Oxidative stress and platelet activation in homozygous homocystinuria

Background-Severe hyperhomocysteinemia due to cystathionine beta -synthase deficiency (C beta SD) is associated with early atherothrombotic vascular d isease. Homocysteine may exert its effects by promoting oxidative damage. I n the present study, we investigated whether in vivo formation of 8-iso-pro staglandin (PG) F-2 alpha, a platelet-active product of arachidonic acid pe roxidation, is enhanced in C beta SD and whether it correlates with in vivo platelet activation, as reflected by thromboxane (TX) metabolite excretion . Methods and Results-Urine and blood samples were obtained from patients wit h homozygous C beta SD (n=13) and age-matched healthy subjects. Urinary 8-i so-PGF(2 alpha) excretion was significantly higher in C beta SD patients th an in control subjects (640 +/- 384 versus 213 +/- 43 pg/mg creatinine; P=0 .0015) and correlated with plasma homocysteine (rho =0.398, P=0.0076). Simi larly, urinary 11-dehydro-TXB2 excretion was enhanced in C beta SD (1166 +/ - 415 versus 324 +/- 72 pg/mg creatinine; P=0.0015) and correlated with uri nary 8-iso-PGF(2 alpha) (p=0.362, P=0.0153). Vitamin E supplementation (600 mg/d for 2 weeks) was associated with a statistically significant increase in its plasma levels (from 16.6 +/-4.6 to 40.4 +/-8.7 mu mol/L, P=0.0002) and with reductions in 8-iso-PGF(2 alpha) (from 790 +/- 159 to 559 +/- 111 pg/mg creatinine, P=0.018) and 11-dehydro-TXB2 (from 1273 +/- 383 to 913 +/ - 336 pg/mg creatinine, P=0.028). A statistically significant inverse corre lation was found between urinary 8-iso-PGF(2 alpha) and plasma vitamin E le vels (rho=-0.745, P=0.0135). Conclusions-The results of the present study suggest that enhanced peroxida tion of arachidonic acid to form bioactive F-2-isoprostanes may represent a n important mechanism linking hyperhomocysteinemia and platelet activation in C beta SD patients. Moreover, they provide a rationale for dose-finding studies of vitamin E supplementation in this setting.