Effect of arsenite on induction of CYP1A and CYP2H in primary cultures of chick hepatocytes

被引:27
作者
Jacobs, J
Roussel, R
Roberts, M
Marek, D
Wood, S
Walton, H
Dwyer, B
Sinclair, P
Sinclair, J
机构
[1] Vet Adm Med Ctr, Res 151, White River Junction, VT 05009 USA
[2] Dartmouth Med Sch, Dept Biochem, Hanover, NH 03755 USA
[3] Dartmouth Med Sch, Dept Pharmacol Toxicol, Hanover, NH 03755 USA
[4] Dartmouth Med Sch, Dept Microbiol, Hanover, NH 03755 USA
关键词
D O I
10.1006/taap.1998.8436
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
In earlier studies, treatment with sodium arsenite was shown to decrease total hepatic CYP in rats. A concomitant increase in heme oxygenase, the rate-limiting step in heme degradation to biliverdin, was considered responsible for the decrease in CYP. Here we investigated the effect of sodium arsenite on induction of CYP2H, CYP1A, and heme oxygenase in primary cultures of chicken embryo hepatocytes. When added simultaneously with inducer, arsenite inhibited phenobarbital-mediated increases in CYP2H and 3-methylcholanthrene-mediated increases in CYP1A, as measured enzymatically and immunochemically. Near maximal decreases were observed in these forms of CYP at a concentration of 2.5 mu M sodium arsenite. The concentration-dependent decreases in CYP2H and CYP1A by sodium arsenite were concomitant with increases in heme oxygenase. Sodium arsenite was not toxic at concentrations as high as 10 mu M, as indicated by protein synthesis and the reduction of MTT by intact cells. Sodium arsenite had no effect on induction of CYP2H1 mRNA, suggesting that the decreases in this form of CYP occurred post-transcriptionally. Treatment of cells with tin mesoporphyrin (SnMeso), an inhibitor of heme oxygenase, resulted in inhibition of arsenite-induced heme oxygenase. However, SnMeso did not alter the effect of arsenite to prevent phenobarbital-mediated increases in CYP2H protein. SnMeso alone inhibited phenobarbital-mediated increases in CYP2H, Inclusion of 2 or 5 mu M exogenous heme with arsenite did not prevent the arsenite-mediated decrease in CYP2H. Combined treatment with heme and phenobarbital induced heme oxygenase to the same extent as treatment with heme, arsenite, and phenobarbital. However, CYP2H activity was decreased only when the treatment included arsenite. These results suggest that elevated levels of heme oxygenase alone are not responsible for arsenite-mediated decreases in CYP2H. (C) 1998 Academic Press.
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页码:376 / 382
页数:7
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