Human T cells are highly sensitive to suppression of mitogenesis by polycyclic aromatic hydrocarbons and this effect is differentially reversed by alpha-naphthoflavone
Human T cells are highly sensitive to suppression of mitogenesis by polycyclic aromatic hydrocarbons and this effect is differentially reversed by alpha-naphthoflavone
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DOI：
10.1006/taap.1996.0173
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发表时间：
1996-08-01
影响因子：
3.8
通讯作者：
Burchiel, SW
中科院分区：
文献类型：
--
作者：
Davila, DR;Romero, DL;Burchiel, SW
多环芳烃（PAHs）对啮齿类动物体内和体外免疫反应的抑制作用已被广泛报道。然而，很少有研究涉及多环芳烃在人体系统中的免疫毒性。在这份报告中，我们研究了9种不同的多环芳烃对人类外周血T细胞有丝分裂的毒性作用。结果表明，苯并（a）芘（BaP）、3-甲基胆蒽（3-MC）和7，12-二甲基苯并（a）蒽（DMBA）对人体具有高度免疫毒性，二苯并（a，c）蒽（DAC）和二苯并（a，h）蒽（DAH）对人体具有中等毒性，9，10-二甲基蒽（DMA）、苯并（e）芘（BeP）和苯并（a）蒽（BA）对人体具有轻度免疫毒性。和蒽（ANTH）在测试浓度下没有可测量的毒性。我们的研究结果使用人类淋巴细胞不同于以往的研究在啮齿类动物中，BaP和3-MC是最具免疫毒性的多环芳烃在人类有丝分裂试验，而DMBA一直被认为是最有效的毒性多环芳烃啮齿类动物的T细胞反应。我们还表明，α-萘甲酮（ANF），这既是一个Ah受体拮抗剂和细胞色素P450活性的抑制剂，能够阻断BaP和DMBA的抑制作用，但不能3-MC。这表明3-MC的免疫毒性可能是通过与BaP或DMBA不同的机制介导的。将四种不同的BaP代谢物直接加入人单核细胞培养物中，结果表明，7，8-dihydrodiol代谢物毒性最强，这种毒性可被等摩尔浓度和10倍浓度的ANF完全阻断。7，8-二氢二醇代谢产物可能进一步代谢为7，8-二醇环氧化物，其毒性不能被ANF有效逆转。4，5-环氧化物代谢物在高浓度（10 μ M）下明显具有细胞毒性，而7-羟基代谢物对增殖没有明显的负面影响。(C)出版社：Academic Press，Inc.
The immunosuppressive effects of polycyclic aromatic hydrocarbons (PAHs) on immune responses in rodents, both in vivo and in vitro, have been widely documented. However, few studies have addressed the immunotoxicity of PAHs in the human system. In this report, we examined the toxic effects of nine different PAHs on human peripheral blood T cell mitogenesis. We found that benzo(a)pyrene (BaP), 3-methylcholanthrene (3-MC), and 7,12-dimethylbenz(a)anthracene (DMBA) were highly immunotoxic in the human system, while dibenz(a,c)anthracene (DAC) and dibenz(a,h)anthracene (DAH) were of intermediate toxicity, 9,10-dimethylanthracene (DMA), benzo(e)pyrene (BeP), and benz(a)anthracene (BA) were mildly immunotoxic, and anthracene (ANTH) had no measureable toxicity at the concentrations tested. Our results using human lymphocytes differed from previous studies in rodents, in that BaP and 3-MC were the most immunotoxic PAHs in the human mitogenesis assay, while DMBA has long been regarded as the PAH that is most potently toxic to rodent T cell responses. We also showed that alpha-naphthoflavone (ANF), which functions as both an Ah receptor antagonist and an inhibitor of cytochrome P450 activity, was able to block the suppressive effects of both BaP and DMBA, but not 3-MC. This suggests that the immunotoxicity of 3-MC may be mediated through a different mechanism than BaP or DMBA. Addition of four different BaP metabolites directly to cultures of human mononuclear cells showed that the 7,8-dihydrodiol metabolite was the most toxic, and that this toxicity could be completely blocked by equimolar and 10-fold greater concentrations of ANF. The 7,8-dihydrodiol metabolite was probably further metabolized to the 7,8-diol epoxide, the toxicity of which could not be effectively reversed by ANF. The 4,5-epoxide metabolite was apparently cytotoxic at high concentrations (10 mu M), while the 7-hydroxy metabolite had no overtly negative effects on proliferation. (C) 1996 Academic Press, Inc.