Expression of CYP1C1 and CYP1A in Fundulus heteroclitus during PAH-induced carcinogenesis.
Expression of CYP1C1 and CYP1A in Fundulus heteroclitus during PAH-induced carcinogenesis.
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DOI：
10.1016/j.aquatox.2010.06.002
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发表时间：
2010-09
影响因子：
4.5
通讯作者：
Lu Wang;A. Camus;Wu Dong;C. Thornton;K. Willett
中科院分区：
文献类型：
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作者：
Lu Wang;A. Camus;Wu Dong;C. Thornton;K. Willett
CYP 1C 1是硬骨鱼细胞色素P450家族1中一个较新发现的成员。然而，CYP 1C 1的表达和生理作用相对于更公认的CYP 1A在多环芳烃（PAHs）诱导的毒性还不清楚。将孵化后6-8 d的异基底鱼（Fundulus heteroclitus）幼鱼分别暴露于二甲基亚砜（DMSO）对照、5 mg/L苯并[a]芘（BaP）或5 mg/L二甲基苯并蒽（DMBA）中6 h，然后在13- 15 d再次暴露。在第二次暴露后0、6、18、24和30 h处死鱼苗。在这些组中，CYP 1A和CYP 1C 1蛋白表达均在第二次暴露后6 h内诱导。免疫组化（IHC）结果显示，鱼苗最强的CYP 1C 1表达在肾小管和肠上皮细胞。在初次接触后8个月，对其他鱼类的肝脏病变进行了检查。在20%的BaP和35%的DMBA处理的鱼肝脏中观察到肉眼病变。组织学检查结果包括细胞改变和肿瘤，包括肝细胞腺瘤、肝细胞癌和胆管瘤。强CYP 1A免疫染色广泛检测到改变的细胞灶和肝细胞癌的浸润边缘。较低的CYP 1A表达见于肿瘤的中心区域。相反，CYP 1C 1仅在增殖的胆管上皮细胞中检测到并高度表达。我们的CYP 1C 1结果表明，组织特异性CYP 1C 1介导的PAH代谢的潜力，但不是一个更慢性的作用进展为肝细胞癌。
CYP1C1 is a relatively newly identified member of the cytochrome P450 family 1 in teleost fish. However, CYP1C1's expression and physiological roles relative to the more recognized CYP1A in polycyclic aromatic hydrocarbons (PAHs) induced toxicities are unclear. Fundulus heteroclitus fry were exposed at 6–8 days post-hatch (dph) and again at 13–15dph for 6h to dimethyl sulfoxide (DMSO) control, 5mg/L benzo[a]pyrene (BaP), or 5mg/L dimethylbenzanthracene (DMBA). Fry were euthanized at 0, 6, 18, 24 and 30h after the second exposure. In these groups, both CYP1A and CYP1C1 protein expression were induced within 6h after the second exposure. Immunohistochemistry (IHC) results from fry revealed strongest CYP1C1 expression in renal tubular and intestinal epithelial cells. Additional fish were examined for liver lesions 8 months after initial exposure. Gross lesions were observed in 20% of the BaP and 35% of the DMBA-treated fish livers. Histopathologic findings included foci of cellular alteration and neoplasms, including hepatocellular adenoma, hepatocellular carcinoma and cholangioma. Strong CYP1A immunostaining was detected diffusely in altered cell foci and on the invading margin of hepatocelluar carcinomas. Lower CYP1A expression was seen in central regions of the neoplasms. In contrast, CYP1C1 was only detectable and highly expressed in proliferated bile duct epithelial cells. Our CYP1C1 results suggest the potential for tissue specific CYP1C1-mediated PAH metabolism but not a more chronic role in progression to liver hepatocellular carcinoma.