Dr. Ron’s Research Review – October 6, 2010

This week’s research review contains articles on vitamin B6 and P5P; Tocotrienols; and Niacinamide to reduce fibrinogen.

B6 and P5P

Biosynthesis of pyridoxal 5'-phosphate  depends upon the relatively specific action of two consecutive enzymes: pyridoxal (pyridoxine, pyridoxamine) kinase and pyridoxine (pyridoxamine) phosphate oxidase. (McCormick and Chen 1999)

Dietary micronutrients reduce cancer risk by curtailing the accumulation of DNA damage and suggests that micronutrient depletion could be part of a defense mechanism against hyperproliferation. (Kanellis, Gagliardi et al. 2007)

Tocotrienols

Tocotrienols, the vitamin E of the 21st century: Its potential against cancer and other chronic diseases (Aggarwal, Sundaram et al. 2010)

Niacin and Fibrinogen

Nicotinic acid treatment shifts the fibrinolytic balance favourably and decreases plasma fibrinogen in hypertriglyceridaemic men (Johansson, Egberg et al. 1997)

Niacin supplementation decreased plasma fibrinogen and low-density lipoprotein cholesterol in subjects with peripheral vascular disease (Philipp, Cisar et al. 1998)

In the News

Celiac Disease Strikes Some Late In Life

By Whitney Blair Wyckoff, NPR News Link

Dr. Ron

 


Articles

Update on interconversions of vitamin B-6 with its coenzyme

(McCormick and Chen 1999) Download

Biosynthesis of pyridoxal 5'-phosphate (PLP) depends upon the relatively specific action of two consecutive enzymes, viz. pyridoxal (pyridoxine, pyridoxamine) kinase and pyridoxine (pyridoxamine) phosphate oxidase. Less specific phosphatases catalyze hydrolyses of the 5'-phosphates of the vitamers pyridoxal, pyridoxamine, and pyridoxine. From the recognition a generation ago of these processes by which the three forms of vitamin B-6 and their 5'-phosphates are interconverted, more recent studies have provided a fairly sophisticated understanding of the molecular characteristics of the enzymes involved. The evolutionary retention of homologous portions of pyridoxal kinase in humans as well as bacteria and the most recent finding of a highly conserved region of the pyridoxine (pyridoxamine) phosphate oxidase, also from both prokaryotic and eukaryotic organisms, emphasize the importance of these catalysts in the formation of a coenzyme that is essential for most organisms. Both kinase and oxidase involved in B-6 metabolism are potential targets for pharmacologic agents.

A screen for suppressors of gross chromosomal rearrangements identifies a conserved role for PLP in preventing DNA lesions

            (Kanellis, Gagliardi et al. 2007) Download

Genome instability is a hallmark of cancer cells. One class of genome aberrations prevalent in tumor cells is termed gross chromosomal rearrangements (GCRs). GCRs comprise chromosome translocations, amplifications, inversions, deletion of whole chromosome arms, and interstitial deletions. Here, we report the results of a genome-wide screen in Saccharomyces cerevisiae aimed at identifying novel suppressors of GCR formation. The most potent novel GCR suppressor identified is BUD16, the gene coding for yeast pyridoxal kinase (Pdxk), a key enzyme in the metabolism of pyridoxal 5' phosphate (PLP), the biologically active form of vitamin B6. We show that Pdxk potently suppresses GCR events by curtailing the appearance of DNA lesions during the cell cycle. We also show that pharmacological inhibition of Pdxk in human cells leads to the production of DSBs and activation of the DNA damage checkpoint. Finally, our evidence suggests that PLP deficiency threatens genome integrity, most likely via its role in dTMP biosynthesis, as Pdxk-deficient cells accumulate uracil in their nuclear DNA and are sensitive to inhibition of ribonucleotide reductase. Since Pdxk links diet to genome stability, our work supports the hypothesis that dietary micronutrients reduce cancer risk by curtailing the accumulation of DNA damage and suggests that micronutrient depletion could be part of a defense mechanism against hyperproliferation.

Tocotrienols, the vitamin E of the 21st century: Its potential against cancer and other chronic diseases

            (Aggarwal, Sundaram et al. 2010) Download

Initially discovered in 1938 as a "fertility factor," vitamin E now refers to eight different isoforms that belong to two categories, four saturated analogues (alpha, beta, gamma, and delta) called tocopherols and four unsaturated analogues referred to as tocotrienols. While the tocopherols have been investigated extensively, little is known about the tocotrienols. Very limited studies suggest that both the molecular and therapeutic targets of the tocotrienols are distinct from those of the tocopherols. For instance, suppression of inflammatory transcription factor NF-kappaB, which is closely linked to tumorigenesis and inhibition of HMG-CoA reductase, mammalian DNA polymerases and certain protein tyrosine kinases, is unique to the tocotrienols. This review examines in detail the molecular targets of the tocotrienols and their roles in cancer, bone resorption, diabetes, and cardiovascular and neurological diseases at both preclinical and clinical levels. As disappointment with the therapeutic value of the tocopherols grows, the potential of these novel vitamin E analogues awaits further investigation.

Nicotinic acid treatment shifts the fibrinolytic balance favourably and decreases plasma fibrinogen in hypertriglyceridaemic men

            (Johansson, Egberg et al. 1997) Download

BACKGROUND: Nicotinic acid in gram doses decreases cholesterol and triglyceride concentrations in plasma, but the effect on haemostatic function is not known. METHODS: Twenty-three men with hypertriglyceridaemia were treated with 4 g nicotinic acid daily for 6 weeks. Tests for haemostatic function and serum lipoproteins were performed before and at the end of the period of treatment. RESULTS: Treatment with nicotinic acid had the expected effect on lipoprotein concentrations: it reduced the serum concentrations of triglyceride and the three major density fractions of triglyceride (very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL)). The VLDL cholesterol concentration was reduced, but that of HDL cholesterol was increased (all P<0.0001). The lipoprotein(a) (Lp(a)) concentration decreased significantly (P<0.01). The total fibrinolytic activity was increased by nicotinic acid treatment as indicated by decreases in plasminogen activator inhibitor-1 activity from 34.3 to 23.8 U/ml (P<0.01) and in alpha2-antiplasmin activity from 1.10 to 0.97 U/ml (P<0.01). The plasma fibrinogen concentration decreased from 3.55 to 3.01 U/ml (P<0.01). Multvariate analysis showed that the changes in alpha2-antiplasmin and Lp(a) concentrations could explain 53% of the change in plasma fibrinogen, suggesting that increased plasmin mobilization could be responsible for the decrease in plasma fibrinogen. CONCLUSION: This study of hypertriglyceridaemic men has shown that long-term treatment with nicotinic acid not only corrects serum lipoprotein abnormalities, but also reduces the fibrinogen concentration in plasma and stimulates fibrinolysis.

Effect of niacin supplementation on fibrinogen levels in patients with peripheral vascular disease

            (Philipp, Cisar et al. 1998) Download

This study demonstrates that niacin supplementation decreases plasma fibrinogen and low-density lipoprotein cholesterol in subjects with peripheral vascular disease randomized to receive niacin, warfarin, antioxidants, or placebo. Changes in fibrinogen levels are highly correlated with changes in low-density lipoprotein cholesterol (r = 0.61; p < 0.009) in subjects taking niacin.


References

Aggarwal, B. B., C. Sundaram, et al. (2010). "Tocotrienols, the vitamin E of the 21st century: Its potential against cancer and other chronic diseases." Biochem Pharmacol.

Johansson, J. O., N. Egberg, et al. (1997). "Nicotinic acid treatment shifts the fibrinolytic balance favourably and decreases plasma fibrinogen in hypertriglyceridaemic men." J Cardiovasc Risk 4(3): 165-71.

Kanellis, P., M. Gagliardi, et al. (2007). "A screen for suppressors of gross chromosomal rearrangements identifies a conserved role for PLP in preventing DNA lesions." PLoS Genet 3(8): e134.

McCormick, D. B. and H. Chen (1999). "Update on interconversions of vitamin B-6 with its coenzyme." J Nutr 129(2): 325-7.

Philipp, C. S., L. A. Cisar, et al. (1998). "Effect of niacin supplementation on fibrinogen levels in patients with peripheral vascular disease." Am J Cardiol 82(5): 697-9, A9.