Munday R, Smith B L, Munday C M
AgResearch, Ruakura Agricultural Research Centre, Hamilton, New Zealand.
Chem Biol Interact. 1999 Dec 15;123(3):219-37. doi: 10.1016/s0009-2797(99)00138-6.
It has previously been shown that rats pre-treated with butylated hydroxyanisole (BHA), a well-known inducer of the enzyme DT-diaphorase, are protected against the toxic effects of 2-methyl-1,4-naphthoquinone but are made more susceptible to the harmful action of 2-hydroxy-1,4-naphthoquinone. In the present experiments, the effects of BHA have been compared with those of other inducers of DT-diaphorase. Rats were dosed with BHA, butylated hydroxytoluene (BHT), ethoxyquin (EQ), dimethyl fumarate (DMF) or disulfiram (DIS) and then challenged with a toxic dose of the naphthoquinones. All the inducers protected against the haemolytic anaemia induced by 2-methyl-1,4-naphthoquinone in rats, with BHA, BHT and EQ being somewhat more effective than DMF and DIS. A similar order of activity was recorded in the relative ability of these substances to increase hepatic activities of DT-diaphorase, consistent with a role for this enzyme in facilitating conjugation and excretion of this naphthoquinone. In contrast, all the compounds increased the haemolytic activity of 2-hydroxy-1,4-naphthoquinone. DMF and DIS were significantly more effective in this regard than BHA, BHT and EQ. DMF and DIS also caused a much greater increase in levels of DT-diaphorase in the intestine, suggesting that 2-hydroxy-1,4-naphthoquinone is activated by this enzyme in the gut. BHA, BHT and EQ had no effect on the nephrotoxicity of 2-hydroxy-1,4-naphthoquinone, but the severity of the renal lesions was decreased in rats pre-treated with DMF and DIS. The results of the present experiments show that modulation of tissue levels of DT-diaphorase may not only alter the severity of naphthoquinone toxicity in vivo, but may also change the relative toxicity of these substances to different target organs.
先前的研究表明，用丁基羟基茴香醚（BHA）预处理的大鼠可免受2-甲基-1,4-萘醌的毒性作用，BHA是一种著名的酶DT-黄递酶诱导剂，但却会使其对2-羟基-1,4-萘醌的有害作用更敏感。在本实验中，将BHA的作用与其他DT-黄递酶诱导剂的作用进行了比较。给大鼠服用BHA、丁基羟基甲苯（BHT）、乙氧喹（EQ）、富马酸二甲酯（DMF）或双硫仑（DIS），然后用萘醌的毒性剂量进行攻击。所有诱导剂都能保护大鼠免受2-甲基-1,4-萘醌诱导的溶血性贫血，其中BHA、BHT和EQ比DMF和DIS更有效。在这些物质增加肝脏DT-黄递酶活性的相对能力方面也记录到了类似的活性顺序，这与该酶在促进这种萘醌的结合和排泄中的作用一致。相反，所有化合物都增加了2-羟基-1,4-萘醌的溶血活性。在这方面，DMF和DIS比BHA、BHT和EQ显著更有效。DMF和DIS还使肠道中DT-黄递酶水平的升高幅度大得多，这表明2-羟基-1,4-萘醌在肠道中被该酶激活。BHA、BHT和EQ对2-羟基-1,4-萘醌的肾毒性没有影响，但用DMF和DIS预处理的大鼠肾损伤的严重程度降低。本实验结果表明，调节DT-黄递酶的组织水平不仅可能改变体内萘醌毒性的严重程度，还可能改变这些物质对不同靶器官的相对毒性。
