Homocysteine metabolism

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(Marja-Leena Silaste 2003).

Homocysteine metabolism can be found at the intersection of two pathways which are : remethylation to methionine, it requires folate and vitamin B12; and transsulfuration to cystathionine, it needs pyrodoxal-5'-phosphate. S-adenosylmethionine as a controller which coordinates the two pathway in turn becomes an allosteric inhibitor of the methylenetetrahydrofolate reductase reaction and act as an activator of cystathionine beta-synthase. (Annu Rev Nutr, 1999) Homocysteine is synthesized from methionine through a multi-step process. First of all, methionine will receive an adenosine group from adenosine triphosphate which is catalyzed by S-adenosyl-methionine synthetase, yielding a S-adenosyl methionine (SAM). The methyl group is transferred by SAM to an acceptor molecule. Next, L-homocysteine is produced by hydrolyzing the adenosine from the previous ATP. Apart from there, L-homocysteine can either be converted back into L-methionine by tetrahydrofolate (THF) or conversion to L-cysteine from the information provided by < http://en.wikipedia.org/wiki/Homocysteine >. Actually some of the excess homocysteine might be used to produce cysteine, which then yield glutathione. Glutathione is a powerful antioxidant. The conversion of homocysteine into glutathione may be increased when the body is under oxidative stress according to < http://www.lef.org/protocols/heart_circulatory/homocysteine_reduction_01.htm >.

Speaking of elevation of homocysteine level in our blood, actually it may due to suffering from oxidative stress or the methylation amount decreases, which causes indirectly effects on our cells' normal functions such as grow and differentiation. Nevertheless, aging and genetic factors can also contribute to the increase of homocysteine level. However, urban lifestyle can cause the elevation of homocysteine in our body such as excessive consumption of coffee and alcohol which had been proven that they might increase the homocysteine levels (De Bree A et al 2002). Dietary intake does play a part to affect homocysteine levels. For instance, red meat, has been proven to elevate blood levels of homocysteine. Similarly, malnutrition of vitamin B may also elevate homocysteine levels (Devlin TM, 2002). < http://www.lef.org/protocols/heart_circulatory/homocysteine_reduction_01.htm >.

Studies had proven that elevation of homocysteine is strongly related to cardiovascular diseases such as myocardial infarction, stroke, peripheral vascular disease, increased risk of premature coronary artery disease and thromboembolism. Imbalance of homocysteine levels contribute to atherosclerosis in three ways:

  1. toxic that damages the intima
  2. interference with clotting factors, and
  3. oxidation of low-density lipoproteins (LDL).

Endothelial dysfunction and injury, which then followed by platelet activation and thrombosis might be the mechanisms that result cardiovascular diseases. Homocysteine will produce cytotoxic on endothelial cells, which is eventually a production of reactive oxygen species (ROS) (Blundell et al. 1996), impaired production of endothelium-derived nitric oxide and damage to the endothelial cells (Stamler et al. 1993, Tawakol et al. 1997), and proliferation of smooth muscle cells. (Tsai et al. 1994) Lipid peroxidation and LDL oxidation are increased by homocysteine which will lead to atherosclerosis, but this is not yet been clinically proven in all the studies (Blom et al. 1992, Halvorsen et al. 1996). On the other hand, formation of free oxygen species or ROS can eventually damage to the vascular, proliferation of smooth-muscle cells, changes of endothelial cell function and structure (Welch & Loscalzo 1998). But, there is another explanation by some of the researchers, after tissue damage, homocysteine level will be increased, which in turn further causing the endothelial cell to be damaged. An increased homocysteine level would be a good indication that shows tissue damage and thus promotes inflammation and thickening of vascular damage. (Dudman 1999) Research from a Finnish agrees that the likelihood that homocysteine is actually a result rather than a factor of vascular damage (Knekt et al. 2001). Some epidemiological studies have proved that little amount of blood folate and B6 vitamin concentrations increase the chances for getting vascular diseases, and the increase blood tHcy would be an indicator of the low vitamin concentrations (Folsom et al. 1998, Robinson et al. 1998, Rimm et al. 1998). Furthermore, a study showed that by comparing 131 patients with severe blockages in two coronary arteries, the moderate blockage of one coronary artery was 88 patients , and without heart disease was the another group of healthy individuals. The researchers discovered a relationship between blood homocysteine levels and severity of the coronary blockages, for every increasing of homocystein by 10%, equally, there will be a rise of risk of developing coronary heart disease. Furthermore, postmenopausal women with increased homocysteine levels had a higher probability of developing coronary heart disease. Besides, study proved that homocysteine levels were much higher in people who developed vein clots than in similar people who did not. The table below shows the reference values of blood homocysteine for both male and female.

Gender

Age

Reference values (µmol/L)

increased

Therapeutic target

female

12-19 years

3.3 ~ 7.2

> 10.4

<6.3
(0.85 mg/L)

> 60 years

4.9 ~ 11.6

male

12-19 years

4.3 ~ 9.9

> 11.4

> 60 years

5.9 ~15.3

To measure serum homocysteine levels blood is drawn after a 12-hour fast.

Range (µmol/L)

Conditions

5 ~ 15

Normal

16 ~ 30

Moderate

31 ~ 100

Intermediate

> 100

Severe

The relationship between homocysteine and cardiovascular disease was discovered about 25 years ago from the observation of people with a rare condition called homocystinuria. They are more likely to have severe and serious cardiovascular disease during adolescent period. This is probably due to the enzyme deficiency which in turn causes accumulation of the homocysteine in the blood and excreted out by urination. Increased of the homocysteine level is linked to 10% ~ 20% of the coronary heart disease. (Stephen Barrett, M.D, 29th March 2003). Hyperhomocysteinemia may cause narrowing and hardening of the arteries which medically known as atherosclerosis. Atherosclerosis is believed to happen by a wide range of ways including increase of blood homocysteine. Changes in the blood vessel structure will disrupt blood flow. Hyperhomocysteinemia may also cause the tendency of excessive blood clotting. Thrombus will be formed within the blood vessel which is called thrombosis which further disrupt the blood flow. As a result, there is a lack of blood supply to the heart muscles and as a result heart attacks occur, same thing goes to the brain which then causes stroke. Increase of blood homocysteine levels have been proved to be closely related with formation of blood clots in veins which are deep vein thrombosis (DVT) and pulmonary embolism. The mechanism which involves in this process is rather complicated. Studies have proved that even a moderately high levels of homocysteine level will have a higher repeated incidence of blood clot formation (Siamak Nabili, MD, MPH )

From the perspective of cardiovascular diseases, there is a closely relationship with smoking. People practice smoking tend to develop cardiovascular disease easier than non- smokers. Thus, there was a study conducted by The Adelaide and Meath Hospital Dublin, incorporating the National Childrens Hospital and Trinity College, Dublin, Ireland in 19 countries in Europe with a control group of less than 60 years-old people and matched with age and gender had showed that non-smoker had a lower blood homocystein level than the smokers. The statistic showed that smoker with a homocystein level which is nearly above 12µmol.l-1 will have a higher chance of getting cardiovascular disease which is a very contrast with the non-smokers but with a normal level of blood homocystein. The more one smokes the higher the level of homocysteine in our body. (European Heart Journal, 23rd 2002) Exposure to smoke actually has an adverse and devastating effect on the folic acid level. Folic acid is a cofactor to aid demethylation of homocysteine to non toxic methionine. Hence, smoking will result an increased of homocysteine level. Homocysteine is normally changed into other acids to be used by the our body cells. If the homocysteine level is beyond the reference range, there could be not enough B vitamins to help the body to catabolise the homocysteine. For those people who lack of folate, vitamin B12 and vitamin B6 in their diet will eventually elevate their homocyseteine level. Some other factors that can increase the homocysteine level include low levels of thyroid hormone, kidney disease, psoriasis or even aging.

Once talks about reduce plasma homocysteine level, we should always go back to the metabolism process of homocyteine or the methionine cycle. Vitamin B6, B12 and folic acid actually play a significant role in the homocysteine metabolism. From there, they are somehow associate with the reducing of homocysteine level. According to < http://www.quackwatch.com/03HealthPromotion/homocysteine.html > dietary products with folic acid can decrease homocysteine levels among most of the patients. Normally, 1 mg/day of folic acid is enough for therapeutic purpose. However, when it is ineffective, Vitamins B6 and B12 can be added together with the folic acid, which should be constantly consumed. Some of the physicians do recommend that patients with atherosclerosis to consume Vitamin B without being tested to find out whether it is useful to reduce the homocysteine level. A research which conducted with 80,000 women for 14 years showed that the risk of getting heart attacks was lowest among for those who take in multivitamins, folic acid and B6. Besides, there was a research involved with 101 men with vascular disease were given folic acid, B6, and B12 supplements. There was a decrease in the amount of carortid plaque in their arteries by ultrasound examinations. Folate and Vitamin B12 may help to convert homocysteine back to a less harmful substance- methionine. Folate can be synthesized in the intestine by consuming more fiber products as well. Food sources of folate include chickpeas, spinach, almonds, walnuts, egg, fruits. Sources of vitamin B12 include salmon, trout, lamb, egg, beef, tuna, cheese and chicken ect. Folic acid and other B Vitamins help catabolise homocysteine in the body. Vitamin B, folate, B12, and B6 may aid in the converting of homocystein back into cysteine and methionine. Thus, lack of B vitamins in the body can actually disrupt the metabolism homocysteine which in turn increase its level in the blood. Intima layer of blood vessels actually can be affected or damaged by homocyestein, which can promote blood thrombosis and thus atherosclerosis as a result.

In a nutshell, homocysteine is actually an amino acid which will be produced everyday by our body metabolism. A balance of homocysteine will not have an adversely effect on our body macroscopic and microscopic major functions. Well, a malnutrition or imbalance homocysteine amount in blood will lead to health issues be it hyperhomocysteinemia or hypohomocysteinemia. A good practice of lifestyle can actually prevent the increased level of homocysteine in our blood to avoid unnecessary to be happened. However, if a person is diagnosed with the symptom of hyperhomocysteinemic, he can actually consume a constant and permanent folic acid, Vitamin B6 and B12 in order to control a well homocysteine metabolism which in turn to lower homocysteinemia level and prevent it going to be increased next time.

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