Kuniharu Suzumura

Antioxidative property of T-0970, a new ureidophenol derivative

We investigated the antioxidative property of T-0970, a newly synthesized ureidophenol derivative. The inhibitory effect of T-0970 on spontaneous lipid peroxidation in rat brain was 10 times greater than those of well-known antioxidants such as butylhydroxytoluene (BHT), probucol and α-tocopherol. T-0970 also showed dose-dependent free radical scavenging activities in vitro for both superoxide anions and hydroxyl radicals. The radical-scavenging potencies of T-0970 were about 10–30 times stronger than those of BHT. We evaluated the in vivo antioxidative ability of T-0970 in the animal model of acute oxidative tissue injury in rats. Intraperitoneal injection of ferric nitrilotriacetate (Fe/NTA) caused an acute and remarkable increase in the level of thiobarbituric acid-reactive substances (TBARS) in both plasma and the liver, and also resulted in a considerable elevation of the plasma levels of GOT and GPT indicative of hepatic injury. Both oral and intravenous administration of T-0970 dose-dependently depressed these diagnostic parameters. These results indicate that T-0970 may have a therapeutic potential in various diseases associated with oxidative tissue injury.

Fluvastatin depresses the enhanced lipid peroxidation in vitamin E-deficient hamsters

Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has recently been reported to have the antioxidative activity in vitro. However, it is still unclear whether chronic treatment with this drug actually leads to amelioration of the redox status in the body. In this study, we investigated the antioxidative effect of fluvastatin in vivo, using a vitamin E-deficient hamster model, an in vivo model of enhanced oxidative stress. After pre-treatment with a vitamin E-deficient diet for 2 months, fluvastatin, pravastatin or probucol was added to the diet for 1 month. Vitamin E deficiency caused a significant increase in the levels of plasma oxidative stress markers such as 8-iso-prostaglandin F2α (8-iso-PGF2α) and hydroperoxides. Furthermore, there was a significant increase in the oxidizability of plasma lipids in the vitamin E-deficient animals, indicating that the oxidative stress was increased in the circulation. Fluvastatin markedly depressed the above oxidative stress markers in plasma, and significantly decreased the oxidizability of plasma lipids without affecting their levels. Probucol, a reference antioxidant, also showed a similar effect while pravastatin, another HMG-CoA reductase inhibitor, showed only a weak improvement. We suggest that the treatment with fluvastatin leads to a reduction of oxidative stress in vivo, which is mainly derived from its antioxidative property rather than its lipid-lowering activity.

Determination of Isoprostanes as Marker Oxidant Stress by LC-ESI/MS.

The isoprostane, 8-iso-PGF2α is formed from arachidonic acid in vivo by a mechanism independent of cyclooxygenase pathway. We developed a new assay method for 8-iso-PGF2α using [2H4]-8-iso-PGF2α as the internal standard (I.S.) by LC-ESI/MS. For this assay, we established a very simple and rapidly pretreatment method using a membrane filter-type solid phase extraction column (Empore™ disk cartridge) for human plasma and urine. LC-ESI/MS was performed in the selected ion monitoring (SIM) mode using target ions at m/z 353.4757 (8-iso-PGF2α) and m/z 357.5073 (I.S.) with a resolution of 3,000. The imprecision for this method was below 14%. Mean inaccuracy was 9% for added levels of 8-iso-PGF2α up to 5,000 pg/mL of urine and 500 pg/mL of plasma. The study of human urinary and plasma 8-iso-PGF2α concentrations may be a convenient diagnostic tool to be able to assess the extent of oxidative stress in vivo not only by smoking but also in other disease states.