Mercado C, Molina F, Navas J, Quiñones C, Eylar E H
Department of Biochemistry, Ponce School of Medicine, Puerto Rico 00732.
Biochem Pharmacol. 1991 Feb 15;41(4):503-8. doi: 10.1016/0006-2952(91)90621-b.
A group of nitrofurans (5-nitro-2-furaldehyde, nifuroxime, nitrofurazone, nitrofurantoin, 5-nitro-2-furoic acid and 2-nitrofuran) were evaluated for inhibition of mitogenesis (DNA synthesis) in human peripheral blood T cells. T cells, either triggered by phorbol myristate acetate (PMA) or in the presence of accessory cells, were activated with a specified mitogen [phytohemagglutin (PHA), concanavalin A (ConA), or anti-CD3] and the amount of tritiated thymidine incorporated into DNA was determined. The results obtained indicate that nitrofurans inhibit mitogenesis irrespective of activator. 5-Nitro-2-furaldehyde was much more inhibitory than the other compounds, while 2-nitrofuran was less inhibitory. When the aldehyde group (5-nitro-2-furaldehyde) was replaced by a carboxyl group (5-nitro-2-furoic acid), the inhibitory activity was also reduced greatly. These results show that while the nitro group alone confers inhibitory activity to the furan ring, the group at the 2 position is crucial. In general, the mitogenic response of purified T cells (lacking accessory cells) triggered by PMA (phorbol ester) was inhibited less than that of the T cell-accessory cell system. With the latter, 50% inhibition of T cell mitogenesis was achieved by nifuroxime, nitrofurazone, and nitrofurantoin at 45-51 and 34-39 microM with PHA and ConA respectively. When purified T cells were used, the values were 71-85 and 55-60 microM respectively. For a given drug concentration, mitogenesis was more inhibited when induced by ConA or anti-CD3 than by PHA. The importance of using a single cell system (purified T cells) was emphasized by the interesting finding that only this system showed enhancement of mitogenesis, up to 35-40% at low drug levels. With the exception of the nitrofuraldehyde, the nitrofurans at strongly inhibitory levels were only moderately cytotoxic, exhibiting 62-85% cell survival after exposure to drug for 68 hr. Our results suggest that nitrofurans inhibit T cell mitogenesis by a relatively non-toxic mechanism; these results are comparable to those obtained for mammalian cells under aerobic conditions.
评估了一组硝基呋喃（5-硝基-2-糠醛、硝呋辛、呋喃西林、呋喃妥因、5-硝基-2-呋喃甲酸和2-硝基呋喃）对人外周血T细胞有丝分裂（DNA合成）的抑制作用。T细胞，无论是由佛波酯肉豆蔻酸乙酸酯（PMA）触发还是在辅助细胞存在的情况下，都用特定的促有丝分裂原[植物血凝素（PHA）、刀豆球蛋白A（ConA）或抗CD3]激活，并测定掺入DNA中的氚标记胸腺嘧啶核苷的量。所得结果表明，无论激活剂如何，硝基呋喃均抑制有丝分裂。5-硝基-2-糠醛的抑制作用比其他化合物强得多，而2-硝基呋喃的抑制作用较弱。当醛基（5-硝基-2-糠醛）被羧基（5-硝基-2-呋喃甲酸）取代时，抑制活性也大大降低。这些结果表明，虽然仅硝基赋予呋喃环抑制活性，但2位的基团至关重要。一般来说，由PMA（佛波酯）触发的纯化T细胞（缺乏辅助细胞）的有丝分裂反应受到的抑制比T细胞-辅助细胞系统小。对于后者，硝呋辛、呋喃西林和呋喃妥因分别在45 - 51μM（PHA）和34 - 39μM（ConA）时可实现50%的T细胞有丝分裂抑制。当使用纯化T细胞时，相应的值分别为71 - 85μM和55 - 60μM。对于给定的药物浓度，由ConA或抗CD3诱导的有丝分裂比由PHA诱导的受到的抑制更大。使用单细胞系统（纯化T细胞）的重要性通过一个有趣的发现得到强调，即只有这个系统显示出有丝分裂增强，在低药物水平下可达35 - 40%。除了硝基糠醛外，处于强抑制水平的硝基呋喃只有中度细胞毒性，在接触药物68小时后细胞存活率为62 - 85%。我们的结果表明，硝基呋喃通过一种相对无毒的机制抑制T细胞有丝分裂；这些结果与在有氧条件下对哺乳动物细胞获得的结果相当。
