Pharmacology of Hyperhomocysteinmia.
Posted in Disease, Pharmacology
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Friday 2 August 2013 By Unknown
· What is hyperhomocysteinemia ?
Hyperhomocysteinemia is condition in which homocysteine level is increased due deficiency of vitamin B12 or defect in methyleneterahydrofolate reductase, methionine synthase and cystathionine beta-synthase. Hyperhomocysteinemia is associated with many disease conditions like coronary artery disease, mental retardation, diabetic complications (retinopathy & neuropathy), thrombosis etc.
· What is homocysteine:-
it is a natural occurring sulfur containing amino acid mainly derived form dierty sources of methionine. It is closely related to cysteine amino acid. It was first introduced in 1932 by Butz and du Vigneaud and eleveted level of homocysteine in urine was reported in mental retarded children by neil and carson in 1962. Homocysteine level in healthy person is 10-12 μmol/L.
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Metabolism of homocysteine :-
Homocysteine is intermediate product of metheonine metabolism and it is metabolised by two pathway
Re-methylation pathway (which regenerates methionine)
Trans-sulfuration pathway (which degrade homocysteine)
Re-methylation pathway:-
Remethylation pathway converts homocysteine into methionine by transfering methyl (-CH3) group either by methylcobalamine or betaine. Methylcobalamine receive methyl group from S–adinosylmethionine (SAM) or 5-methyltetrahydrofolate (5-MTHF). SAM is a universal methyl group donor which is associated with many metabolic reaction. SAM is converted into S-adinosylhomocysteine (SAH) to donate methyl group. Under normal metabolic condition 50% of homocysteine remethylated into methionine.
Trans-sulfuration pathway:-
Trans-sulfuration pathway degrades methionine and homocysteine into cysteine and taurine. Cysteine and taurine is important for cardiac health, hepatic detoxification, cholesterol level etc.
this pathway is depend on diatery consumption of vitamin B6 and its conversion into active form. In this pathway homocysteine is converted into cystothionine by enzyme cystathionie beta synthase (CBS) and amino acid serine which is formed from glycine. Futher cystathionie is converted into cysteine by pyridoxal-5-phosphate (P5P) which act as a cofactor.
· Etiology:-
1. Genetic defects: - CBS and MTHFR (methyltetrahydrofolate reductase) are two main enzymes involved in the metabolism of homocysteine. Due to heterozygous mutation in both enzymes can lead to elevated level of homocysteine. While homozygous mutation is mainly occurs with MTHFR. Because of mutation in protein become thermolabile and inactivated by heat.
2. Deficiency of vitamin B6:- Vit B6 play important role in trans-sulfutation pathway. Due to deficiency in Vit B6 homocysteine could not converted into cysteine and thus hyperhomocysteinemia can occurs.
3. Anti-hyperlipidemic drug:- drug like fibrate and nicotinic acid can elevate homocysteine level by 30%. Fibrate and nicotinic acid act via peroxisome proliferation activated receptor α (PPAR α) which lead to increased in activation of gene involved in metabolism of lipid and fatty acid.
4. Chronic kidney failure:- chronic kidney failure can increase homocysteine level due to decrease in the excretion and metabolism impairment.
5. Cigarette smoking: - can also cause hyperhomocysteinemia.
· Pathophysiology:-
Hyperhomocysteinemia is associated with number of diseases state which are as following
Ø Phase II detoxification reaction.
Ø Heart disease.
Ø Pregnancy
Ø Disease of nervous system
Ø Kidney failure
Phase II detoxification reaction:- Phase II detoxification reaction involved conjugation of activated metabolite with glutathione, sulfate, glycine etc. but due to high level of homocysteine further pathway of metabolism become impaired & other molecule which are involved in phase II reaction are not synthesised like glutathione (GSH), sulfate, glycine etc. methionine and cysteine is used for cyanide-thiocyanate detoxification.
Heart disease:- Homocysteine produce hydrogen peroxide by reacting with LDL cholesterol and endothelial cell membrane which catalyze cellular injury. To protect endothelial cell membrane from hydrogen peroxide, EDRF (endothelium derived relaxing factor) released NO and other oxide of nitrogen oxide. NO react with homocysteine and form S-nitrosohomocysteine to protect endothelium form hydrogen peroxide. Increase in homocysteine level will overload protective mechanism and allow damage to endothelium.
Re-methylation of homocysteine and formation of SAM is necessary for the synthesis of L-argenine, creatinine etc. and trans-sulfuration pathway produced GSH, cysteine, taurine etc. All these nutrient are important for reduction of oxidative stress and treat heart disease. Increase level of homocysteine will decrease level of all above important nutrients which increase the risk for heart disease.
Pregnancy:- deficiency in folic acid and vit B12 can cause neural tube defects (opening in brain or spinal cord ). Impairment in methylation and homocysteine may cause the NTD( neural tube defect ). It can be prevented by folic acid supplementation.
Disease of nervous system:- homocysteine has critical impact on number of nervous system disorder including schizophrenia, Parkinson’s disease etc and can be correlated with homocysteine level.
Methaylation of homocysteine via SAM also include methylation of DNA and myelin, are very important for CNS. Due to defect in enzyme methionine synthase, complication of deficiency of vit B12 are occurs. Alternative pathway for remathylation is not present in nervous system so defect in MS complications of nervous system can occurs.
Homocysteine is found to be a neurotoxin in condition where glycin level is increased. Increased level of homocysteine bind with NMDA receptor and facilitate the entery of Ca+ ion, which produced free redicals in neurons and causes neurotoxicity. It was found that patient with Alzheimer’s disease has high level of homocysteine. Methylation reaction is very vital for the methylation of mylien sheath, but high level of homocysteine can defect the methylation reaction and can cause the condition called as subacute combine degeneration of spinal cord (SCD).
Kidney failure:- because homocysteine is cleared by kidney, kidney failure can cause the increased level of homocysteine. Homocysteine level in kidney failure is 26 ± 1.5 µmol/L. in kidney failure increased homocysteine level causes endothelial defects and due to this auto-oxidation of homocysteine is occurs and thus bioavailability of nitric oxide is reduced. increased level of homocysteine causes accumulation of inhibitor of NO synthase is occurs.
· Symptoms:-
In general, high homocysteine does not cause symptoms until and unless one of the diseases with which it is associated, appears. Extremely high homocysteine can cause blood clots, rapid bone loss, and in children mental retardation.
· Treatment:-
The best way to prevent hyperhomocysteinemia is to eat foods which contain B6, B12, and folate such as potato, greens, beans and fish. Supplementation with pyridoxine, folic acid, B12, or betaine reduces the concentration of homocysteine in the bloodstream. N-acetyl-cysteine (NAC) has shown the ability to significantly reduce homocysteine levels. It is belived that N-acetyl-cysteine displace homocysteine form the blood stream and allow formation of cysteine.
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