Selenoxides inhibit δ-aminolevulinic acid dehydratase

The effect of two selenides and their selenoxides on delta -aminolevulinic acid dehydratase (delta -ALA-D) from liver of adult rats was investigated. In vivo, selenides can be oxidized to selenoxides by flavin-containing monooxygenases (FMO) and selenoxides can regenerate selenides by thiol oxidation. Phenyl methyl selenide (PhSeCH3) and 1-hexynyl methyl selenide (C4H9C=CSeCH3) were converted to selenoxides by reaction with H2O2. PhSeCH3 and C4H9C=CSeCH3 had no effect on delta -ALA-D up to 400 muM. Conversely, their selenoxides inhibited delta -ALA-D, and the IC50 for enzyme inhibition was about 100 and 70 muM, respectively. Partially purified delta -ALA-D (P-55) from swine liver was also inhibited by these selenoxides. The inhibitory action of selenoxides was antagonized by dithiotreitol (DTT). Moreover, delta -ALA-D fi om a plant source was inhibited by the selenoxides, suggesting a possible involvement of SH groups in a distinct site of the homologous region implicated in Zn2+ binding in mammalian delta -ALA-D. After exposure to PhSeCH3 (500 mu mol/kg/day) for 45 or 30 days, the activity of delta -ALA-D from liver of mice decreased to about 50%, of the control group. The in vivo inhibitory action of this compound was not antagonized by DTT. PhSeCH3 and C4H9C=CSeCH3 had no effect on the rate of DTT oxidation, but their selenoxides oxidized DTT. The results of the present study suggest that hepatic delta -ALA-D of rodents is a potential molecular target for selenides as a consequence of their metabolism to selenoxides by FMO. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.