Homocysteine, a new cardiovascular risk factor, is also a powerful uremic toxin

homocystinuria, an inherited disease in which plasma levels of homocysteine are high, was discovered in the sixties and it soon became clear that the affected patients had striking features of generalized atherosclerosis. The most common causes of death were arterial and venous thrombosis, stroke, o r myocardial infarction. Observations in this human model of hyperhomocyste inemia led to studies in the general population whose findings suggest - th ough not conclusively - that homocysteine is a cardiovascular risk factor. The same is true for patients with chronic renal failure who almost always have moderate to severe high blood homocysteine levels. Homocysteine accumu lates in relation to the concentration of its precursor, S-adenosylhomocyst eine, a powerful competitive transmethylation inhibitor. Inhibition of a me thyltransferase required to repair damaged proteins has actually been detec ted in uremic patients' red blood cells. However, in view of the multiple, widespread metabolic roles of S-adenosylmethionine-dependent methyltransfer ases, in many organs and tissues including the vascular endothelium, hypome thylation is currently interpreted as one of homocysteine's most important mechanisms of action. Various biological compounds, including small molecul es and nucleic acids, as web as proteins, which are involved in the pathoph ysiology of thrombosis and atherosclerosis, are all potential targets of hy pomethylation. Epidemiological studies and experimental models tend to conf irm that homocysteine is both a cardiovascular risk factor and a uremic tox in, acting through different mechanisms.