Invivo Redox Effects of Antioxidants

As with in-vitro studies, the effects an antioxidant produces in vivo are likely to be dependent on its concentration, the presence of metal ions, and the amount of other antioxidants and ROS present. In addition, the metabolism of the compound can greatly affect its redox reactivity. For example, quercetin, which shows both antioxidant and prooxidant effects in vitro, occurs in the plasma mainly in its conjugate forms (i.e., quercetin combined with glucuronic acid, a derivative of glucose). The conjugate form is less reactive than free quercetin in vitro and generally acts as a mild antioxi-dant in vivo.139-143

Similar to vitamin C, normal dietary doses of most an-tioxidants will probably have antioxidant effects in most in-vivo conditions, and one is more assured if combinations of antioxidants are used.144 For example, oral administration of a diverse group and high quantity of antioxidants produced greater protection from oxidative damage in rodents than fewer antioxidants and lower quantities.145'146'147 In another study, combinations of antioxidants were more effective in reducing cancer initiation in hamsters than single antioxidants.148 Like vitamin C, however, all antioxidants are capable of acting as prooxidants under limited circumstances. As the dose increases beyond a crucial point, the chances of producing a prooxidant effect also increase, especially when used alone or given intravenously.

One antioxidant that has received quite a bit of attention is beta-carotene. In a large trial on smokers (the Beta-Carotene and Retinol Efficiency Trial), researchers found that 30 milligrams of beta-carotene per day actually increased lung cancer rates.149-154 Reasons for this unexpected effect are still uncertain but are probably due to oxidation of beta-carotene in the free-radical-rich environment of a smoker's lungs and/or the altered metabolism of beta carotene caused by changed detoxification enzymes in the smoker's lungs.155 One other factor may have been the high plasma concentration of beta-carotene produced, relative to that provided by normal dietary intake. For example, one in-vitro study reported that at concentrations created by normal dietary intake (1 to 3 pM), beta-carotene provided protection from oxidative DNA damage. However, at concentrations just above this level (4 to 10 pM, as can be produced during supplementation), the protection was lost and beta-carotene (and lycopene) facilitated DNA damage.156

Other human studies on in-vivo effects of beta-carotene are mixed. Some reported that supplementation of beta-carotene had no effect on oxidative DNA damage in lymphocytes, while others found that beta-carotene supplementation (at 25 milligrams per day) was protective.157-160 Still others reported that beta-carotene (at 60 milligrams per day) increased oxidative damage in the lymphocytes of smokers but was protective in nonsmokers.161

The effect of vitamin E on DNA damage has also been studied in vivo. Again, studies suggest vitamin E can produce antioxidant or prooxidant effects, depending on conditions. Vitamin E supplementation (at 280 milligrams per day) produced both DNA protection in human lymphocytes and, under the right conditions, carcinogenic effects in animals.138,158162 One study reported that susceptibility of red blood cells to oxidative damage was increased by high and prolonged doses of vitamin E (1600 I.U. per day for 20 weeks) in nonsmokers, but not at lower doses, for shorter time periods, or in smok-ers.163 Supplementation with normal therapeutic doses of vitamin E (400 to 800 I.U. per day) probably produces antioxidant effects under most in-vivo condi-tions.164

The effect of other antioxidants on oxidative DNA damage has been studied in vivo as well. From earlier discussions, we know that high doses of vitamin C (especially given intravenously) can produce prooxidant effects in vivo. In other studies, oral supplementation with small doses of vitamin C (100 to 250 milligrams per day) protected DNA from oxidative damage in humans, while in still others, oral vitamin C showed no protective effect.158,160,161,162 Neutral results were seen in one of these studies even though plasma concentration of vitamin C increased during supplementation.

Even studies on multivitamin supplements have produced surprising results. One reported that multivitamin supplements increased mortality from cancer in male smokers but decreased it in nonsmokers or quitters.165 Some subjects took additional vitamin A, C, or E with their multivitamins, and the results were the same.

The inconsistencies in these experiments again point to the dynamic nature of redox reactions in vivo and the likelihood that various factors, such as antioxidant dose, the presence of other antioxidants, the presence of metal ions, and the degree of oxidative stress, may determine the effect seen. It is hoped that future studies on anti-oxidants will consider these factors in their design. For example, we may one day find that doses of antioxidants are best determined based on the results of patient monitoring. Along these lines, one recent study on the use of ^-acetylcysteine (NAC) to treat cancer cachexia (tissue wasting) based the dose on the plasma cystine to thiol ratio (this ratio is an indicator of oxidative stress).166 In this type of design, an excess amount of antioxidants would not be given, and any prooxidant effects produced would be quickly discovered.

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