Add time:09/29/2019         Source:sciencedirect.com

The usual cause of premature death in patients with homocystinuria due to cystathionine β-synthase deficiency (EC 4.2.1.22) is vascular disease which occurs with high plasma-homocysteine concentrations. In animal models, experimental homocysteinemia produced by chronic homocysteine thiolactone infusions has been associated with continuing endothelial damage which could be the initiating factor in the pathogenesis of vascular disease in homocystinuric patients.It is shown in the present experiments first that hydroiysis of 1 mol of homocysteine thiolactone at pH 7.4 in dilute phosphate buffer produces 1 mol of homocysteine and 1 equivalent of H+ at 37°C (t12 > 30 hr). Pig liver carboxylesterase strongly catalyzes this hydrolysis: for l-homo-cysteine thiolactone, V = 26.9 unitsA280, Km = 14.0 mm, and stereo-specificity favors the l-enantiomer over the d-enantiomer, but is weak. Thus in animals given homocysteine thiolactone infusions, most hydrolysis will occur in esterase-rich tissues, and the acid which this reaction produces may damage those tissues. Secondly, at neutral pH, the thiolactone covalently modifies proteins which in animal models may produce changes unrelated to homocysteinemia. Thirdly, concentrated solutions of the thiolactone at neutral pH readily form the diketopiperazine which may precipitate.We conclude the changes in vascular morphology reported after chronic homocysteine thiolactone infusions may not result solely from high plasma-homocysteine concentrations, and that this diminishes the relevance of these experiments to the pathogenesis of vascular disease in clinical homocystinuria. The infusion of homocysteine itself is preferable in animal model experiments.

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