Pyridoxal-5-Phosphate
Reducing the Risk of Heart Disease and Cancer

Scientists investigating the ability of folate, vitamin B12 and pyridoxal-5'-phosphate (P5P) to lower the body's levels of homocysteine - a potential risk factor in cardiovascular disease - discovered an interesting fact: rather than lowering homocysteine across the board, each of these vitamins interacted with specific types of homocysteine. Consequently, folate and vitamin B12 reduced fasting hyperhomocystinemia, whereas P5P lowered homocysteine only after the administration of high doses of methionine, the amino acid from which homocysteine is metabolized.

P5P's specialized ability could have implications for those consuming diets high in methionine, an essential amino acid found in meats (especially red meats) and dairy products. That P5P can lower methionine-induced elevated homocysteine levels is an important argument to support its protective role against myocardial infarctions (heart attacks), arrhythmias, and other cardiovascular diseases. Furthermore, P5P deficiency has been linked with hypertension and pancreatic and cervical cancer.

The Metabolic Link
P5P is the active enzyme form of vitamin B6 that does not require activation by the liver. Its ability to alter homocysteine concentrations may arise from its important status in homocysteine metabolism. Homocysteine is metabolized through one of two pathways: remethylation and transsulfuration. (see Homocysteine: The Amino Acid with Life or Death Implications in this issue of Vitamin Research News) In remethylation, vitamin B12, folate and betaine are necessary to convert homocysteine back into methionine. By contrast, the transsulfuration pathway is catalyzed by P5P-containing enzymes and results in the formation of the amino acid cysteine, which is then transformed into inorganic sulfates or taurine. These are either used by the body or excreted, thus depleting the body's excess homocysteine. A vitamin B6 deficiency or a genetic defect in the P5P-containing enzymes can interfere with homocysteine metabolism and lead to hyperhomocystinemia.1

P5P and Coronary Heart Disease (CHD)
Scientists have established a correlation between low P5P levels and coronary heart disease. In animal studies, vitamin B6 deficiency has resulted in atherosclerosis. In one human study, P5P levels were significantly lower in 750 vascular disease cases than 800 controls. The higher the blood levels of folate, vitamin B12 and P5P, the lower the plasma homocysteine concentration. The vascular disease patients also were significantly less likely than controls to be taking B-vitamin supplements.2

Participants of another study who subsequently developed CHD tended to have lower mean plasma concentrations of folate, P5P, and vitamin B12 and lower supplemental vitamin use than controls. However, only the mean plasma P5P significantly reduced the risk of CHD. Users of vitamin supplements had higher plasma B-vitamin concentrations than nonusers, suggesting that vitamin supplementation contributed to the association between reduced CHD risk and plasma P5P. The researchers concluded, "Our findings point more strongly to the possibility that vitamin B6 offers independent protection [against CHD]."3

Research has indicated that P5P also may protect against arrhythmia, where the heart may seem to skip a beat or beat irregularly. Arrhythmia is responsible for the damage inflicted in more than two-thirds of heart disease patients and kills more males in the Western world than any other condition. One study reported a P5P deficiency in patients with ischemic heart disease and arrhythmias, a deficiency associated with failure of heart muscle tissue cells.4

In addition to its direct effects on cardiovascular disease, P5P may protect high blood pressure sufferers against coronary artery disease and cerebral vascular disease, two common causes of death or disability in hypertensive patients. In a three-year study of 24 male patients with high blood pressure aged 35-55 years, researchers found that in some of the patients, long-term administration of antihypertensive drugs led to a P5P deficiency.5

Myocardial Infarctions and Thrombi
P5P's powerful impact was suggested in an analysis of 84 patients with acute myocardial infarction (MI) and 84 controls. The mean levels of vitamin B6 was lower in patients than in controls, and subjects with the least amount of plasma P5P were five times more likely to have a myocardial infarction compared with those who had the highest amounts.6

P5P's role in the prevention of myocardial infarctions is related to the formation of thrombi, or blood clots, the cause behind MI. P5P has been shown to inhibit the platelet aggregation that causes blood clots. It is thought to accomplish this by inhibiting glycoprotein IIb (GPIIb), a substance which plays a major role in platelet aggregation. One study showed that P5P down-regulated GPIIb activity by 63% as compared to untreated controls.7

Pancreatic and Cervical Cancer
Scientists have explored the role P5P plays in inhibiting the formation of tumors. These studies have yielded interesting results. In one study, unlike controls, women with cervical cancer exhibited a deficiency of vitamin B6. The researchers called for further study to determine whether the deficiency was the cause of the disease or a consequence of the tumor.8

New research has demonstrated that P5P may protect against pancreatic cancer. The 126 smokers with pancreatic cancer taking part in the study had statistically significant lower levels of serum and dietary folate, lower levels of serum P5P, and greater pack years of smoking compared to the 247 controls. Those with the highest levels of folate and P5P had half the risk of contracting pancreatic cancer compared with those with the lowest levels, a finding that was independent of other risk factors, including smoking, history and diet. The potential protective effects of P5P were stronger among men with the highest levels of the nutrient and who smoked the least. Interestingly, fifty percent of the total study group, including both subjects and controls, had less than adequate P5P levels. The researchers concluded that 26% of the pancreatic cancer cases in their study could potentially have been prevented if the subjects with the lowest levels of P5P had increased their intake prior to contracting the disease.9

Conclusion
The evidence suggests that P5P may have a protective effect against cardiovascular disease and some cancers. In light of this research, supplementation with P5P may be the first line of defense against the overabundance of methionine in the Western diet.

References
1. Selhub J. Homocysteine metabolism. Annu Rev Nutr. 1999; 19:217-46.

2. Graham IM, Daly LE, Refsum HM, Robinson K, Brattstrom LE, Ueland PM, Palma-Reis RJ, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA. 1997; 277(22):1775-81.

3. Folsom AR, Nieto FJ, McGovern PG, Tsai MY, Malinow MR, Eckfeldt JH, Hess DL, Davis CE. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 1998; 98(3):204-10.

4. Rudzite V, Jirgensons J, Jurika E, Sileniece G, Zirne R, Jirgensone S. Peculiarities of nicotinic acid formation in coronary heart disease with special reference to heart arrhythmias. Z Gesamte Inn Med. [Article in German]. 1988; 43(3):60-5.

5. Rudzite VK, Vitols AV, Liepinja DJ, Silava AK. Increased blood kynurenine level as a factor inhibiting the therapeutic effect of antihypertensive agents in combined long-term treatment of essential hypertension. Cor Vasa. 1990; 32(1):56-63.

6. Kok FJ, Schrijver J, Hofman A, Witteman JC, Kruyssen DA, Remme WJ, Valkenburg HA. Low vitamin B6 status in patients with acute myocardial infarction. Am J Cardiol. 1989; 63(9):513-6.

7. Chang SJ, Chuang HJ, Chen HH. Vitamin B6 down-regulates the expression of human GPIIb gene. J Nutr Sci Vitaminol (Tokyo). 1999; 45(4):471-9.

8. Ramaswamy PG, Natarajan R. Vitamin B6 status in patients with cancer of the uterine cervix. Nutr Cancer. 1984; 6(3):176-80.

9. Stolzenberg-Solomon RZ, Albanes D, Nieto FJ, Hartman TJ, Tangrea JA, Rautalahti, et al. Pancreatic cancer risk and nutrition-related methyl-group availability indicators in male smokers. J Natl Cancer Inst. 1999; 91(6):535-41.