Helga Refsum

Homocysteine metabolism : from basic science to clinical medicine

Preface I. Graham, et al. Biochemistry and Genetic Studies. The Regulation of Homocysteine Metabolism J.D. Finkelstein. Methionine Kinetics and Balance V.R.Young, et al. On the Formation and Fate of Total Plasma Homocysteine H. Refsum, et al. Methylenetetrahydrofolate Reductase: Comparison of the Enzyme from Mammalian and Bacterial Sources R.G. Matthews, et al. Genetics of Mammalian 5,10-Methylenetetrahydrofolate Reductase R. Rozen. Thermolabile Methylenetetrahydrofolate Reductase Soo-sang Kang, et al. The Long-Term Outcome in Homocystinuria D.E.L. Wilcken, B. Wilcken. Characterization of the Human and Porcine Methionine Synthases and their Redox Partners R. Banerjee, Zhiqiang Chen. Inherited Disorders of Folate and Cobalamin D.S. Rosenblatt. Molecular Genetics of Cystathionine beta-Synthase in Homocystinuria and Vascular Disease J.P. Kraus. Cystathionine beta-Synthase Deficiency: Metabolic Aspects S.H. Mudd. Vitamins, Pathology, and Drug Therapy. Homocysteine and Other Metabolites in the Diagnosis and Follow-Up of Cobalamin and Folate Deficiencies R.H. Allen, et al. Vitamin Status and Hyperhomocysteinemia in a Healthy Population J.B. Ubbink. Association Between Plasma Homocysteine, Vitamin Status, and Extracranial Carotid-Artery Stenosis in the Framingham Study Population J. Selhub, et al. Treatment of Mild Hyperhomocysteinemia G.H.J. Boers, et al. Folate, Vitamin B12, and Neuropsychiatric Disorders T. Bottiglieri. Vitamins, Homocysteine, and Neural Tube Defects T.K.A.B. Eskes. The Etiology of Neural Tube Defects J.M. Scott, et al. Plasma Homocysteine in Renal Failure, Diabetes Mellitus, and Alcoholism B. Hultberg, et al. Homocysteine and Drug Therapy P.M. Ueland, et al. Homocysteine, Cancer, and Cardiovascular Disease. Is Methionine Useful for the Prevention of Hyperhomocysteinemia-Associated Cardiovascular Disease? R.M. Hoffman, Yuying Tam. Synthesis of Homocysteine Thiolactone in Normal and Malignant Cells H. Jakubowski. Folate Status: Modulation of Colorectal Carcinogenesis J.B. Mason. The Hordaland Homocysteine Study: Lifestyle and Total Plasma Homocysteine in Western Norway S.E. Vollset, et al. Blood Homocysteine Levels in the National Health and Nutrition Examination Survey (NHANES III) in the United States: Preliminary Findings by Age and Sex I.H. Rosenberg, et al. Heritability of Plasma Homocysteine Concentration M.R. Malinow, et al. Plasma Homocysteine and Coronary Artery Disease M.R. Malinow. Homocysteine and Cerebral and Peripheral Vascular Disease L. Brattstrom. Plasma Homocysteine and its Relationship to Cardiovascular Risk Factors in a Japanese Population A. Araki, et al. Biological Chemistry of Thiols in the Vasculature and in Vascular-Related Disease J.S. Stamler, A. Slivka. Intervention Studies and Concepts for the Future. Homocysteine and Vascular Disease: The European Concerted Action Project I. Graham, et al. Prospective Studies of Homocysteine and Vascular Disease M.J. Stampfer, P. Verhoef. A Meta-Analysis of Plasma Homocysteine as a Risk Factor for Arteriosclerotic Vascular Disease and the Potential Preventive Role of Folic Acid C.J. Boushey, et al. Pathology of Homocystinuria K.S. McCully. Lipoprotein(a), Homocysteine, and Atherogenesis P.C. Harpel, W. Barth. Endothelial and Leukocyte-Mediated Mechanisms in Homocysteine-Associated Occlusive Vascular Disease N.P.B. Dudman, S.E.T. Hale. Index.

Clinical significance of pharmacological modulation of homocysteine metabolism

The metabolic fate of homocysteine is linked to vitamin B12, reduced folates, vitamin B6 and sulfur amino acids. Clinical and experimental data suggest that elevated plasma homocysteine is an independent risk factor for premature vascular disease. This is particularly significant because plasma homocysteine levels are altered in several diseases, including folate and vitamin B12 deficiencies, and because many commonly used drugs have now been shown to interfere with homocysteine metabolism. In summarizing the data, Helga Refsum and Per Ueland highlight the clinical implications for these metabolic changes.

The Hordaland Homocysteine Study: Lifestyle and Total Plasma Homocysteine in Western Norway

The Hordaland Homocysteine Study is a cohort of approximately 18,000 men and women, ages 40–67, who had their total plasma homocysteine (tHcy) determined in 1992 or 1993. The long-term aim of the study is to relate plasma tHcy to future cardiovascular disease incidence, cause-specific, and all-cause mortality. In Norway, complete mortality follow-up is assured for all individuals who do not leave the country permanently, and the study will have access to mortality data kept at the Central Bureau of Statistics. Furthermore, we plan to register all hospitalizations for cardiovascular disease, including coronary angiographies, coronary surgery, and balloon angioplasties in the six hospitals that serve Hordaland. Complete cancer incidence data for the cohort members will also be available through the Cancer Registry of Norway, which keeps records of all cancer cases diagnosed in the country. No follow-up data are available yet, and so far we have focused on the study of cross-sectional associations between plasma tHcy and established cardiovascular risk factors and lifestyle.

Serum homocysteine levels in postmenopausal breast cancer patients treated with tamoxifen

Adjuvant treatment of breast cancer with tamoxifen may be associated with reduced risk of cardiovascular disease. Serum homocysteine level has been suggested to be a risk factor for cardiovascular disease influenced by estrogenic hormones. We evaluated a subset of postmenopausal women who had participated in a longitudinal, double-blind, randomized, placebo-controlled toxicity study of tamoxifen 10 mg orally, twice daily. Twenty-seven treated subjects and 37 placebo subjects had measurements of serum homocysteine levels made on previously frozen samples obtained at baseline and after 12 months. After treatment with tamoxifen, we found lower levels of serum homocysteine of borderline statistical significance.

On the Formation and Fate of Total Plasma Homocysteine

The total concentration of homocysteine (tHcy)* in plasma is a useful marker of impaired function of cobalamin and folate. Moreover, it is an independent risk factor for atherosclerotic disease [1]. These findings have encouraged the search for determinants of plasma tHcy level [1, 2].

Homocysteine and Drug Therapy

Several agents other than vitamins involved in homocysteine (Hcy) metabolism affect plasma homocysteine (tHcy) total concentration. The mechanisms behind the hyperhomocysteinemia vary from altered homocysteine production, impaired homocysteine metabolism, and possibly by direct reaction (through thiol-disulphide exchange) with extracellular Hcy. Some drugs change plasma Hcy by mechanisms not known. This review summarizes effects of drug therapy on plasma tHcy, with emphasis on data obtained during the last five years.

Homocysteine and Vascular Disease: The European Concerted Action Project

Aterosclerotic cardiovascular disease, notably coronary heart disease, remains the major cause of death in developed countries [1]. A high-fat diet, hypertension, and smoking are regarded as causal factors [2], and changes in these factors appear to contribute to coronary heart disease mortality trends [3]. Nevertheless, these factors remain incomplete predictors of both the occurrence of and changes in cardiovascular mortality.

Monitoring Cobalamin Inactivation During Nitrous Oxide Anesthesia by Determination of Homocysteine and Folate in Plasma and Urine

The effects of nitrous oxide-induced cobalamin inactivation on homocysteine and folate metabolism have been investigated. Plasma levels of cobalamin, folate, homocysteine, and methionine were determined in 40 patients before and after operation under nitrous oxide anesthesia (range of exposure time, 70 to 720 minutes). Twelve patients anesthetized with total intravenous anesthesia served as control subjects (range of exposure time, 115 to 600 minutes). Postoperative plasma levels of folate and homocysteine increased (p less than 0.001) up to 220% and 310%, respectively, in nitrous oxide-exposed patients, whereas plasma levels of methionine decreased (p less than 0.025). Response occurred after 75 minutes of nitrous oxide exposure. The percentage increase of plasma folate and homocysteine correlated significantly with exposure time (p less than 0.025 and p less than 0.0001, respectively). In eight patients receiving nitrous oxide anesthesia plasma homocysteine levels had not returned to preoperative levels within 1 week (p less than 0.01). Urinary excretion of folate and homocysteine increased during and after nitrous oxide exposure (p less than 0.01 and p less than 0.002, respectively) and correlated with exposure time (p less than 0.01 and p less than 0.005, respectively). It can be concluded that disturbance of homocysteine and folate metabolism by nitrous oxide develops with little delay and return to normal levels requires several days. Elevation of plasma homocysteine levels may therefore be used for monitoring nitrous oxide-induced cobalamin inactivation.