Relationship between homocysteine and superoxide dismutase in homocystinuria - Possible relevance to cardiovascular risk

A modest homocysteine elevation is associated with an increased cardiovascu lar risk. Marked circulating homocysteine elevations occur in homocystinuri a due to cystathionine beta-synthase (C beta S) deficiency, a disorder asso ciated with a greatly enhanced cardiovascular risk. Lowering homocysteine l evels reduces this risk significantly. Because homocysteine-induced oxidati ve damage may contribute to vascular changes and extracellular superoxide d ismutase (EC-SOD) is an important antioxidant in vascular tissue, we assess ed EC-SOD and homocysteine in patients with homocystinuria. We measured cir culating EC-SOD, total homocysteine (free plus bound), and methionine level s during the treatment of 21 patients with homocystinuria, 18 due to C beta S deficiency, aged 8 to 59 years, and 3 with remethylating defects. We mea sured total homocysteine by immunoassay, EC-SOD by ELISA, and methionine by amino acid analysis and assessed interindividual and intraindividual relat ionships. 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 afte r taking into account intraindividual patient variation (r=0.607, N=62, P<0 .0001). In 2 newly diagnosed CPS-deficient patients, treatment that lowered the markedly elevated pretreatment homocysteine level (from 337 to 72 and from 298 to 50 mu mol/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 oxidat ive damage and contribute to reducing cardiovascular risk in homocystinuric patients. EC-SOD levels may be relevant to the pathogenesis of vascular di sease in other patient groups.