ClinicalsIncreased plasma levels of homocysteine and other thiol compounds in rheumatoid arthritis women
Introduction
Premature vascular atherosclerosis is a multifactorial disease and it is well known that various factors may interact to promote atherogenesis leading to coronary heart disease. Patients with premature vascular disorders often have elevated circulating homocysteine concentrations (1). Mild hyperhomocysteinemia is an established risk factor for coronary heart disease, cerebral and peripheral vascular diseases 2, 3, 4, and for deep-vein thrombosis in the general population 4, 5.
The atherogenic and thrombotic effects of homocysteine are likely the result of direct endothelial injury induced by hydrogen peroxide generated from oxygen in a reaction catalyzed by homocysteine. The injured endothelium is consequently unable of activating protein C sufficiently due to a decreased thrombomodulin binding (6). Another effect of homocysteine is related with the factor V activity. It has been described that endothelial cells of human umbilical veins exhibit enhanced factor V activity and increased prothrombin activation after treatment with homocysteine (7).
Also, it has been suggested that homocysteine alters the intact lipoprotein(a) particle, increasing the reactivity of the plasminogen-like apolipoprotein(a) portion of the molecule and the affinity of lipoprotein(a) for fibrin 8, 9. Homocysteine can also enhance auto-oxidation of low-density lipoprotein LDL cholesterol (9), cause changes in redox thiol status (10) and increase adhesiveness of the platelets (11). Other physiological thiol compounds such as cysteine, cysteinglycine and glutathione could differentially mediate Cu2+- and Fe3+-dependent low-density lipoprotein (LDL) oxidation, an early event in atherogenesis (12), as well as cysteine and homocysteine could regulate plasma ceruloplasmin redox state and copper transport into cells, which in turn affects the intracellular reduced glutathione level and leukotriene B4 production by neutrophils in rheumatoid arthritis patients (13).
Homocysteine may be either methylated to form methionine or condensated with serine to form the thioether cystathionine and then cysteine. Homocysteine metabolism is dependent on three vitamins, i.e., vitamin B6 (pyridoxine), whose derivative pyridoxal 5-phosphate acts as a cofactor for cystathionine β-synthase, and vitamin B12 and methyltetrahydrofolate that serve as coenzyme and cosubstrate, respectively, for methylenetetrahydrofolate reductase. Hyperhomocysteinemia may have multiple causes. It may be due to enzyme polymorphisms and variants, i.e., cystathionine β-synthase deficiency or possession of a thermolabile variant of methylenetetrahydrofolate reductase, the enzyme required in the remethylation of homocysteine to methionine 14, 15. It is also possible that nutritional deficiencies could contribute to hyperhomocysteinemia because the effective metabolism of homocysteine requires an adequate supply of vitamin B6, vitamin B12, and folate. Elevated levels may result from low levels of folate, vitamin B6, or vitamin B12 16, 17, 18. Another cause of mild or moderate hyperhomocysteinemia is renal insufficiency or nephropathy, presumably due to an impaired excretion of this compound (3).
It has long been known that rheumatoid arthritis (RA) is associated with a shortened life span of patients. Cardiovascular disease is the first cause of death in RA patients, the incidence of this disease being higher than in the control population (19). Because it has been shown a relationship between hyperhomocysteinemia and cardiovascular disease in the general population, we studied total plasma levels of homocysteine and other related physiological thiol compounds in rheumatoid arthritis patients as compared to healthy controls to evaluate if the high risk of cardiovascular diseases of these patients could be explained by the existence of increased total plasma homocysteine levels and an impaired redox thiol status produced by changes in the total plasma concentration of cysteine, cysteinglycine and glutathione.
Section snippets
Material and methods
We studied 38 women with rheumatoid arthritis (52 ± 9 years old) who met the American Rheumatism Association (ARA) 1987 revised criteria with a mean disease duration of 10 ± 7 years. All patients had positive IgM-rheumatoid factor in order to decrease variability in the results, and they were not selected on the base of personal or familial history of cardiovascular disease. These patients had active disease and their functional status was II-III of the American College of Rheumatology revised
Results
Total plasma levels of homocysteine were significantly higher (p < 0.001) in RA patients than in the control group (Table 2). We did not found any difference in homocysteine concentration between RA patients with (n = 25, 16.7 ± 7.5 μmol/L) and without methotrexate treatment (n = 13, 18.4 ± 8.0 μmol/L). Methionine and cysteine, amino acids related to the metabolic cycle of homocysteine were also significantly higher in RA patients than in the control group (Table 2, Table 3 ). To determine
Discussion
In our study, we found that the total plasma levels of homocysteine and the other thiol compounds studied but glutathione were significantly higher in RA patients than in the control group. The increase of homocysteine levels was similar in both treated and untreated patients with small doses of methotrexate, which has been found to decrease folic acid levels and in turn increase homocysteine levels in children with acute lymphoblastic leukemia treated with methotrexate (25). However, our RA
Acknowledgements
This work has been supported by a FIS grant no. 0179/96 from the Ministerio de Sanidad.
References (37)
- et al.
Vitamin requirements for the treatment of hyperhomocysteinemia in humans
J Nutr
(1994) - et al.
Reduced, oxidized and protein-bound forms of homocysteine and other aminothiols in plasma comprise the redox thiol status—a possible element of the extracellular antioxidant defense system
J Nutr
(1996) - et al.
Physiological thiol compounds exert pro- and anti-oxidant effects, respectively, on iron- and copper-dependent oxidation of human low-density lipoprotein
Biochim Biophys Acta
(1997) Plasma thiols, copper and rheumatoid arthritis
Med Hypotheses
(1994)- et al.
Vitamin B-12, vitamin B-6 and folate nutritional status in men with hyperhomocysteinemia
Am J Clin Nutr
(1993) - et al.
Homocysteine increases as folate decreases in plasma of healthy men during short-term dietary folate and methyl group restriction
J Nutr
(1994) - et al.
Rapid high-performance liquid chromatographic assay for total homocysteine levels in human serum
J Chromat
(1991) - et al.
Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection
J Chromat
(1987) - et al.
Elevated plasma concentrations of reduced homocysteine in patients with human immunodeficiency virus infection
Am J Clin Nutr
(1996) - et al.
DNA hypomethylation in inflammatory arthritisreversal with methotrexate
J Lab Clin Med
(1996)