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Ebselen is a seleno-organic compound that inhibits oxidative stress by lipid peroxidation through a glutathione peroxidase-like activity. We studied the effect of ebselen on the expression of hepatic drug-metabolizing enzymes in rats with deoxycholic acid-induced liver injury. Hydrophobic bile acids, such as deoxycholic acid, are known to cause cholestatic liver injury, and it was reported that expression of hepatic cytochrome P-450 (CYP) was reduced by deoxycholic acid administration in rats. Hydrophobic bile acids induce lipid peroxidation in the liver, and this may be one mechanism of the development of liver injury. In the present study, we investigated the effect of ebselen (30 mg/kg/day for 10 days) on rats ingesting deoxycholic acid (1% of diet for 10 days). Deoxycholic acid decreased levels of CYP1A1, 2B1, 2E1 and 3A2 to 34, 58, 62 and 37% of control values, respectively, and increased serum alkaline phosphatase (ALP) and alanine aminotransferase (ALT) activities to 1.8 and 8.6 times the levels of controls, respectively. Administration of ebselen with deoxycholic acid prevented the decreases in levels of CYP1A1 and 3A2 (86 and 65% of control, respectively) and the increases in serum ALP and ALT activities (1.4 and 1.9 times of control, respectively) caused by deoxycholic acid. These results indicate that ebselen may have a protective effect against hydrophobic bile acid-induced liver injury.

The effects of chelating agents (citric acid, tartaric acid, penicillamine and ethylenediaminetetraacetic acid) and cysteine on the absorption of HgCl2 were investigated in rats. Perfusion of the small intestine showed that the chelating agents and cysteine decreased the absorption of HgCl2 depending on their stability of constants with Hg2+, under the predominant conditions of water absorption and secretion. The difference in absorption of HgCl2 between both conditions was inversely correlated with their logarithmic stability constant values. These agents decreased the transport of HgCl2 through the everted intestinal wall and the uptake of HgCl2 by the intestinal brush border membrane in a similar manner. From these results, it is suggested that the chelating agents and cysteine decrease the absorption of HgCl2 through the pores of the brush border membrane due to the solvent drag effect.

To obtain evidence for difference in the absorptive forms of HgCl2 and HgO from duodenum, the Hg distributions after the duodenal administration of HgCl2 and HgO and the effect of Na2SeO3 on their Hg distributions were compared. The Hg concentrations in erythrocytes and liver 2 hr after the administration of HgCl2 were significantly lower and higher than those of HgO, respectively, but their Hg distributions at 3.5 or 5 hr became identical. The administration of Na2SeO3 (intravenously) 2 hr after the administration of HgCl2 and HgO resulted in significant differences in their Hg concentrations in plasma, erythrocytes and kidney at 3.5 or 5 hr. These results suggest that the absorptive form of HgCl2 from the duodenum differs from that of HgO and this difference is a cause for the marked difference in effect of Na2SeO3 on the Hg distributions of HgCl2 and HgO.

The transport of various inorganic mercuric compounds (HgX2s) was compared in everted intestinal sacs and intestinal brush border membrane vesicles (BBMV) of the rat. The preparations were incubated in a medium containing 10(-4) M HgX2 at pH 5.5, 6.4 or 7.4, respectively. The order of transport through the intestinal wall at each pH (HgOAc)2 greater than HgCl2 greater than Hg(SCN)2 greater than HgBr2 greater than Hg(CN)2) was the reverse order of their stability constants, and an increase in pH tended to increase the transport of HgX2. In the experiment with BBMV, similar results were obtained except for the transport of Hg(CN)2. These results suggest that the extent of transport of a certain HgX2 depends on its stability constant, and that the increase in pH promotes the transport possibly as a result of the conversion of HgX2 to Hg(OH)X and Hg(OH)2.

A correlation between absorption of organic mercuric compounds and their molecular weight or lipophilicity was investigated by the perfusion of rat small intestine. The intestine was perfused for 1.0 hr at different osmolarity and different pH with buffers containing 10(-4) M organic mercuric compounds, methyl mercuric chloride (MMC), phenyl mercuric chloride (PMC), p-chloromercuribenzoic acid (PCMB) and p-chloromercuriphenylsulfonic acid (PCMBS). The order of absorption of these compounds at several osmolarities and pHs (MMC greater than PMC greater than PCMB greater than PCMBS) was inversely correlated to their molecular weight. The increase in pH decreased markedly the absorption and n-octanol/water partition coefficient of PCMB, and it decreased scarcely those of MMC, PMC and PCMBS. The order of the coefficients at each pH was as follows; PMC greater than MMC greater than PCMB greater than PCMBS, in disagreement with the order of absorption. These results suggest that the molecular weight is more important factor in the intestinal absorption of organic mercuric compounds than the lipophilicity.

Composite effects of pH and halide ions on the transport of HgCl2 into brush border membrane vesicles (BBMV) were investigated in rats. BBMV were incubated for 10 min. in buffer solution at different pH containing 10(-4) M HgCl2. The increase in pH increased the uptake of Hg by BBMV as a result of the increase in transport of Hg into intravesicular space and decrease in binding of Hg to BBMV. The isotonic displacement of NaCl in the buffer solution by LiCl or KCl did not change the uptake of Hg at each pH. The displacement of NaCl by mannitol increased the uptake of Hg at each pH, while the displacement by NaBr or NaI decreased the uptake and diminished the increasing effect of pH on the uptake of Hg. These changes in uptake of Hg due to the displacement were mainly ascribed to the changes in transport of Hg. These results suggest that the increase in pH mainly increases the transport of HgCl2 as a result of the conversion to hydroxide forms of Hg such as Hg(OH)Cl and Hg(OH)2, and Cl- Br- and I- act as the competing ions with OH- and decrease the transport of Hg.

A correlation of mercury absorption with water absorption was investigated by using the perfusion of rat small intestine with buffers containing 10(-4) M HgCl2. With a decrease in the osmolarity of the buffers or with increases in the sodium ion and urea concentrations in the buffers, absorption of water and mercury and accumulation of mercury in the intestinal tissue increased, and the increases in mercury absorption and accumulation were found to correlate with the increase in water absorption. Both the decrease in osmolarity and the increase in sodium ion concentration increased mercury accumulation in the epithelial cell after the perfusion. But these changes did not alter the mercury distribution in subcellular fractions. The results suggest that the increase in water absorption due to the hyptonicity or the increase in concentration of sodium ion or urea increases the mercury absorption and accumulation in the epithelial cell without change in the distributional pattern of mercury in the cell.