The antioxidant vitamins C and E

ments, there was a slight but nonsignificant risk of hemorrhagic stroke (+3%) and
ischemic stroke (+16%) in users of vitamin E.
Hence, intervention trials to date do not support a regimen of high-dose vitamin E
ingestion for reducing risk of cardiovascular and/or cancer death in high-risk populations.
Furthermore, there is some evidence indicating a potential adverse effect on risk
for hemorrhagic stroke in users of vitamin E supplements. Hemorrhagic stroke is classified
as subarachnoid hemorrhage or intracerebral hemorrhage, and the risk profiles
of these two subtypes are distinct. Subarachnoid hemorrhage is typically caused by
rupture of an arterial aneurysm and has been related to a smoking-induced elastase/αantitrypsin
imbalance (17), whereas intracerebral hemorrhage may be related more to
hypertension and necrosis of small arterioles (18). The number of cigarettes smoked
increased the risk of subarachnoid hemorrhage but not intracerebral hemorrhage (18).
In smokers, vitamin E supplementation raised the risk of fatal subarachnoid hemorrhage
(+181%, P = 0.005) but did not alter risk of fatal intracerebral hemorrhage (19);
furthermore, a high serum vitamin E concentration was related to a 53% lower incidence
of intracerebral hemorrhage in smokers (18). Thus, the antiplatelet and anticlotting
actions of vitamin E may, to some degree, exacerbate an arterial rupture, particularly
in smokers, but these actions, as well as the antioxidant action of vitamin E,
might lesson the development of fibrinoid necrosis (18). The antiplatelet and anticlotting
actions of vitamin E are discussed in a later section.
Adverse Reactions to Supplemental Vitamin C
In the general population, the data overwhelmingly indicate that regular ingestion of
vitamin C supplements is unlikely to have major adverse effects. The low toxicity of
supplemental vitamin C can probably be attributed to decreased bioavailability and
increased urinary excretion as the dose is increased. In one study, ~70% of a 500-mg
dose was absorbed and >50% of the absorbed dose was excreted in urine unmetabolized.
At the 1250-mg dosage level, only 50% of the dose was absorbed and nearly all
of the absorbed dose was excreted (20). Furthermore, the oxidized form of vitamin C,
dehydroascorbic acid, is not highly reactive and is effectively cleared from fluids and
rapidly reduced to ascorbic acid (21,22). Nonetheless, concerns have been raised
regarding adverse effects of high doses of vitamin C.
Systemic Conditioning (Rebound Scurvy)
There is some evidence that systemic conditioning (the accelerated metabolism or disposal
of ascorbic acid) may occur after prolonged supplementation of high doses of
vitamin C. The physiologic relevance of accelerated vitamin C metabolism in otherwise
healthy individuals, however, has not been addressed adequately. In human subjects
consuming a vitamin C–deficient diet (5 mg/d) in a live-in metabolic unit, abrupt
withdraw of vitamin C supplementation (600 mg/d for 3 wk) was associated with a
significant reduction in the mean leukocyte vitamin C concentration (16.8 ± 4.37 and
9.4 ± 5.33 µg vitamin C/108 cells, presupplementation and at 4 wk after withdrawal of
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