Pharmacodynamic of the antioxidant action of alpha-tocopherol and its derivatives in liver, brain, heart and skeletal muscles.
The aim of the present work was to determine the pharmacodynamics of antioxidant effect of alpha-tocopherol and its derivatives (alpha-tocopheryl esters and chromanols with different chain-length) in the animal tissues, as well as the role of cytochrome P-450 in biotransformation of these compounds. Alpha-tocopherol and its derivatives were injected intraperitoneally in rats or mice in a single dose of 100 mmol per kg b.w. The animals were sacrificed at different time intervals (0, 1, 2, 4, 8, 12, 24, 36 hours) and the liver, heart, brain and skeletal muscles were removed, homogenized and incubated with lipid peroxidation (LPO) inducers (Fe2+ + ascorbate). LPO was evidenced by the generated malone dialdehyde (MDA). Data were expressed as percentage of LPO inhibition by alpha-tocopherol or its derivatives as compared to control group. The kinetic curves of the inhibitory action of alpha-tocopherol and its derivatives on LPO were characterized by three phases: a phase of increasing antioxidant activity, a phase of maximal antioxidant activity (about 60-95% LPO inhibition), and a phase of decreasing antioxidant activity. Alpha-tocopheryl esters possessed dynamics of antioxidant action the same as alpha-tocopherol. Therefore the hydrolysis of alpha-tocopheryl esters in animal organism is not a limiting factor for their antioxidant effect. The alpha-tocopherol derivatives with short chain-length (C1, C6) had a shorter half-life in animal tissues as compared to alpha-tocopherol or its esters. In vitro experiments showed that C1 and C6 are substrates of cytochrome P-450. In contrast, alpha-tocopherol and its esters did not bind to cytochrome P-450 even at concentrations as high as 10 mmol/l. Apparently, C1 and C6 underwent biotransformation and were excreeted more quickly from the organism.