TY - JOUR
T1 - Inhibition of δ-aminolevulinate dehydratase in trichloroethylene-exposed rats, and the effects on heme regulation
AU - Fujita, Hiroyoshi
AU - Koizumi, Akio
AU - Yamamoto, Masayuki
AU - Kumai, Miho
AU - Sadamoto, Tetsuo
AU - Ikeda, Masayuki
N1 - Funding Information:
The authors are grateful to Dr. N. Hayashi (the first Department of Biochemistry, Tohoku University School of Medicine) and Professor S. Sano (Department of Public Health, Kyoto University Faculty of Medicine) for their interest and fruitful discussions on this work. We also express our gratitude to Professor M. Watanabe, Drs. T. Omachi and H. Fujii (the Research Institute for Tuberculosis and Cancer, Tohoku University), Mr. and Mrs. Ohta (Laboratory for Radioisotopic Research, Tohoku University School of Medicine), Dr. R. Yamamoto (Department of Public Health, Tohoku University School of Medicine) and Mr. K. Sato (Kyoto Industrial Health Association) for their kindly support of this work. The work was supported by Scientific Research Fund of the Ministry of Education, Science and Culture of Japan (No. 58770391).
PY - 1984/7/16
Y1 - 1984/7/16
N2 - A pronounced and irreversible depression of the erythroid and liver δ-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 δ-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 to a reduction in the enzyme amount but to enzyme inhibition. The purified holoenzyme (fully activated δ-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 δ-aminolevulinate synthase (EC 2.3.1.37) increased. After exposure to trichloroethylene at 2.14 g/m3, urinary δ-aminolevulinic acid increased to 142% of the control, while the excretion of coproporphyrin was reduced to 19.6% of the control.
AB - A pronounced and irreversible depression of the erythroid and liver δ-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 δ-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 to a reduction in the enzyme amount but to enzyme inhibition. The purified holoenzyme (fully activated δ-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 δ-aminolevulinate synthase (EC 2.3.1.37) increased. After exposure to trichloroethylene at 2.14 g/m3, urinary δ-aminolevulinic acid increased to 142% of the control, while the excretion of coproporphyrin was reduced to 19.6% of the control.
KW - (Rat liver)
KW - Heme regulation
KW - Trichloroethylene exposure
KW - δ-Aminolevulinate dehydratase
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U2 - 10.1016/0304-4165(84)90087-4
DO - 10.1016/0304-4165(84)90087-4
M3 - Article
C2 - 6743680
AN - SCOPUS:0021163092
VL - 800
SP - 1
EP - 10
JO - Biochimica et Biophysica Acta - General Subjects
JF - Biochimica et Biophysica Acta - General Subjects
SN - 0006-3002
IS - 1
ER -