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© Borgis - Postępy Nauk Medycznych 7/2010, s. 571-576
Joanna Malinowska, Joanna Kołodziejczyk, *Beata Olas
Prophylaxis and treatment of hyperhomocysteinemia
Profilaktyka i leczenie hiperhomocysteinemii
Department of General Biochemistry, University of Łódź
Head of Department: prof. zw. dr hab. Barbara Wachowicz
Homocysteina (Hcys) jest niebiałkowym aminokwasem będącym metabolitem pośrednim na szlakach przemiany metioniny. Podwyższone stężenie homocysteiny (> 15 ?M, tzw. hyperhomocysteinemia) jest skorelowane z występowaniem u ludzi schorzeń, takich jak choroby sercowo-naczyniowe, choroby neurodegeneracyjne oraz choroby nerek. Wyróżnia się hiperhomocysteinemię łagodną, umiarkowaną i ciężką, gdzie stężenie Hcys w osoczu mieści się w przedziałach: 16-30 ?M, 31-100 ?M oraz przekracza 100 ?M. Prawidłowe całkowite stężenie Hcys w osoczu mieści się w przedziale od 5 do 15 ?M (średnio 10 ?M). Homocysteina występuje we krwi człowieka w kilku formach, jako forma niezwiązana (np. jak forma zredukowana w stężeniu 100 nM) oraz w połączeniu z białkami, ale najbardziej aktywną formą homocysteiny jest tiolakton homocysteiny (HTL). W niniejszej pracy przedstawiono kilka dróg metabolizmu Hcys, który jest skorelowany z poziomem różnych witamin (witaminy B6, B12 i kwasu foliowego). Ponadto, genetyczne i środowiskowe przyczyny hiperhomocysteinemii oraz profilaktyka i leczenie hiperhomocysteinemii zostały także omówione.
Homocysteine (Hcys) is a non-protein sulfur-containing amino acid, an intermediate product of methionine metabolism. It is known that elevated concentration of homocysteine (> 15 ?M; hyperhomocysteinemia) in humans is correlated with various diseases, including cardiovascular, neurodegenerative and kidney disorders. Hyperhomocysteinemia has been classified into three types, depending on the plasma levels of Hcys – mild (16-30 ?M), moderate (31-100 ?M) and severe (> 100 ?M). Normal plasma level of homocysteine ranges from 5 to 15 ?M (mean 10 ?M). Homocysteine exists in the blood in several forms: in free (e.g. as reduced form – about 100 nM) and protein bound form, but the most reactive form of Hcys is homocysteine thiolactone (HTL). In the article, some pathways of Hcys metabolism, which is correlated with the level of various vitamins (B6, B12 and folic acid), are described. Moreover, genetic and environmental causes of hyperhomocysteinemia, as well as prophylaxis and treatment of hyperhomocysteinemia, are also discussed.

Homocysteine (Hcys) is a homologue of the amino acid cysteine, at the same time being a derivate of methionine, from which it differs by the lack of a methylene group at the sulfur atom (fig. 1). Hcys was discovered in the 1930s, together with cysteine and glutathione. These three compounds constitute a group of low-molecular-mass biological thiol compounds. Elevated plasma level of homocysteine is considered to be an unequivocal risk factor of cardiovascular diseases. There are many literature reports available showing elevated Hcys level as an independent factor of premature atherosclerosis development (besides hypercholesterolemia). The role of Hcys in pathogenesis of vascular disorders, as well as its procoagulant effect, results from its influence on blood vessel walls, blood platelets (fig. 2) and the coagulation/fibrinolysis proteins. Detailed descriptions of the effect of Hcys on selected hemostasis elements, including blood platelets and coagulation, have been provided by Karolczak and Olas (1), as well as by Malinowska et al. (1). Elevated homocysteine level (hyperhomocysteinemia) in blood can result from genetic, congenital metabolic anomalies or from environmental factors (acquired, in connection with lifestyle). It is estimated that every one in ten Europeans has an elevated blood Hcys level, which leads to increased cardiovascular risk, including atherosclerosis and myocardial infarction.
Fig. 1. Chemical structure of homocysteine in reduced form and its concentration in human blood (1, modified).
Fig. 2. Regulatory role of homocysteine and its thiolactone in blood vessel wall and blood platelets. LDL – low density lipoproteins, Hcys-LDL – homocysteinylated LDL, ox-LDL – oxidized LDL, RFN – reactive forms of nitrogen, RFO – reactive forms of oxygen, NO?-nitric oxide, NO-LDL – nitrated LDL, TXA2 – thromboxane A2 (1, modified).
Moreover, increased blood Hcys levels are observed in patients with chronic renal failure, hypothyroidism, various cancer types, malignant anemia, liver diseases, and in persons with malnutrition, especially with low folic acid intake. It should also be noted that an increase in Hcys levels correlates with the severity of some other disorders, including Alzheimer's disease and other types of dementia, Parkinson's disease, multiple sclerosis, and chronic fatigue syndrome.
Proteins that are absorbed with food are metabolized in the human body into amino acids. One of the products of protein degradation is the amino acid methionine (Met). Some of the Met is recycled and used again for protein synthesis, while the remaining portion may be metabolized into homocysteine (2). Hcys is a thiol amino acid, which is synthesized in all types of animal (including human) cells. S-adenosylmethionine transferase (SAM synthetase) catalyses the reaction of adenosine transfer (from ATP) to methionine. S-adenosylmethionine (SAM) is the main donor of the methyl group (–CH3) for various methylation reactions. After the methyl group is transferred by SAM synthetase to various compounds, SAM turns into S-adenosylhomocysteine (SAH). Subsequently SAH is hydrolyzed by specific SAH hydrolase into adenosine and homocysteine (fig. 3) (3), and its plasma level can be measured. Moreover, it is known that Hcys does not have its own codon, so it cannot be incorporated into protein chains in the way that other amino acids can (4). But it can bind with them through the ε-amino group of lysine. Hcys can also bind to proteins and/or cysteine via disulfide bonds. It has been shown that approximately 33% of the total Hcys circulates as oxidized low-mass disulphide compounds, 1% as a free, reduced form, and about 66% is bound to proteins (as N-homocysteinylated – or S-homocysteinylated proteins) (5, 6).
Fig. 3. Formation of homocysteine from methionine (4, modified).
Literature reports describe 2 pathways of Hcys metabolism. The first one is based on re-methylation of Hcys into methionine, with substantial involvement of folic acid, which acts here as a methyl group donor (7, 8). Vitamin B12 (cobalamin) and Vitamin PP (niacin) are necessary co-factors for metabolism of tetrahydrofolate derivates (9). The second pathway leads to cysteine through Hcys transsulfuration, with pyridoxal-5-phosphate as a co-factor (active form of vitamin B6) (fig. 4) (10, 11).
Fig. 4. Homocysteine metabolism and the role of vitamins B6, B12 and folic acid in Hcys transformations (11, modified).
Another form of Hcys in plasma is its thiolactone, homocysteine thiolactone (HTL) (fig. 5). HTL is much more reactive than Hcys. Its synthesis results from erroneous homocysteine activation, e.g. by methionyl-t-RNA synthetase (MetRS) (12). It is worth noting that homocysteine thiolactone may undergo non-enzymatic hydrolysis, but mostly it is metabolized by plasma HTL hydrolase, also known as homocysteine thiolactonase (HTLase) or paraoxonase (PON 1).
Fig. 5. Chemical structure of homocysteine thiolactone and its concentration in human blood (1, modified).
It has been observed that impaired metabolism of homocysteine leads to a rise of its level in the blood and further to various abnormalities. Normal blood Hcys levels range from 5 to 15 μM. A preprandial level of Hcys exceeding 15 μM is termed hyperhomocysteinemia. There are three types of this disorder – mild, moderate and severe – with plasma Hcys levels 16-30 μM, 31-100 μM and above 100 μM, respectively. Although the severe form is rare, 5-7% of the general population suffer from mild hyperhomocysteinemia. Subjects with mild form of hyperhomocysteinemia do not show clinical symptoms until they reach 40 years of age, when signs of premature atherosclerosis start to show. Moderate hyperhomocysteinemia can pose a significant danger for young women, as it increases the risk of complications during pregnancy (13).
In recent years numerous data on possible genetic causes of cerebrovascular diseases have been collected. It has been observed that stroke occurs significantly more often in twins, especially monozygotic twins, as well as in subjects whose parents suffered from cerebral stroke (14). A significant clinical role here has been attributed to genetically conditioned alterations of homocysteine metabolism.
An elevated Hcys level may result from genetic defects of enzymes involved in its metabolism, among others cystathionine-β-synthase (CBS), methionine synthase (MS) and methylenetetrahydrofolate reductase (MTHFR). Heterozygous lack of CBS, CBS mutations and methylenetetrahydrofolate reductase gene polymorphism are thought to be the most probable causes of hyperhomocysteinemia. In CBS, Ile278Thr and Gly307Ser are the most common mutations. If they occur homozygously, they may lead to significant elevation of homocysteine level and to an increased risk of atherosclerosis of carotid arteries (15). Methylenetetrahydrofolate reductase gene polymorphism involves substitution of cytosine by thymine in position 677 (C677&ro;T). This nucleotide exchange leads to the synthesis of a thermolabile enzyme form with decreased activity. As a result synthesis of methylenetetrahydrofolate (donor of methyl group in re-methylation of homocysteine) is decreased. Prevalence of this mutation is race dependent. In Asian and Caucasian populations (including Poland) there are 50% C7T heterozygotes and 10-13% T/T homozygotes, while in the Afro-American population cases of this polymorphism are rare (16). T/T homozygotes have on average 2.5 μM higher levels of Hcys than C/C homozygotes. However, this difference has been observed in the case of folic acid and riboflavin deficiency in the diet (17). It has also been observed that A&ro;C transversion in position 1298 of the MTHFR gene leads to substitution of glutamate with alanine in the enzyme, which leads to its decreased activity (18).
Acquired hyperhomocysteinemia may result from various factors. Among others, lifestyle, diet, various diseases, medications, drugs, sex and age influence levels of Hcys. Dietary errors leading to deficiency of vitamins B2, B6, B12 and folic acid may in turn cause an increase of Hcys level. Also alimentary tract disorders connected with impaired absorption of these vitamins may play an important role.

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otrzymano: 2010-04-28
zaakceptowano do druku: 2010-06-16

Adres do korespondencji:
*Beata Olas
Department of General Biochemistry,
University of Łódź
ul. Banacha 12/16, 90-237 Łódź
tel./fax: (42) 635-44-84
e-mail: olasb@biol.uni.lodz.pl

Postępy Nauk Medycznych 7/2010
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