Chaloupka K, Steinberg M, Santostefano M, Rodriguez L V, Goldstein L, Safe S
Texas A & M University, College Station 77843-4466, USA.
Chem Biol Interact. 1995 Jun 14;96(3):207-21. doi: 10.1016/0009-2797(94)03586-w.
The potential non-additive interactions of polynuclear aromatic hydrocarbon (PAH) mixtures as inducers of Cyp1a-1 and Cyp1a-2 gene expression were investigated in B6C3F1 mice using a reconstituted PAH mixture. The chemical composition (% by weight) of the reconstituted PAH mixture was: 2-ring PAHs--indan (0.22), naphthalene (23.8), 2-methylnaphthalene (23.2) and 1-methylnaphthalene (13.3); 3-ring PAHs--acenaphthylene (7.7), acenaphthene (0.6), dibenzofuran (0.7), fluorene (4.3), phenanthrene (10.5) and anthracene (3.4); > or = 4-ring PAHs--fluoranthene (2.4), pyrene (4.3), benz[a]anthracene (1.4), chrysene (1.5), benzo[b]fluoranthene (0.8), benzo[k]fluoranthene (0.9) and benzo[a]pyrene (0.9). The composition of the 2-, 3- and > or = 4-ring PAH fractions were based on the relative concentration of individual PAHs as noted above. The > or = 4-ring PAH fractions were based on the relative concentration of individual PAHs as noted above. The > or = 4-ring PAH fraction and reconstituted mixture induced hepatic microsomal ethoxyresorufin O-deethylase (EROD) activity and Cyp1a-1 mRNA levels, whereas the 2- and 3-ring PAHs were only weakly active. Direct comparison of the potencies of the reconstituted mixture and > or = 4-ring PAHs showed that the Cyp1a-1 induction activity of the reconstituted mixture was due to the > or = 4-ring PAHs. The reconstituted PAH mixture and > or = 4-ring PAHs also induced Cyp1a-2 hepatic mRNA levels and microsomal methoxyresorufin O-deethylase (MROD) activity; however, their dose-response curves indicated that the reconstituted PAH mixture was more potent as a Cyp1a-2 inducer than the > or = 4 ring PAHs. The differences in potency were due to 3-ring PAHs which were found to be strong inducers of hepatic Cyp1a-2 mRNA levels and microsomal MROD activity at the lowest dose administered (37 mg/kg). The 3-ring mixture caused a maximal 29-fold increase in hepatic MROD activity at a dose of 292 mg/kg, but only 28% of maximal induction of EROD activity. Northern analysis of liver mRNA from mice treated with 3-ring PAHs showed that there was minimal induction of Cyp1a-1 mRNA levels. The 3-ring PAHs did not competitively bind to the mouse hepatic cytosolic aryl hydrocarbon (Ah) receptor suggesting that 3-ring PAHs are a new class of Cyp1a-2 inducers which do not act through the Ah receptor.
使用重组多环芳烃（PAH）混合物，在B6C3F1小鼠中研究了多环芳烃混合物作为Cyp1a - 1和Cyp1a - 2基因表达诱导剂的潜在非加性相互作用。重组PAH混合物的化学组成（重量百分比）为：二环PAHs——茚满（0.22）、萘（23.8）、2 - 甲基萘（23.2）和1 - 甲基萘（13.3）；三环PAHs——苊烯（7.7）、苊（0.6）、二苯并呋喃（0.7）、芴（4.3）、菲（10.5）和蒽（3.4）；≥四环PAHs——荧蒽（2.4）、芘（4.3）、苯并[a]蒽（1.4）、 Chrysene（1.5）、苯并[b]荧蒽（0.8）、苯并[k]荧蒽（0.9）和苯并[a]芘（0.9）。二环、三环和≥四环PAH馏分的组成基于上述各PAHs的相对浓度。≥四环PAH馏分基于上述各PAHs的相对浓度。≥四环PAH馏分和重组混合物诱导肝微粒体乙氧基异吩恶唑酮O - 脱乙基酶（EROD）活性和Cyp1a - 1 mRNA水平，而二环和三环PAHs活性较弱。重组混合物和≥四环PAHs效力的直接比较表明，重组混合物的Cyp1a - 1诱导活性归因于≥四环PAHs。重组PAH混合物和≥四环PAHs也诱导Cyp1a - 2肝mRNA水平和微粒体甲氧基异吩恶唑酮O - 脱乙基酶（MROD）活性；然而，它们的剂量反应曲线表明，重组PAH混合物作为Cyp1a - 2诱导剂比≥四环PAHs更有效。效力差异归因于三环PAHs，在最低给药剂量（37 mg/kg）时，三环PAHs被发现是肝Cyp1a - 2 mRNA水平和微粒体MROD活性的强诱导剂。三环混合物在剂量为292 mg/kg时使肝MROD活性最大增加29倍，但仅为EROD活性最大诱导的28%。对用三环PAHs处理的小鼠肝脏mRNA的Northern分析表明，Cyp1a - 1 mRNA水平的诱导最小。三环PAHs不与小鼠肝细胞质芳烃（Ah）受体竞争性结合，表明三环PAHs是一类新的Cyp
