Effect of lindane and heptachlor on delta-aminolaevulinate synthase and its regulation.

ABSTRACT

The effect of lindane and heptachlor on haem metabolism was studied with the aim to elucidate the mechanism of their porphyrinogenic action. The effects of these compounds on delta-aminolaevulinate synthase (ALA-S) and ferrochelatase were evaluated and the mechanism of increase of ALA-S activity was especially studied. The results indicated the following (1) Lindane and heptachlor produced increases in ALA-S activity; this effect was dependent on the drug dose, the time of treatment, and the development of the animal, the maximum response being obtained prior to hatching. Lindane was observed to have a greater effect on ALA-S than heptachlor. In fact, when effects of lindane and heptachlor were compared we observed that lindane produced (a) greater increases in ALA-S activity (six fold vs four fold), both with respect to dimethyl sulphoxide (DMSO) controls (3.8+/-0.3 nmol ALA/g liver per h); (b) earlier ALA-S response (1.5 h vs 4 h); (c) responses at lower doses (0.3 mg/egg vs 1 mg/egg). (2) The increase in ALA-S activity produced by lindane or heptachlor is an induction and not an activation process since it depends on protein synthesis and the drugs per se have no effect. Thus, our results obtained from studies in ovo with actinomycin D and cycloheximide suggest that lindane is acting at the translational level while heptachlor interferes at the level of transcription. (3) The study of ALA-S subcellular distribution indicated no accumulation in the cytosol of DMSO controls and in the lindane or heptachlor treated embryos, neither of the chlorinated pesticides alter the normal subcellular distribution of this regulatory enzyme in the liver. (4) Exogenous haem was able to prevent or decrease the induction of ALA-S elicited by both pesticides, thus showing that lindane or heptachlor-induced ALA-S respond to haem regulation. (5) Lindane had no effect on ferrochelatase activity at the doses and times assayed, but heptachlor decreased this enzyme activity. The porphyrinogenic mechanism of lindane and heptachlor is discussed on the basis of the present results.