REGULATION OF CYTOCHROME P4501A1 IN TELEOSTS - SUSTAINED INDUCTION OF CYP1A1 MESSENGER-RNA, PROTEIN, AND CATALYTIC ACTIVITY BY 2,3,7,8-TETRACHLORODIBENZOFURAN IN THE MARINE FISH STENOTOMUS CHRYSOPS
REGULATION OF CYTOCHROME P4501A1 IN TELEOSTS - SUSTAINED INDUCTION OF CYP1A1 MESSENGER-RNA, PROTEIN, AND CATALYTIC ACTIVITY BY 2,3,7,8-TETRACHLORODIBENZOFURAN IN THE MARINE FISH STENOTOMUS CHRYSOPS
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DOI：
10.1006/taap.1994.1153
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发表时间：
1994-08-01
影响因子：
3.8
通讯作者：
STEGEMAN, JJ
中科院分区：
文献类型：
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作者：
HAHN, ME;STEGEMAN, JJ
细胞色素P4501A1(细胞色素P4501A1)在包括鱼类在内的脊椎动物体内对致癌物和其他毒物的激活和解毒起着重要作用。虽然在哺乳动物系统中进行了广泛的研究，但对其他脊椎动物中CYP1A形式的调节知之甚少。我们研究了2，3，7，8-四氯二苯并呋喃(TCDF)诱导海水鱼黄胸藻(Stenotomus chrysops，Scup)细胞色素P1A1基因和蛋白表达的时程和剂量-反应关系。单次ip 2，3，7，8-TCDF(10nmol/kg)后，测定细胞色素P1A1的诱导时间。肝脏乙氧基间苯二酚O-脱乙基酶活性在治疗后1d开始升高，8d时达到最大值，14d后仍明显升高。肝脏中免疫可检测到的CYP1A1蛋白含量在第1天开始升高，并持续到第14天。心脏和鳃中的CYP1A1蛋白含量在给药后第2天开始显著升高，一直持续到第14天。肝脏中的CYP1A1基因在给药后第1天开始强烈诱导，并持续升高到第14天。2，3，7，8-TCDF对CYP1A1 mRNA的持续诱导与以前用非卤化诱导剂处理的鱼的瞬时诱导形成对比，很可能反映了诱导剂的持久性差异。剂量-反应研究表明，2，3，7，8-TCDF的剂量低至0.4nmol/kg(120 ng/kg)，在污染环境中测量到的这种同系物的全身含量范围内，就会诱导该同系物的基因、蛋白质和催化活性。在Scup中产生半最大诱导的估计剂量约为2-10nmoL/kg，这表明这些鱼对诱导的敏感性可能与大鼠一样大或更高。与之前用3，3‘，4，4’-四氯联苯(TCB)和β-萘黄酮(似乎抑制或灭活鱼类和其他脊椎动物中的CYP1A1)所获得的结果相反，在不同剂量的2，3，7，8-TCDF作用下，个体鱼类的CYP1A1 mRNA、蛋白质水平和催化活性之间存在很好的相关性。对2，3，7，8-TCDF和3，3‘，4，4’-TCB的反应差异可能反映了这两个化合物作为CYP1A1催化活性抑制剂的诱导效力的差异。在评估氯化二苯并呋喃诱导鱼类细胞色素P1A1的构效关系的其他研究中，用2，3，6，8-四氯二苯并呋喃(2，3，6，8-TCDF)处理Scup。在10或50nmol/kg时，2，3，6，8-TCDF不能作为CYP1A1 mRNA、蛋白或催化活性的诱导剂。总体而言，这些结果说明了在鱼类中诱导CYP1A1的时间和剂量依赖的方面，这些方面是高度诱导剂特异性的；结果还表明，CYP1A1调控的基本特征在鱼类和哺乳动物中似乎是保守的，这是两个差异很大的脊椎动物群体。(C)1994年学术出版社。
Cytochrome P4501A1 (CYP1A1) is known to play important roles in the activation and detoxification of carcinogens and other toxicants in vertebrate animals, including fish. Although extensively studied in mammalian systems, the regulation of CYP1A forms in other vertebrates is less well understood. We examined the time course and dose-response relationships for induction of CYP1A1 mRNA, protein, and catalytic activity by 2,3,7,8-tetrachlorodibenzofuran (TCDF) in the marine fish Stenotomus chrysops (scup). The time course of CYP1A1 induction was determined following a single ip dose (10 nmol/kg) of 2,3,7,8-TCDF. Hepatic ethoxyresorufin O-deethylase activity was increased after 1 day, reached a maximum by 8 days, and was still elevated 14 days after treatment. The content of immunodetectable CYP1A1 protein in liver was elevated on Day 1 and continued to increase through 14 days. CYP1A1 protein content was also strongly induced in heart and gill beginning at 2 days after treatment and extending through Day 14. Hepatic CYP1A1 mRNA was strongly induced by 1 day after dosing and remained elevated through 14 days. The sustained induction of CYP1A1 mRNA by 2,3,7,8-TCDF contrasts with the transient induction seen previously in fish treated with nonhalogenated inducers and most likely reflects differences in persistence of the inducers. Dose-response studies indicated that induction of CYP1A1 mRNA, protein, and catalytic activity occurred following doses of 2,3,7,8-TCDF as low as 0.4 nmol/kg (120 ng/kg), within the range of whole-body contents of this congener measured in fish from contaminated environments. The estimated dose producing half-maximal CYP1A1 induction in scup was approximately 2-10 nmol/kg, suggesting that the sensitivity of these fish to induction may be as great as or greater than that of rats. In contrast to previous results obtained with 3,3',4,4'-tetrachlorobiphenyl (TCB) and beta-naphthoflavone, which appear to inhibit or inactivate CYP1A1 in fish and other vertebrates, there was a good correlation among levels of CYP1A1 mRNA, protein, and catalytic activity in individual fish following various doses of 2,3,7,8-TCDF. The difference in response to 2,3,7,8-TCDF versus 3,3',4,4'-TCB may reflect differences in the inducing potencies of the two compounds relative to their similar potencies as inhibitors of CYP1A1 catalytic activity. In additional studies to evaluate structure-activity relationships for CYP1A1 induction by chlorinated dibenzofurans in fish, scup were treated with 2,3,6,8-tetrachlorodibenzofuran (2,3,6,8-TCDF). At 10 or 50 nmol/kg, 2,3,6,8-TCDF was inactive as an inducer of CYP1A1 mRNA, protein, or catalytic activity. Overall, these results illustrate temporal and dose-dependent aspects of CYP1A1 induction in fish that are highly inducer-specific; the results also indicate that fundamental features of CYP1A1 regulation appear to be conserved in fish and mammals, two widely divergent groups of vertebrates. (C) 1994 Academic Press, Inc.