Evaluation of mutagenic activity of the organo-selenium compound Selol by use of the Salmonella typhimurium mutagenicity assay.

We examined the mutagenic activity of the anti-oxidant Selol, an organo-selenium compound, by use of the Salmonella typhimurium mutagenicity assay (Ames test) with strains TA97a, TA98, TA100, TA 1535 and TA102 in the absence and in the presence of metabolic activation with an S9 fraction from Aroclor-induced rat liver. Doses were 330, 500, 1000 and 5000 microg per plate. Selol contains the element selenium (valency, +4) in its structure and it may have chemopreventive and anticancer activity. Selol was found to be non-toxic and non-mutagenic for test doses up to 5% per plate (which designates the declared content of Selenium (+4) as 5000 microg per plate) in all the S. typhimurium strains.

Changes in antioxidant defense systems induced by thiram in V79 Chinese hamster fibroblasts.

The role of antioxidant defence systems in protection against oxidative damage of lipids and proteins induced by fungicide thiram during in vitro exposure was investigated in cultured Chinese hamster V79 cells with normal, depleted, and elevated glutathione (GSH) levels. We analyzed the catalytic activities of superoxide dismutases (SOD1 and SOD2), Se-dependent and Se-independent glutathione peroxidases (GSH-Px), glutathione reductase (GR), and catalase (CAT), as well as total glutathione/glutathione disulfide ratio (GSH(total)/GSSG). Thiram treatment resulted in an increase in activities of SOD1, Se-dependent GSH-Px, and GR at the highest tested dose (150 microM). On the contrary, inhibition of CAT and Se-independent GSH-Px activities, and no significant changes in the level of SOD2 activity was observed at any tested doses (100-150 microM). GSH(total)/GSSG ratio in the 100 microM thiram treated cells was not significantly changed comparing to the control, despite significant decrease of GSH total (50%). In 150 microM thiram treated cells the ratio falls to 43% of control value. Pretreatment with l-buthionine sulfoximine (L-BSO), an inhibitor of GSH synthesis, significantly enhanced decrease in CAT and Se-independent GSH-Px activities, as well as GSH(total)/GSSG ratio, and reduced Se-dependent GSH-Px activity, following exposure to thiram. Simultaneously, L-BSO pretreatment enhanced increase in SOD1 activity, and had no effect on SOD2, following thiram exposure. Pretreatment with N-acetyl cysteine (NAC), a GSH precursor, prevented enzymatic changes in CAT, Se-dependent GSH-Px, GR, SOD1 activities, and significantly decreased SOD2 activity following exposure to thiram. GSH(total)/GSSG ratio was restored to the control value. This study suggests that following the changes in antioxidant defense systems thiram can act through the production of free radicals.

Specific spectrophotometric method with trifluoroacetic acid for the determination of selenium(IV) in selenitetriglycerides.

The role of selenium as an antioxidant and anticancer agent is very well documented in the literature. Selenium compound showing the highest activity as a free radicals scavenger and as an anticancer agent should contain selenium at +4 oxidation level. The synthesis of selenitetriglycerides (named selol) was carried out in the Department of Drug Analysis at Warsaw Medical University (Polish Patent 1999). Selenitetriglycerides showed a dimeric structure. In a single dose toxicity studies performed in rats, LD50 was 100 mg Se kg(-1) after oral administration of selol. The subcutaneous and intraperitoneal administration of selol showed extremely low toxicity. The aim of this work was to develop a new specific method for the determination of Se(IV) in selol. We stated that selenitetriglycerides react quantitatively with trifluoroacetic acid (TFA) in dichloromethane giving a red-coloured conjugate. However, recorded spectrum showed the maximum absorption in the wavelength 380 nm. The optimal conditions of the reaction were established, namely temperature 35 degrees C and reaction time 35 min. The reaction was proved to be specific because neither selenites nor other selol constituents react with TFA. The constructed calibration curve obeyed the Lambert-Beer law in the range of 0.1-7.4 mg ml(-1). Molar absorption coefficient is epsilon =9.46 x 10(3) l mol(-1) cm(-1) and epsilon =2.36 x 10(5) l mol(-1) cm(-1) calculated for selenium and selenitetriglyceride dimer (m.w. 1972.72), respectively. Obtained results for selenium determination were confirmed by AAS method. The developed method showed specificity and high sensitivity.

Pharmacokinetics of selol, a new agent containing selenium, in rats.

The pharmacokinetic properties of selol, a new organoselenium compound, were evaluated in rats. Each animal was given a single oral or subcutaneous dose of selol 12 mg/kg. The selenium concentration was determined in whole blood and tissues by non flame carbon furnace atomic-absorption spectrometry. The pharmacokinetic parameters Cmax and tmax differed statistically between oral (p.o.) and subcutaneous (s.c.) treatment. The selenium average peak concentrations in the blood were 494 +/- 8 ng/ml after oral and 322 +/- 5 ng/ml after subcutaneous administration. They were reached after 1.9 +/- 0.1 h and 2.4 +/- 0.1 h, respectively. For the AUC0 mean values of 1373 +/- 56 ng.h/ml (p.o.) and 1273 +/- 137 ng.h/ml (s.c.) were found. The mean residence time (MRT) was significantly longer after subcutaneous administration. Selenium distributes quickly to the main organs with prevalence to the adrenal gland. Moreover, its concentrations in the examined organ were evidently higher after subcutaneous treatment as compared to the oral route. Our data suggest that Selol may be used as a possible source of selenium for the treatment of selenium-deficient patients, particularly via the subcutaneous route.

Toxicity studies of a new selenium compound, Selol, in rats.

Selol is a new organoselenium compound synthesized in the Department of Drug Analysis, Warsaw. The general acute and cumulative toxicities of Selol were tested in rats. The compound did not display any toxic effects after parenteral administration up to 500 mg/kg-1 s.c. and 100 mg/kg-1 i.p. However, given orally it exhibited high toxicity. LD50 value after a single oral administration amounted to 100 mg/kg-1 and after administration in an increasing-dose schedule to 80 mg/kg-1. On the basis of these results the authors conclude that Selol may be converted to a more toxic product during digestion. Therefore, Selol as a source of selenium is safer given by the parenteral route.

The enkephalin-hydrolytic activity of cerebral and cardiac muscle tissue in Wistar rats with streptozotocin diabetes.

Enkephalin-hydrolytic activity was evaluated in cerebral and cardiac tissue of Wistar rats with experimental streptozotocin-induced diabetes by comparison of the degree of amino acid cleavage from leu-enkephalin in vitro. Ninety days after induction of diabetes the enkephalin-hydrolytic activity was elevated in the cerebral tissue but depressed in the cardiac muscle.