Homocysteine toxicity

Kataoka (1997) describes a method for the analysis of 21 protein amino acids and 33 nonprotein amino acids with NPD detection. One disadvantage of this method is the use of diazomethane, which is explosive and toxic (Kataoka, 1997). A method for homocysteine with GC-FID analysis uses a one-step derivatization with ethyl chloroformate and an extraction procedure (Husek et al., 2003). 

A high level of homocysteine is an indication of a low rate of conversion of homocysteine to methionine and hence a low level of the methylating agent S-adenosyl methionine. The latter, plus the toxic effects of homocysteine, provides a link between the reactions listed above and three diseases cardiovascular disease (Chapter 22), senile dementia (Chapter 14) and cancer (Chapter 21). 

The answer is A. The constellation of symptoms exhibited by this patient is characteristic of homocystinuria. The impairment of her cognitive function could be attributed to many conditions, but the key findings are ectopia lentis with downward lens dislocation and osteoporosis in a female of this age. Homocystinuria is produced by inherited deficiency of one of the enzymes in the pathway of Met conversion to Cys. The most common form is cystathionine P-synthase deficiency, which results in accumulation of all upstream components of the pathway, including homocysteine, which is responsible for the toxic effects, and Met, which becomes elevated in the blood. Cystathionine and cysteine, which are both downstream of the block in the pathway caused by cystathionine P Synthase deficiency, would be decreased. Metabolic pathways for lactate and urea are not involved in this disease mechanism. 

Cyanocobalamin A cofactor required for essential enzymatic reactions that form tetrahydrofolate, convert homocysteine to methionine, and metabolize l-methylmalonyl-CoA Adequate supplies are required for amino acid and fatty acid metabolism, and DNA synthesis Treatment of vitamin B12 deficiency, which manifests as megaloblastic anemia and is the basis of pernicious anemia Parenteral vitamin B12 is required for pernicious anemia and other malabsorption syndromes Toxicity No toxicity associated with excess vitamin B12... 

Reported rate constants for the reaction of 02 with GSH have varied from 102 to > 105 M 1 s. A re-examination of this reaction by spin trapping with DMPO established that earlier studies had been confounded by the direct reduction of the DMPO/ OOH adduct to DMPO/ OH by GSH. Taking account of this reaction, the revised rate constant was reported to be 200 M-1 g-i.25i.2S2 other workers have examined, for example, the effects of GSH and N-acetyl-L-cysteine on lipid peroxidation 253 and the role of GS in the toxicity of the diabetogenic agent alloxan.254 Direct EPR has been used to detect binuclear Cu(II) complexes of homocysteine. The interactions of such complexes with blood-vessel linings may account for the link between elevated homocysteine and atherosclerosis.255... 

Vitamins B6, B12, and folate An elevated plasma homocysteine level is associated with increased cardiovascular risk (see p. 263). Homocysteine, which is thought to be toxic to the vascular endothelium, is converted into harmless amino acids by the action of enzymes that require the B vitamins—folate, B6 (pyridoxine), and B12 (cobalamin). Ingesting foods rich in these vitamins can lower homocysteine levels and possibly decrease the risk of car diovascular disease. Folate and B6 are found in leafy green veg etables, whole grains, some fruits, and fortified breakfast cereals. B12 comes from animal food, for example, meat, fish, and eggs. 

Vitamin B12 (cobalamin) has as its active forms, methylcobalamin and deoxyadenosyl cobalamin. It serves as a cofactor for the conversion of homocysteine to methionine, and methylmalonyl CoA to succinyl CoA. A deficiency of cobalamin results in pernicious (megaloblastic) anemia, dementia, and spinal degeneration. The anemia is treated with IM or high oral doses of vitamin B12. There is no known toxicity for this vitamin. 

When present in excess methionine is toxic and must be removed. Transamination to the corresponding 2-oxoacid (Fig. 24-16, step c) occurs in both animals and plants. Oxidative decarboxylation of this oxoacid initiates a major catabolic pathway,305 which probably involves (3 oxidation of the resulting acyl-CoA. In bacteria another catabolic reaction of methionine is y-elimination of methanethiol and deamination to 2-oxobutyrate (reaction d, Fig. 24-16 Fig. 14-7).306 Conversion to homocysteine, via the transmethylation pathway, is also a major catabolic route which is especially important because of the toxicity of excess homocysteine. A hereditary deficiency of cystathionine (3-synthase is associated with greatly elevated homocysteine concentrations in blood and urine and often disastrous early cardiovascular disease.299,307 309b About 5-7% of the general population has an increased level of homocysteine and is also at increased risk of artery disease. An adequate intake of vitamin B6 and especially of folic acid, which is needed for recycling of homocysteine to methionine, is helpful. However, if methionine is in excess it must be removed via the previously discussed transsulfuration pathway (Fig. 24-16, steps h and z ).310 The products are cysteine and 2-oxobutyrate. The latter can be oxidatively decarboxylated to propionyl-CoA and further metabolized, or it can be converted into leucine (Fig. 24-17) and cysteine may be converted to glutathione.2993... 

Neurotoxins produced by the body. Some normal body constituents are neurotoxic in excess. These incluse quinolinic acid (Fig. 25-11),889 3-hydroxykynurenine (Fig. 25-11 p. 1444),890 and homocysteine.891 Elevated levels of homocysteine are also associated with vascular disease and stroke (Chapter 24). 3-Hydroxykynurenine is a precursor to ommochrome pigments of insects and an intermediate in conversion of tryptophan into the nicotinamide ring of NAD in humans (Fig. 25-11). 6-Hydroxydopamine (Fig. 30-26), which may be formed in the body, is severely toxic to catecholaminergic neurons.892... 

Homocysteine, HSCH2CH2CH(NH2)C02H, is a toxic amino acid that is thought to acylate lysine residues on proteins via its corresponding thiolactone (72) (Scheme 19). Now, for the first time, the kinetics have been studied of the aminolysis of (72) and of two model compounds, y-thiobutyrolactone (72 H instead of NH2) and N-trimethylamino homocysteine thiolactone (72 Me3N+ instead of NH2). A Brpnsted plot for homocysteine thiolactone (72) gave ft = 0.66. This and other data supported... 

In rats, the effects of various thiol compounds (mercaptopropionic acid, D-penicil-lamine, Ucysteine, DL-homocysteine, 2-mercaptoethylamine and mercaptoethane) on the absorption and elimination of bismuth subnitrate given orally were determined. All of the thiol substances, and particularly cysteine, homocysteine and mercaptopropionic acid, enhanced Bi absorption and elimination. Moreover, the acute toxicity of Bi was enhanced when Bi was given as a complex with cysteine (LDjq = 156mgkg ). Studies of and N NMR confirmed complexation of Bi and cysteine. The enhancement of the absorption, elimination and acute toxicity of Bi may be caused by the increases of solubility and permeability of Bi arising from complexation with thiol compounds. 

In another letter to the editor (12) it was mentioned that the suspicion of partiality about the Committee on Toxicity becomes more plausible when one considers the issue of homocysteine. This intermediate metabolite may well turn out to be of greater importance as a risk factor for cardiovascular disease than cholesterol and blood pressure. Raised homocysteine concentrations appear to be accessible to treatment with pyridoxine (100 mg/day) together with vitamin B12 and foUc acid (13). Furthermore, the statement that there is no good evidence for the efficacy of pyridoxine in any disease, apart from depression, was criticized, because this ignores important studies in autism, pregnancy outcome, asthma, and sickle-cell anemia (12). 

---