Reactive oxygen species and various electrophiles are involved in the etiology of diseases varying from cancer to cardiovascular and pulmonary disorders. The human body is protected against damaging effects of these compounds by a wide variety of systems. An important line of defense is formed by antioxidants. Vitamin E (consisting of various forms of tocopherols and tocotrienols) is an important fat-soluble, chain-breaking antioxidant. Besides working as an antioxidant, this compound possesses other functions with possible physiological relevance. The glutathione-dependent enzymes form another line of defense. Two important enzymes in this class are the free radical reductase and glutathione S-transferases (GSTs). The GSTs are a family of phase II detoxification enzymes. They can catalyze glutathione conjugation with various electrophiles. In most cases the electrophiles are detoxified by this conjugation, but in some cases the electrophiles are activated. Antioxidants do not act in isolation but form an intricate network. It is, for instance, known that vitamin E, together with glutathione (GSH) and a membrane-bound heat labile GSH-dependent factor, presumably an enzyme, can prevent damaging effects of reactive oxygen species on polyunsaturated fatty acids in biomembranes (lipid peroxidation). This manuscript reviews the interaction between the two defense systems, vitamin E and glutathione-dependent enzymes. On the simplest level, antioxidants such as vitamin E have protective effects on glutathione-dependent enzymes; however, we will see that reality is somewhat more complicated.
Dietary antioxidants play a major role in maintaining the homeostasis of the oxidative balance. They are believed to protect humans from disease and aging. Vitamin C (ascorbic acid), vitamin E (tocopherol), beta-carotene and other micronutrients such as carotenoids, polyphenols and selenium have been evaluated as antioxidant constituents in the human diet. This article addresses data provided from clinical trials, highlighting the clinical pharmacokinetics of vitamin C, vitamin E, beta-carotene, lycopene, lutein, quercetin, rutin, catechins and selenium. The bioavailability of vitamin C is dose-dependent. Saturation of transport occurs with dosages of 200-400 mg/day. Vitamin C is not protein-bound and is eliminated with an elimination half-life (t((1/2))) of 10 hours. In Western populations plasma vitamin C concentrations range from 54-91 micro mol/L. Serum alpha- and gamma-tocopherol range from 21 micro mol/L (North America) to 27 micro mol/L (Europe) and from 3.1 micro mol/L to 1.5 micro mol/L, respectively. alpha-Tocopherol is the most abundant tocopherol in human tissue. The bioavailability of all-rac-alpha-tocopherol is estimated to be 50% of R,R,R-alpha-tocopherol. The hepatic alpha-tocopherol transfer protein (alpha-TTP) together with the tocopherol-associated proteins (TAP) are responsbile for the endogenous accumulation of natural alpha-tocopherol. Elimination of alpha-tocopherol takes several days with a t((1/2)) of 81 and 73 hours for R,R,R-alpha-tocopherol and all-rac-alpha-tocopherol, respectively. The t((1/2)) of tocotrienols is short, ranging from 3.8-4.4 hours for gamma- and alpha-tocotrienol, respectively. gamma-Tocopherol is degraded to 2, 7, 8-trimethyl-2-(beta-carboxyl)-6-hyrdoxychroman by the liver prior to renal elimination. Blood serum carotenoids in Western populations range from 0.28-0.52 micro mol/L for beta-carotene, from 0.2-0.28 for lutein, and from 0.29-0.60 for lycopene. All-trans-carotenoids have a better bioavailability than the 9-cis-forms. Elimination of carotenoids takes several days with a t((1/2)) of 5-7 and 2-3 days for beta-carotene and lycopene, respectively. The bioconversion of beta-carotene to retinal is dose-dependent, and ranges between 27% and 2% for a 6 and 126mg dose, respectively. Several oxidised metabolites of carotenoids are known. Flavonols such as quercetin glycosides and rutin are predominantly absorbed as aglycones, bound to plasma proteins and subsequently conjugated to glucuronide, sulfate, and methyl moieties. The t((1/2)) ranges from 12-19 hours. The bioavailabillity of catechins is low and they are eliminated with a t((1/2)) of 2-4 hours. Catechins are degraded to several gamma-valerolactone derivatives and phase II conjugates have also been identified. Only limited clinical pharmacokinetic data for other polyphenols such as resveratrol have been reported to date.