Effect of sodium arsenite on heme metabolism in cultured chick embryo hepatocytes.
We had previously reported that low concentrations of sodium arsenite (1-5 microM) decreased the induction of cytochrome P450 CYP1A and CYP2H in cultured chick embryo hepatocytes in parallel with increases in heme oxygenase. However, in those studies exogenous heme did not prevent the decrease in CYPs. In this study, we investigated the effect of arsenite on the synthesis and degradation of heme. Arsenite had no effect on induction of 5-aminolevulinic acid synthase mRNA or activity. Arsenite, at concentrations from 1 to 25 microM, had no effect on protoporphyrin synthesis from 5-aminolevulinic acid and did not increase the accumulation of other porphyrins, indicating that the enzymes in the pathway between 5-aminolevulinic acid synthase and ferrochelatase were unaffected by arsenite. Synthesis of heme from radioactive 5-aminolevulinic acid was slightly decreased (less than 20%) by 2.5 microM arsenite, a concentration that decreased induction of CYP1A and CYP2H by greater than 50%. Rates of biliverdin formation and degradation of exogenous heme were not different in cultures treated simultaneously with arsenite and heme or with heme alone. However, arsenite treatment increased biliverdin formation from heme synthesized from added 5-aminolevulinic acid by 60% and decreased the endogenous heme content of the cells by 30%. Our results suggest that although 2.5 microM arsenite induced heme oxygenase four- to sixfold, this had no effect on degradation of exogenous heme. Degradation of heme synthesized from 5-aminolevulinic acid was increased but this did not affect the regulatory heme pool.
Jacobs
J M
JM
Veterans Administration Medical Center, White River Junction, Vermont 05009, USA.
Marek
D
D
Walton
H S
HS
Sinclair
P R
PR
Sinclair
J F
JF
D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D018053:Arsenites / Q000494:pharmacology*; D002478:Cells, Cultured; D002642:Chick Embryo; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006418:Heme / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D011166:Porphyrins / Q000378:metabolism; D017670:Sodium Compounds / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
D018053:Arsenites; D011166:Porphyrins; D017670:Sodium Compounds; D006418:Heme; C017947:sodium arsenite; D003577:Cytochrome P-450 Enzyme System; D000624:5-Aminolevulinate Synthetase