Cytochrome p450 1B1 is required for 7,12-dimethylbenz(a)-anthracene (DMBA) induced spleen cell immunotoxicity
Cytochrome p450 1B1 is required for 7,12-dimethylbenz(a)-anthracene (DMBA) induced spleen cell immunotoxicity
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DOI：
10.1093/toxsci/kfi176
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发表时间：
2005-07-01
影响因子：
3.8
通讯作者：
Burchiel, SW
中科院分区：
文献类型：
--
作者：
Gao, J;Lauer, FT;Burchiel, SW
7,12-二甲基苯(a)蒽（DMBA）是一种强致癌物，可诱导小鼠和其他物种的体液免疫和细胞介导免疫的免疫抑制。先前的研究表明CYP1B1是DMBA对小鼠骨髓产生毒性所必需的。因此，本研究的目的是确定脾细胞免疫毒性是否需要CYP1B1。雌性C57BL/6N野生型（WT）和CYP1B1基因敲除（-/-）小鼠分别以0、17、50或150 mg/kg（累积剂量）的DMBA玉米油灌胃，每天1次，连续5天。一些免疫毒理学试验被用来评估DMBA对全身免疫的影响。其中包括使用直接斑块形成细胞（PFC）测定对绵羊红细胞（SRBC）的体外T依赖性抗体反应，Con a和LPS诱导的T和b细胞有丝分裂，以及使用NK细胞毒性测定评估非特异性细胞介导的免疫。此外，使用特定的细胞表面标记物，流式细胞术测量淋巴细胞亚群。DMBA治疗5天后，WT和CYP1B1（-/-）小鼠的体重和脾脏细胞表面标记物均无明显变化。在WT小鼠中，50mg /kg DMBA剂量的NK活性降低，但在CYP1B1（-/-）小鼠中没有。有趣的是，在150 mg/kg剂量的DMBA下，CYP1B1缺失的小鼠NK活性降低，而WT小鼠则没有。SRBC PFC反应表明，DMBA在WT小鼠中以剂量依赖的方式抑制IgM抗体反应（在50和150 mg/kg时显著）。然而，在CYP1B1（-/-）小鼠中，任何DMBA试验组的SRBC PFC反应均未发生变化。同样，在C57BL/6N WT小鼠中，50和150 mg/kg剂量水平的DMBA抑制了B细胞和t细胞的有丝分裂，但在CYP1B1（-/-）小鼠中未见影响。因此，CYP1B1似乎对小鼠DMBA的免疫抑制至关重要，这表明生物反应性代谢物在DMBA产生的脾细胞免疫毒性中发挥了作用。
7,12-Dimethylbenz(a)anthracene (DMBA) is a potent carcinogen that induces immunosuppression of both humoral and cell-mediated immunity in mice and other species. Previous studies have shown that CYP1B1 is required for bone marrow toxicity produced by DMBA in mice. Therefore, the purpose of these studies was to determine whether CYP1B1 was required for spleen cell immunotoxicity. Female C57BL/6N wild-type (WT) and CYP1B1 knockout (-/-) mice were treated with 0, 17, 50, or 150 mg/kg (cumulative dose) DMBA in corn oil by oral gavage once a day for five days. Several immunotoxicological assays were used to assess the effects of DMBA on systemic immunity. These included the in vitro T-dependent antibody response to sheep red blood cells (SRBC) measured using a direct plaque forming cell (PFC) assay, T- and B-cell mitogenesis induced by Con A and LPS, and nonspecific cell-mediated immunity was evaluated using an NK cytotoxicity assay. In addition, lymphocyte subpopulations were measured by flow cytometry using specific cell surface markers. Following five days of DMBA treatment, the body weights and spleen cell surface markers of the WT and CYP1B1 (-/-) mice showed no significant changes. A decrease in NK activity was found at the 50 mg/kg DMBA dose in WT mice, but not in the CYP1B1 (-/-) mice. Interestingly, at the 150 mg/kg dose of DMBA, CYP1B1 null mice had decreased NK activity, whereas WT mice did not. The SRBC PFC response demonstrated that the IgM antibody response was suppressed by DMBA in WT mice in a dose-dependent manner (significant at 50 and 150 mg/kg). However, there were no changes in the SRBC PFC responses in any DMBA test group in the CYP1B1 (-/-) mice. Similarly, while DMBA suppressed B- and T-cell mitogenesis at the 50 and 150 mg/kg dose levels in C57BL/6N WT mice, no effect was seen in CYP1B1 (-/-) mice. Thus, CYP1B1 appears to be critical for the immunosuppression of DMBA in mice, suggesting a role for bioreactive metabolites in the spleen cell immunotoxicity produced by DMBA.