Sadar M D, Blomstrand F, Andersson T B
Department of Zoophysiology, University of Göteborg, Sweden.
Biochem Biophys Res Commun. 1996 Aug 14;225(2):455-61. doi: 10.1006/bbrc.1996.1194.
Phenobarbital (PB) induces CYP1A1 at the transcriptional level and causes nuclear translocation of the aromatic hydrocarbon (Ah) receptor in primary cultures of rainbow trout hepatocytes (1). The results from this study suggest that PB induction of CYP1A1 in rainbow trout hepatocytes is regulated by cAMP-dependent pathways (PKA), whereas TCDD induction is not dependent upon PKA. Epinephrine, which increases cAMP levels and activates PKA-dependent pathways, was a potent inhibitor of PB induction, while having no effect on TCDD induction of CYP1A1 gene expression. When PKA-dependent pathways were inhibited, PB induction of CYP1A1 gene expression was greatly potentiated, whereas TCDD induction was affected to a lesser extent. Inhibitors of calcium-phospholipid-dependent protein kinase (PKC) had modest or no effect on PB and TCDD induction of CYP1A1, respectively. Whether the relatively weak-to-no inhibition of CYP1A1 in response to PKC inhibitors in fish is due to differences in the types and levels of PKC isoenzymes, cell permeability, protocol, or the role of PKC in the mechanism of CYP1A1 induction in fish remains to be established. PB induced persistent and transient increases in the intracellular calcium concentration. This may be an important factor regulating PKC which may have a role in PB-mediated induction of CYP1A1 gene transcription.
苯巴比妥（PB）在转录水平诱导细胞色素P450 1A1（CYP1A1），并导致虹鳟鱼肝细胞原代培养物中芳烃（Ah）受体的核转位（1）。本研究结果表明，PB对虹鳟鱼肝细胞中CYP1A1的诱导受环磷酸腺苷（cAMP）依赖性途径（蛋白激酶A，PKA）调控，而2,3,7,8-四氯二苯并对二恶英（TCDD）诱导则不依赖PKA。肾上腺素可提高cAMP水平并激活PKA依赖性途径，它是PB诱导的强效抑制剂，而对CYP1A1基因表达的TCDD诱导无影响。当PKA依赖性途径受到抑制时，PB对CYP1A1基因表达的诱导作用大大增强，而TCDD诱导受到的影响较小。钙磷脂依赖性蛋白激酶（PKC）抑制剂分别对PB和TCDD诱导CYP1A1的作用有适度影响或无影响。鱼类中PKC抑制剂对CYP1A1的抑制作用相对较弱或无抑制作用，这是由于PKC同工酶的类型和水平、细胞通透性、实验方案的差异，还是PKC在鱼类CYP1A1诱导机制中的作用，仍有待确定。PB诱导细胞内钙浓度持续和短暂升高。这可能是调节PKC的一个重要因素，而PKC可能在PB介导的CYP1A1基因转录诱导中发挥作用。
