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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1199.)
© 2000 American Heart Association, Inc.

Vascular Biology

Relationship Between Homocysteine and Superoxide Dismutase in Homocystinuria

Possible Relevance to Cardiovascular Risk

David E. L. Wilcken; Xing Li Wang; Tetsuo Adachi; Hirokazu Hara; Natalia Duarte; Kathryn Green; Bridget Wilcken

From the Department of Cardiovascular Medicine (D.E.L.W., X.L.W., N.D.), Prince of Wales Hospital, and University of New South Wales Centre for Thrombosis and Vascular Research, Sydney, Australia; the Laboratory of Clinical Pharmaceutics (T.A., H.H.), Gifu Pharmaceutical University, Gifu, Japan; and the NSW Biochemical Genetics Service (K.G., B.W.), the Royal Alexandra Hospital for Children, Sydney, Australia.

Correspondence to Professor David Wilcken, Cardiovascular Genetics Laboratory, Edmund Blacket Building, Prince of Wales Hospital, Randwick, NSW 2031, Australia. E-mail d.wilcken{at}unsw.edu.au

Abstract—A modest homocysteine elevation is associated with an increased cardiovascular risk. Marked circulating homocysteine elevations occur in homocystinuria due to cystathionine ß-synthase (CßS) deficiency, a disorder associated with a greatly enhanced cardiovascular risk. Lowering homocysteine levels reduces this risk significantly. Because homocysteine-induced oxidative damage may contribute to vascular changes and extracellular superoxide dismutase (EC-SOD) is an important antioxidant in vascular tissue, we assessed EC-SOD and homocysteine in patients with homocystinuria. We measured circulating EC-SOD, total homocysteine (free plus bound), and methionine levels during the treatment of 21 patients with homocystinuria, 18 due to CßS deficiency, aged 8 to 59 years, and 3 with remethylating defects. We measured total homocysteine by immunoassay, EC-SOD by ELISA, and methionine by amino acid analysis and assessed interindividual and intraindividual relationships. There was a significant, positive relationship between EC-SOD and total homocysteine. For the interindividual assessment, levels were highly correlated, r=0.746, N=21, P<0.0001. This relationship was maintained after taking into account intraindividual patient variation (r=0.607, N=62, P<0.0001). In 2 newly diagnosed CßS-deficient patients, treatment that lowered the markedly elevated pretreatment homocysteine level (from 337 to 72 and from 298 to 50 µmol/L) reduced the associated elevated EC-SOD in each by 50%. EC-SOD and methionine levels were unrelated (r=0.148, n=39, P=0.368). The positive relationship between circulating EC-SOD and homocysteine could represent a protective antioxidant response to homocysteine-induced oxidative damage and contribute to reducing cardiovascular risk in homocystinuric patients. EC-SOD levels may be relevant to the pathogenesis of vascular disease in other patient groups.

Key Words: homocysteine • superoxide dismutase • oxidative stress • vascular disease • cystathionine ß-synthase deficiency

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