Farina M, Folmer V, Bolzan R C, Andrade L H, Zeni G, Braga A L, Rocha J B
Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, 97105-900, RS, Santa Maria, Brazil.
Toxicol Lett. 2001 Feb 3;119(1):27-37. doi: 10.1016/s0378-4274(00)00296-4.
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 (C4H9Ctriple bondCSeCH3) were converted to selenoxides by reaction with H2O2. PhSeCH3 and C4H9Ctriple bondCSeCH3 had no effect on delta-ALA-D up to 400 microM. Conversely, their selenoxides inhibited delta-ALA-D, and the IC(50) for enzyme inhibition was about 100 and 70 microM, 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 from 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 micromol/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 C4H9Ctriple bondCSeCH3 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.
研究了两种硒化物及其亚硒酸盐对成年大鼠肝脏δ-氨基乙酰丙酸脱水酶（δ-ALA-D）的影响。在体内，硒化物可被含黄素单加氧酶（FMO）氧化为亚硒酸盐，而亚硒酸盐可通过硫醇氧化再生为硒化物。苯甲基硒（PhSeCH3）和1-己炔基甲基硒（C4H9C≡CSeCH3）与H2O2反应可转化为亚硒酸盐。在高达400μM的浓度下，PhSeCH3和C4H9C≡CSeCH3对δ-ALA-D没有影响。相反，它们的亚硒酸盐抑制δ-ALA-D，酶抑制的IC(50)分别约为100μM和70μM。来自猪肝的部分纯化的δ-ALA-D（P(55)）也受到这些亚硒酸盐的抑制。亚硒酸盐的抑制作用可被二硫苏糖醇（DTT）拮抗。此外，来自植物源的δ-ALA-D也受到亚硒酸盐的抑制，这表明SH基团可能参与了哺乳动物δ-ALA-D中与Zn2+结合相关的同源区域的一个独特位点。在以500μmol/kg/天的剂量暴露于PhSeCH3 45天或30天后，小鼠肝脏中δ-ALA-D的活性降至对照组的约50%。该化合物的体内抑制作用不能被DTT拮抗。PhSeCH3和C4H9C≡CSeCH3对DTT的氧化速率没有影响，但它们的亚硒酸盐可氧化DTT。本研究结果表明，由于硒化物被FMO代谢为亚硒酸盐，啮齿动物肝脏中的δ-ALA-D是硒化物的一个潜在分子靶点。
