Plasma homocysteine is decreased in the hypothyroid rat René L. Jacobs, Lori M. Stead, Margaret E. Brosnan, and John T. Brosnan Abstract: Recent clinical studies have indicated that plasma homocysteine was significantly increased in hypothyroid patients. Since hyperhomocysteinemia is an independent risk factor for cardiovascular disease we investigated homocysteine metabolism in hypothyroid rats. Hypothyroidism was induced in one study by addition of propylthiouracil (PTU) to the drinking water for 2 weeks. In a second study, thyroidectomized and sham-operated rats were used with thyroid hormone replacement via mini-osmotic pumps. Unlike the human hypothyroid patients, both groups of hypothyroid rats exhibited decreased total plasma homocysteine (30% in PTU rats, 50% in thyroidectomized rats) versus their respective controls. Thyroid replacement normalised homocysteine levels in the thyroidectomized rat. Increased activities of the hepatic trans-sulfuration enzymes were found in both models of hypothyroidism. These re- sults provide a possible explanation for the decreased plasma homocysteine concentrations. The hypothyroid rat cannot be used as a model to study homocysteine metabolism in hypothyroid patients. Key words: homocysteine, cystathionine β-synthase, cystathionine γ-lyase, thyroid hormone. Résumé : De récentes études cliniques ont indiqué que l’homocystéine plasmatique augmentait significativement chez les patients hypothyroïdiens. L’hyperhomocystéinémie étant un facteur de risque indépendant de maladie cardio-vasculaire, nous avons examiné le métabolisme de l’homocystéine chez des rats hypothyroïdiens. Dans la première expérience, l’hypothyroïdie a été induite en ajoutant du propylthiouracil (PTU) à l’eau potable pendant 2 semaines. Dans la deuxième expérience, des rats opérés de manière fictive et thyroïdectomisés ont été soumis à une hormonothérapie thyroïdienne substitutive à l’aide de mini-pompes osmotiques. Contrairement aux humains hypothyroïdiens, les deux groupes de rats hypothyroïdiens ont subi une diminution du taux d’homocystéine plasmatique totale (30 % chez les rats PTU, 50 % chez les rats thyroïdectomisés) par rapport à leurs témoins respectifs. L’hormonothérapie thyroïdienne substitutive a normalisé les taux d’homocystéine chez les rats thyroïdectomisés. Une augmentation des activités des enzymes de trans-sulfuration hépatique a été observée dans les deux modèles d’hypothyroïdie. Ces résultats pourraient expliquer les diminutions des taux d’homocystéine plasmatique. Le rat hypothyroïdien ne peut être utilisé comme modèle d’étude du métabolisme de l’homocystéine chez les patients hypothyroïdiens. Mots clés : homocystéine, cystathionine β-synthase, cystathionine γ-lyase, hormone thyroïdienne. [Traduit par la Rédaction] 570 Jacobs et al. Introduction Increased plasma homocysteine is recognised as an inde- pendent risk factor for the development of cardiovascular diseases (Kang et al. 1992; Malinow 1994). Homocysteine levels are influenced by many factors, including vitamin sta- tus and hormone levels. Folate and vitamin B–12 are re- quired for the re-methylation of homocysteine to methionine via the enzyme methionine synthase. Pyridoxal-phosphate is a cofactor for both enzymes of the trans-sulfuration pathway, which is involved in the catabolism of homocysteine to cysteine. Homocysteine levels are known to be affected by a number of hormones. Insulin deficiency (i.e., insulin de- pendent diabetes mellitus) in the rat has been shown to de- crease plasma homocysteine (Jacobs et al. 1998), an effect also observed in humans (Robillon et al. 1994). It has been suggested that sex hormones alter plasma homocysteine (Giltay et al. 1998), presenting a possible reason why women have lower homocysteine concentrations than men. A recent study by Nedrebo et al. (1998) investigated homocysteine status in hypothyroid patients. They observed that total plasma homocysteine was elevated in hypothyroid patients versus healthy controls. Hussein et al. (1999) ob- served that hypothyroid patients who received L-thyroxine treatment have normal plasma homocysteine. These observa- tions are of particular importance since hypothyroid patients have an increased risk for cardiovascular diseases (Steinberg 1968), related to elevated low-density lipoprotein choles- terol. However, altered lipid levels do not fully explain the accelerated pathogenesis. The relationship between thyroid status and folate levels has also been investigated (Stokstad et al. 1980). Liver folate levels are decreased in the hypothy- roid rat which would provide a plausible explanation for ob- served increases in homocysteine concentrations in humans. The present study was undertaken to investigate the role of thyroid hormone on homocysteine metabolism in the rat. Can. J. Physiol. Pharmacol. 78: 565–570 (2000) © 2000 NRC Canada 565 Received December 31, 1999. Published on the NRC Research Press web site on June 5, 2000. R.L. Jacobs, L.M. Stead, M.E. Brosnan, and J.T. Brosnan. 1 Department of Biochemistry, Memorial University of Newfoundland, St. John’s, NF A1B 3X9, Canada. 1 Author to whom all correspondence should be addressed (e-mail: jbrosnan@morgan.ucs.mun.ca).