To cope with environmental fluctuations and to prevent invasion by pathogens, plant metabolism must be flexible and dynamic. Active oxygen species, whose formation is accelerated under stress conditions, must be rapidly processed if oxidative damage is to be averted. The lifetime of active oxygen species within the cellular environment is determined by the antioxidative system, which provides crucial protection against oxidative damage. The antioxidative system comprises numerous enzymes and compounds of low molecular weight. While research into the former has benefited greatly from advances in molecular technology, the pathways by which the latter are synthesized have received comparatively little attention. The present review emphasizes the roles of ascorbate and glutathione in plant metabolism and stress tolerance. We provide a detailed account of current knowledge of the biosynthesis, compartmentation, and transport of these two important antioxidants, with emphasis on the unique insights and advances gained by molecular exploration.

ASCORBATE AND GLUTATHIONE: Keeping Active Oxygen Under Control

CONTEXT\nAntihypertensive therapy is well established to reduce hypertension-related morbidity and mortality, but the optimal first-step therapy is unknown.\n\n\nOBJECTIVE\nTo determine whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of coronary heart disease (CHD) or other cardiovascular disease (CVD) events vs treatment with a diuretic.\n\n\nDESIGN\nThe Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, active-controlled clinical trial conducted from February 1994 through March 2002.\n\n\nSETTING AND PARTICIPANTS\nA total of 33 357 participants aged 55 years or older with hypertension and at least 1 other CHD risk factor from 623 North American centers.\n\n\nINTERVENTIONS\nParticipants were randomly assigned to receive chlorthalidone, 12.5 to 25 mg/d (n = 15 255); amlodipine, 2.5 to 10 mg/d (n = 9048); or lisinopril, 10 to 40 mg/d (n = 9054) for planned follow-up of approximately 4 to 8 years.\n\n\nMAIN OUTCOME MEASURES\nThe primary outcome was combined fatal CHD or nonfatal myocardial infarction, analyzed by intent-to-treat. Secondary outcomes were all-cause mortality, stroke, combined CHD (primary outcome, coronary revascularization, or angina with hospitalization), and combined CVD (combined CHD, stroke, treated angina without hospitalization, heart failure [HF], and peripheral arterial disease).\n\n\nRESULTS\nMean follow-up was 4.9 years. The primary outcome occurred in 2956 participants, with no difference between treatments. Compared with chlorthalidone (6-year rate, 11.5%), the relative risks (RRs) were 0.98 (95% CI, 0.90-1.07) for amlodipine (6-year rate, 11.3%) and 0.99 (95% CI, 0.91-1.08) for lisinopril (6-year rate, 11.4%). Likewise, all-cause mortality did not differ between groups. Five-year systolic blood pressures were significantly higher in the amlodipine (0.8 mm Hg, P =.03) and lisinopril (2 mm Hg, P<.001) groups compared with chlorthalidone, and 5-year diastolic blood pressure was significantly lower with amlodipine (0.8 mm Hg, P<.001). For amlodipine vs chlorthalidone, secondary outcomes were similar except for a higher 6-year rate of HF with amlodipine (10.2% vs 7.7%; RR, 1.38; 95% CI, 1.25-1.52). For lisinopril vs chlorthalidone, lisinopril had higher 6-year rates of combined CVD (33.3% vs 30.9%; RR, 1.10; 95% CI, 1.05-1.16); stroke (6.3% vs 5.6%; RR, 1.15; 95% CI, 1.02-1.30); and HF (8.7% vs 7.7%; RR, 1.19; 95% CI, 1.07-1.31).\n\n\nCONCLUSION\nThiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive. They should be preferred for first-step antihypertensive therapy.

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Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT)

The main dietary sources of polyphenols are reviewed, and the daily intake is calculated for a given diet containing some common fruits, vegetables and beverages. Phenolic acids account for about one third of the total intake and flavonoids account for the remaining two thirds. The most abundant flavonoids in the diet are flavanols (catechins plus proanthocyanidins), anthocyanins and their oxidation products. The main polyphenol dietary sources are fruit and beverages (fruit juice, wine, tea, coffee, chocolate and beer) and, to a lesser extent vegetables, dry legumes and cereals. The total intake is approximately 1 g/d. Large uncertainties remain due to the lack of comprehensive data on the content of some of the main polyphenol classes in food. Bioavailability studies in humans are discussed. The maximum concentration in plasma rarely exceeds 1 microM after the consumption of 10-100 mg of a single phenolic compound. However, the total plasma phenol concentration is probably higher due to the presence of metabolites formed in the body's tissues or by the colonic microflora. These metabolites are still largely unknown and not accounted for. Both chemical and biochemical factors that affect the absorption and metabolism of polyphenols are reviewed, with particular emphasis on flavonoid glycosides. A better understanding of these factors is essential to explain the large variations in bioavailability observed among polyphenols and among individuals.

Dietary Intake and Bioavailability of Polyphenols

Vitamin C in humans must be ingested for survival. Vitamin C is an electron donor, and this property accounts for all its known functions. As an electron donor, vitamin C is a potent water-soluble antioxidant in humans. Antioxidant effects of vitamin C have been demonstrated in many experiments in vitro. Human diseases such as atherosclerosis and cancer might occur in part from oxidant damage to tissues. Oxidation of lipids, proteins and DNA results in specific oxidation products that can be measured in the laboratory. While these biomarkers of oxidation have been measured in humans, such assays have not yet been validated or standardized, and the relationship of oxidant markers to human disease conditions is not clear. Epidemiological studies show that diets high in fruits and vegetables are associated with lower risk of cardiovascular disease, stroke and cancer, and with increased longevity. Whether these protective effects are directly attributable to vitamin C is not known. Intervention studies with vitamin C have shown no change in markers of oxidation or clinical benefit. Dose concentration studies of vitamin C in healthy people showed a sigmoidal relationship between oral dose and plasma and tissue vitamin C concentrations. Hence, optimal dosing is critical to intervention studies using vitamin C. Ideally, future studies of antioxidant actions of vitamin C should target selected patient groups. These groups should be known to have increased oxidative damage as assessed by a reliable biomarker or should have high morbidity and mortality due to diseases thought to be caused or exacerbated by oxidant damage.

Vitamin C as an Antioxidant: Evaluation of Its Role in Disease Prevention

Humans are unable to synthesise L-ascorbic acid (L-AA, ascorbate, vitamin C), and are thus entirely dependent upon dietary sources to meet needs. In both plant and animal metabolism, the biological functions of L-ascorbic acid are centred around the antioxidant properties of this molecule. Considerable evidence has been accruing in the last two decades of the importance of L-AA in protecting not only the plant from oxidative stress, but also mammals from various chronic diseases that have their origins in oxidative stress. Evidence suggests that the plasma levels of L-AA in large sections of the population are sub-optimal for the health protective effects of this vitamin. Until quite recently, little focus has been given to improving the L-AA content of plant foods, either in terms of the amounts present in commercial crop varieties, or in minimising losses prior to ingestion. Further, while L-AA biosynthesis in animals was elucidated in the 1960s, 1 it is only very recently that a distinct biosynthetic route for plants has been proposed. 2 The characterisation of this new pathway will undoubtedly provide the necessary focus and impetus to enable fundamental questions on plant L-AA metabolism to be resolved. This review focuses on the role of L-AA in metabolism and the latest studies regarding its bio- synthesis, tissue compartmentalisation, turnover and catabolism. These inter-relationships are considered in relation to the potential to improve the L-AA content of crops. Methodology for the reliable analysis of L-AA in plant foods is briefly reviewed. The concentrations found in common food sources and the effects of processing, or storage prior to consumption are discussed. Finally the factors that determine the bioavailability of L-AA and how it may be improved are considered, as well as the most important future research needs. # 2000 Society of Chemical Industry

Plant L‐ascorbic acid: chemistry, function, metabolism, bioavailability and effects of processing

Determinants of the recommended dietary allowance (RDA) for vitamin C include the relationship between vitamin C dose and steady-state plasma concentration, bioavailability, urinary excretion, cell concentration, and potential adverse effects. Because current data are inadequate, an in-hospital depletion-repletion study was conducted. Seven healthy volunteers were hospitalized for 4-6 months and consumed a diet containing <5 mg of vitamin C daily. Steady-state plasma and tissue concentrations were determined at seven daily doses of vitamin C from 30 to 2500 mg. Vitamin C steady-state plasma concentrations as a function of dose displayed sigmoid kinetics. The steep portion of the curve occurred between the 30- and 100-mg daily dose, the current RDA of 60 mg daily was on the lower third of the curve, the first dose beyond the sigmoid portion of the curve was 200 mg daily, and complete plasma saturation occurred at 1000 mg daily. Neutrophils, monocytes, and lymphocytes saturated at 100 mg daily and contained concentrations at least 14-fold higher than plasma. Bioavailability was complete for 200 mg of vitamin C as a single dose. No vitamin C was excreted in urine of six of seven volunteers until the 100-mg dose. At single doses of 500 mg and higher, bioavailability declined and the absorbed amount was excreted. Oxalate and urate excretion were elevated at 1000 mg of vitamin C daily compared to lower doses. Based on these data and Institute of Medicine criteria, the current RDA of 60 mg daily should be increased to 200 mg daily, which can be obtained from fruits and vegetables. Safe doses of vitamin C are less than 1000 mg daily, and vitamin C daily doses above 400 mg have no evident value.

https://www.pnas.org/content/pnas/93/8/3704.full.pdf

K R Dhariwal

Papers

Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance.

Ascorbic acid and dehydroascorbic acid analyses in biological samples.

Ascorbic acid and dehydroascorbic acid measurements in human plasma and serum.

Millimolar concentrations of ascorbic acid in purified human mononuclear leukocytes. Depletion and reaccumulation.

Determination of optimal vitamin C requirements in humans