Selenoxides inhibit delta-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 mono oxygenases (FMO) and selenoxides can regenerate selenides by thiol oxidatio n. Phenyl methyl selenide (PhSeCH3) and 1-hexynyl methyl selenide (C4H9C=CS eCH3) were converted to selenoxides by reaction with H2O2. PhSeCH3 and C4H9 C=CSeCH3 had no effect on delta -ALA-D up to 400 muM. Conversely, their sel enoxides inhibited delta -ALA-D, and the IC50 for enzyme inhibition was abo ut 100 and 70 muM, respectively. Partially purified delta -ALA-D (P-55) fro m swine liver was also inhibited by these selenoxides. The inhibitory actio n of selenoxides was antagonized by dithiotreitol (DTT). Moreover, delta -A LA-D fi om a plant source was inhibited by the selenoxides, suggesting a po ssible involvement of SH groups in a distinct site of the homologous region implicated in Zn2+ binding in mammalian delta -ALA-D. After exposure to Ph SeCH3 (500 mu mol/kg/day) for 45 or 30 days, the activity of delta -ALA-D f rom 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 selenox ides oxidized DTT. The results of the present study suggest that hepatic de lta -ALA-D of rodents is a potential molecular target for selenides as a co nsequence of their metabolism to selenoxides by FMO. (C) 2001 Elsevier Scie nce Ireland Ltd. All rights reserved.