ReviewHyperhomocysteinemia is a risk factor for cancer and a new potential tumor marker
Introduction
Homocysteine is largely derived from cellular methionine, an essential amino acid drawn from dietary intake. Intracellular homocysteine is normally secreted extracellularly, at rapid rates. Consequently, the concentration of homocysteine in the plasma and urine reflects the balance between intracellular homocysteine production and utilization, while the blood concentration of homocysteine reflects the cellular homocysteine (Hcy) concentration [1].
In the circulating blood, the majority of the homocysteine binds to albumin, forming a disulfide linkage. Approximately 10% to 20% of the Hcy also exists as a mixed disulfide with cysteine or with homocysteine itself (Fig. 1). Very little Hcy is present in the circulating blood in a free reduced form (approximately 1%) [2], [3]. Current procedures employed for the measurement of plasma homocysteine concentrations measure the total concentration of homocysteine (tHcy), which includes albumin bound homocysteine, homocysteine in all of the disulfide linkages, and the free reduced form of homocysteine. It was correctly pointed out by Mudd and Levy [4] that the term homocyst(e)ine, not homocysteine, should be used to reflect the fact that in circulating blood, both reduced and oxidized forms exist. “Homocysteine” only represents the reduced form. However, just for the sake of convenience and simplicity, we use tHcy to represent all forms of “total homocysteine” in the circulation throughout this paper.
Section snippets
Normal level
According to Jacobsen [5], the normal range of plasma tHcy for “healthy adults” is 5–15 μmol/l; 15 to 25 μmol/l indicates mild hyperhomocysteinemia; 25 to 50 μmol/l is considered intermediate hyperhomocysteinemia and >50 μmol/l, severe. It was recommended that plasma tHcy be kept under 10 μmol/l.
Metabolic pathway involving homocysteine
It is much easier to understand the various conditions that lead to hyperhomocysteinemia and also the underlying biochemical mechanisms by examining the metabolic pathways involving homocysteine. As shown in Fig. 2, there are three major metabolic reactions involving homocysteine: remethylation, transsulfuration and transmethylation [6]. We now know that in most cases, anything that goes wrong involving these three reactions would alter homocysteine concentration and yield hyperhomocysteinemia.
As a new tumor marker
As shown in Fig. 4 in our earlier study, we were surprised to find so many cases of elevated serum tHcy in patients with breast, ovarian and pancreatic carcinoma who were not taking anti-folate drugs. One of the explanations related the elevation is to the rapid proliferation rate of tumor cells, as Ueland and Refsum [6] experienced with their leukemia patients. In fact, it has also been reported by Corona et al. [9] that elevated tHcy was found in the serum and cystic fluid of a patient with
As a risk factor
Several biochemical changes recently identified in association with hyperhomocysteinemia indicate that elevated tHcy in blood circulation creates a risk for cancer, and it is likely that hyperhomocysteinemia is a risk factor for carcinogenesis.
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