Inhibition of delta-aminolevulinate dehydratase in trichloroethylene-exposed rats, and the effects on heme regulation.
A pronounced and irreversible depression of the erythroid and liver delta-aminolevulinate dehydratase (porphobilinogen synthase; 5-aminolevulinate hydro-lyase, EC 4.2.1.24) activity was observed in rats exposed to trichloroethylene, a widely used solvent. The depression could not be restored after the treatment with dithiothreitol and zinc; however, radioimmunoassay of delta-aminolevulinate dehydratase indicated that trichloroethylene exposure did not essentially decrease the amount of enzyme. The depression of the enzyme activity thus proved to be due not to a reduction in the enzyme amount but to enzyme inhibition. The purified holoenzyme (fully activated delta-aminolevulinate dehydratase with 1 atom zinc per subunit) and apoenzyme (fully activated enzyme with the remaining zinc less than 0.1 atom per subunit) were prepared to investigate the in vitro inhibition of the enzyme by trichloroethylene. Incubation with trichloroethylene did not inhibit the holoenzyme, but inhibited the apoenzyme dose-dependently. Trichloroethylene inhibited the holoenzyme when incubated with the mixed function oxidase system. The in vitro experiments reported here indicate two mechanisms of the enzyme inhibition by trichloroethylene. In the liver of rats exposed to trichloroethylene, cytochrome P-450 concentration and heme saturation of tryptophan pyrrolase (EC 1.13.11.11) are reduced; in addition, the activity of delta-aminolevulinate synthase (EC 2.3.1.37) increased. After exposure to trichloroethylene at 2.14 g/m3, urinary delta-aminolevulinic acid increased to 142% of the control, while the excretion of coproporphyrin was reduced to 19.6% of the control.
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000201:enzymology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004229:Dithiothreitol / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology*; D006418:Heme / Q000378:metabolism*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009249:NADP / Q000494:pharmacology; D000623:Porphobilinogen Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D014241:Trichloroethylene / Q000633:toxicity*; D014366:Tryptophan Oxygenase / Q000378:metabolism
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014241:Trichloroethylene; D006418:Heme; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D014366:Tryptophan Oxygenase; D000623:Porphobilinogen Synthase; D004229:Dithiothreitol