Sinal C J, Webb C D, Bend J R
Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada.
J Biochem Mol Toxicol. 1999;13(1):29-40. doi: 10.1002/(sici)1099-0461(1999)13:1<29::aid-jbt4>3.0.co;2-x.
Male Sprague-Dawley rats were treated intraperitoneally with corn oil, the aryl hydrocarbon receptor (AHR) agonist beta-naphthoflavone (betaNF), or the relatively weak AHR agonist alpha-naphthoflavone (alphaNF). Animals treated with betaNF experienced a significant loss (12%) of total body mass over 5 days and a dramatic elevation of CYP1A1 mRNA in all of the organs studied. Treatment with alphaNF had no significant effect on body mass after 5 days and caused only minor increases of liver, kidney, and heart CYP1A1 mRNA. In contrast, lung CYP1A1 mRNA was increased by alphaNF treatment to levels comparable to that seen with betaNF treatment. CYP2E1 mRNA levels were also elevated in liver, lung, kidney, and heart in response to betaNF treatment, whereas alphaNF was without effect. Large increases of CYP1Al-dependent 7-ethoxyresorufin O-deethylation (EROD) activity occurred with microsomes prepared from the tissues of betaNF-treated animals. Comparatively small changes were associated with alphaNF treatment, with the exception of lung, where EROD activity was increased to approximately 60% of that with betaNF treatment. CYP2E1-dependent p-nitrophenol hydroxylase (PNP) activity was also increased by betaNF treatment in microsomes prepared from kidney (3.1-fold), whereas alphaNF was without effect. In contrast, alphaNF or betaNF treatment caused significant decreases of lung microsomal PNP (72% and 27% of corn oil control, respectively) and 7-pentoxyresorufin O-deethylation (48% and 17% of corn oil control, respectively) activities, indicating that PNP activity may be catalyzed by P450 isoforms other than CYP2E1 in rat lung. We conclude that betaNF and alphaNF have differential effects on the expression and catalytic activity of CYP1A1 and CYP2E1, depending upon the organ studied. These changes most likely occur as a result of the direct actions of these compounds as AHR agonists, in addition to secondary effects associated with AHR-mediated toxicity.
将雄性斯普拉格-道利大鼠腹腔注射玉米油、芳烃受体（AHR）激动剂β-萘黄酮（βNF）或相对较弱的AHR激动剂α-萘黄酮（αNF）。用βNF处理的动物在5天内体重显著下降（12%），并且在所有研究的器官中CYP1A1 mRNA急剧升高。用αNF处理5天后对体重没有显著影响，仅使肝脏、肾脏和心脏的CYP1A1 mRNA略有增加。相比之下，αNF处理使肺CYP1A1 mRNA增加到与βNF处理相当的水平。βNF处理还使肝脏、肺、肾脏和心脏中的CYP2E1 mRNA水平升高，而αNF则无此作用。用βNF处理的动物组织制备的微粒体中，CYP1Al依赖性7-乙氧基异吩恶唑酮O-脱乙基酶（EROD）活性大幅增加。αNF处理引起的变化相对较小，但肺除外，肺中的EROD活性增加到βNF处理的约60%。βNF处理还使肾脏制备的微粒体中CYP2E1依赖性对硝基苯酚羟化酶（PNP）活性增加（3.1倍），而αNF则无此作用。相比之下，αNF或βNF处理导致肺微粒体PNP（分别为玉米油对照的72%和27%）和7-戊氧基异吩恶唑酮O-脱乙基酶（分别为玉米油对照的48%和17%）活性显著降低，表明PNP活性可能由大鼠肺中CYP2E1以外的P450同工酶催化。我们得出结论，βNF和αNF对CYP1A1和CYP2E1的表达和催化活性具有不同的影响，这取决于所研究的器官。这些变化很可能是这些化合物作为AHR激动剂的直接作用的结果，此外还与AHR介导的毒性相关的继发效应有关。
