of 1% CLA and below, but no further beneficial effect was evident at levels above 1%.

Fat reduction may take larger amounts of CLA. One study³ reported that, using a mixture of synthetically prepared cis-9,trans-11-CLA (37%) and trans-10,cis-12-CLA (46%) in mice, there was no significant effect on weight gain if diets contained 0.5% CLA or less. In another study,⁴ it was reported that the trans-10,cis-12-CLA isomer is responsible for body-composition changes in mice in vivo, whereas the cis-9,trans-11-CLA isomer was without activity in this respect.

A recent study⁵ reported that mice fed diets enriched in trans-10,cis-12-CLA at 0.4% w/w for 4 weeks developed lipoatrophy (loss of fat), hyperinsulinemia (abnormally high insulin levels), and fatty livers, whereas diets enriched in cis-9,trans-11-CLA had no significant effects. The researchers suggest that the hyperinsulinemia may have induced fatty liver by increasing liver fatty acid intake and lipogenesis. They note that a trend toward an increase in insulin levels in CLA-supplemented humans has been reported. However, a different paper reporting on a double-blind, 12-week study of 53 healthy men and women, aged 23–63, receiving either 4.2 g/d of CLA or the same amount of olive oil, observed no major differences in plasma insulin, blood glucose, serum lipoproteins, nonesterified fatty acids, or plasminogen activator inhibitor I.⁶

The authors⁵ explain that CLA-induced decrease in adipose tissue mass is associated with an increase in energy expenditure [which may be secondary to a stimulation of the sympathetic (adrenergic) nervous system] and that CLA reduces lipid uptake and storage by inhibiting lipoprotein lipase and stearoyl-CoA desaturase I. They note that it has been suggested that the decrease in fat tissue involves an apoptotic mechanism (cell death of fat cells) linked to an increase in tumor necrosis factor-alpha production. Tumor necrosis factor-alpha is a cytokine involved in inflammation, among other things.

A study reported in the August 2001 International Journal of Obesity found that 14 men with significant abdominal fat receiving 4.2 grams of CLA a day for 4 weeks had an average loss of 1.4 cm in waist circumference, while there was no decrease in the placebo group. The average person eats about 500 grams of food a day. 4.2 grams of CLA then represents 0.84% of the diet. This is 8 times the 0.1% CLA that was reported to reduce mammary cancers in carcinogen-treated mice.

One (for women) or two (for men) glasses of alcohol a day provides a myriad of health benefits, including reduced risk of cardiovascular disease, increased HDL, and increased insulin sensitivity, but 16 glasses of wine a day may very well result in a fatty liver.

Also, the detrimental effects on animals deprived of essential fatty acids are enhanced by CLA.⁷ Hence, those on a low-fat diet who are also taking CLA may be particularly vulnerable to those adverse effects.

Living a long time means you have to be careful about risks. Mice and rats are not people and may be more sensitive to the effects of CLA that result in fatty liver and hyperinsulinemia, but until more studies of potential adverse effects have been done at the high doses of CLA used in weight-reducing regimens, you don't know. For several months, Durk was taking 4 grams a day of CLA (and hadn't noticed any effect on either weight or percent body fat), and Sandy was taking 3 grams a day (she didn't notice any effects on weight or body fat, either) before we read this paper. (Neither of us was on a calorie-restricted diet.) We have both reduced our dose to 1 gram a day, which we expect to provide significant anticarcinogenic effects, until there are more data available on possible side effects of high-dose CLA.

1. Ip, Clement, Scimeca, Thompson. Conjugated linoleic acid. Cancer 74:1050-4 (1994).
2. Ip, Singh, Thompson, Scimeca. Conjugated linoleic acid suppresses mammary carcinogenesis and proliferative activity of the mammary gland in the rat. Cancer Res 54:1212-5 (1994).
3. Hayman et al. High intake, but not low intake, of CLA impairs weight gain in growing mice. Lipids 37(7):689-92 (2002).
4. Pariza, Park, Cook. Conjugated linoleic acid and the control of cancer and obesity. Toxicol Sci 52(Suppl):107-10 (1999).
5. Clement, Poirier, et al. Dietary trans-10,cis-12 conjugated linoleic acid induces hyperinsulinemia and fatty liver in the mouse. J Lipid Res 43:1400-9 (2002).
6. Smedman, Vessby. Conjugated linoleic acid supplementation in humans—metabolic effects. Lipids 36(8):773-81 (2001).
7. Reaney, Westcott. Conjugated linoleic acid—seven decades of achievement. Inform 13:802-5 (2002)

Why We Take Cysteine Rather Than N-Acetylcysteine

N-Acetylcysteine is a xenobiotic (not normally found in the body), although it is an acetylated form of the natural amino acid cysteine. It can be sold as a dietary supplement even though it is a xenobiotic, because it was being sold as a dietary supplement before passage of the Dietary Supplement Health and Education Act, thereby "grandfathering" it. N-Acetylcysteine is an FDA-approved prescription drug used in the treatment of Tylenol^® (acetaminophen) overdose (liver toxicity). N-Acetylcysteine treatment for this purpose lasts up to about 3 days. The treatment works by increasing liver glutathione levels.

Cysteine acts as the limiting natural precursor to glutathione and increases its levels. (Methionine can also act as a precursor to glutathione, but homocysteine is a byproduct of this pathway.) It is easier to get permission to use N-acetylcysteine in human and even animal studies because of its FDA-approved status. Moreover, there is a belief that cysteine is more toxic than N-acetylcysteine because the latter is more water-soluble, and cysteine can be oxidized to cystine. However, taking at least twice as much vitamin C as cysteine prevents oxidation of cysteine to cystine (which can cause cystine stones in the kidneys and urinary bladder).

The acetyl group in N-acetylcysteine is labile, that is, it can acetylate many things indiscriminately. Aspirin, acetylsalicylic acid, also contains an acetyl group, but its acetylation is more specific. Aspirin acetylates a specific amino acid site in the enzyme that synthesizes thromboxane, thus acting as an anticlotting agent. Since N-acetylcysteine has been tested for and approved for a very short-term use, we do not feel that we know enough about it to consider taking it on a long-term, everyday basis.

N-Acetylcysteine can inhibit blood clotting by increasing prothrombin time.¹ Hence, in combination with other anticlotting agents, such as low-dose aspirin, ginkgo, or fish oils, blood-clotting time could be excessively extended. Your doctor can easily check your prothrombin time, or it can be inexpensively and safely tested at a walk-in clinical laboratory testing firm.

1. Pol and Lebray. N-Acetylcysteine for paracetamol poisoning: effect on prothrombin. Lancet 360:1115 (2002)

More Global Warming: A Giant Coincidence or What?

There have now been three bodies in the solar system other than Earth that have been reported to be warming: Mars, Triton, and Pluto. On July 20 and then on August 21 of this year, Pluto passed directly between Earth and certain stars in the constellation Ophiuchus, thus allowing scientists to obtain information on Pluto's atmosphere. Researchers Marc W. Buie (Lowell University) and James L. Elliott (MIT) found that, although Pluto is now 3% farther from the sun than it was in 1988 (the last time Pluto occulted a star seen from Earth), the planet's surface is now slightly warmer. Another team at the Observatory of Paris also measured an increase in Pluto's surface temperature. (See "Pluto and the Occult," Science News, Sept. 7, 2002.)

According to B. Buratti of the NASA Jet Propulsion Laboratory, Triton's light curve has recently increased in amplitude, its spectrum has reddened distinctly more than once, and even its atmospheric pressure has been increasing. A light curve is the variation of a body's apparent brightness with time. [Reported in "Out on the Edge," Nature 418:135 (2002).]

"Using [Mars Global] Surveyor's camera, Malin and his colleagues found that during a full Martian year - about 2 years - the walls of pits in the south polar ice cap receded by about 1 to 3 meters. The cap is mostly frozen carbon dioxide, and the dramatic shrinkage suggests that large amounts of the material have evaporated into the Martian atmosphere." (Quoted from the Jan. 19, 2002 Science News.) Malin et al. (in the Dec. 7, 2001 Science) called the rate and amount of erosion "phenomenal." "In Leighton and Murray's model, a 1% change in the mass of the Martian atmosphere would only require a 0.1% change in the long-term solar reflectance of a residual carbon dioxide deposit." [Paige, "Global Change on Mars?" Science 294:2107-8 (2001).] A paper in that same issue of Science by Shindell et al. presents evidence that "relatively small solar forcing may play a significant role in century-scale NH [northern hemisphere] winter climate change. This suggests that colder winter temperatures over the NH continents during portions of the 15th through the 17th centuries (sometimes called the Little Ice Age) and warmer temperatures during the 12th through 14th centuries . . . may have been influenced by long-term solar variations."

Though we have read speculations (a different one for each body) to account for the surface warming for Mars, Pluto, and Triton, a mechanism that would apply to all three (and a warming Earth as well) would be an increase in the sun's output. Despite the reports on Mars, Pluto, and Triton, there hasn't been a peep from anyone in Science orNature concerning a possible connection between warming of these bodies and putative Earth warming.

Remember the case of the dog that didn't bark? This may be another one. NASA is being given huge amounts of money to study global warming, yet it hasn’t proposed the obvious project of designing a small, inexpensive satellite to precisely measure solar output over time. Studies of solar variability to date have relied upon data from old satellites not designed for the purpose of reliable multigenerational solar output measurements, and proxy data in, for example, deep-sea sediment cores. [See, for example, Haigh et al., "Climate Variability and the Influence of the Sun," Science294:2109-11 (2001).] The U.S. pays about $2 billion a year of our money for global warming studies; that can buy a lot of silence.