Damon M, Fautrel A, Guillouzo A, Corcos L
Faculté de Pharmacie, Université de Rennes I, France.
Biochem J. 1996 Jul 15;317 ( Pt 2)(Pt 2):481-6. doi: 10.1042/bj3170481.
The aim of this study was to investigate the effect of the genetic background on the phenobarbital inducibility of cytochrome P-450 2b-9, cytochrome P-450 2b-10 and aldehyde dehydrogenase type 2 mRNAs in mice. We analysed the basal expression and the phenobarbital inducibility of both cytochrome P-450 mRNAs by semi-quantitative specific reverse transcription-PCR analyses in five inbred mouse strains (A/J,BALB/cByJ,C57BL/6J, DBA/2J and SWR/J). Male mice constitutively expressed cytochrome P-450 2b-9 and cytochrome P-450 2b-10 mRNAs, but a number of differences in their response to phenobarbital were observed. In all these mouse strains, phenobarbital induced cytochrome P-450 2b-10 mRNA whereas it could have either a positive or a negative effect on cytochrome P-450 2b-9 expression, depending on the strain and the sex of the mice. Specifically, phenobarbital increased cytochrome P-450 2b-9 expression in C57BL/6J males while it decreased it in DBA/2J mice. Interestingly, dexamethasone was able to mimic the phenobarbital effect on both cytochromes P-450 in these two strains. Aldehyde dehydrogenase type 2 mRNA was always induced by phenobarbital, except in the C57BL/6J strain. Genetic analysis revealed that the phenobarbital-inducible phenotype was either a semi-dominant or a recessive trait in F1 animals from a C57BL/6J x DBA/2J cross for the cytochrome P-450 2b-9 and the aldehyde dehydrogenase type 2 genes, respectively. This study suggests that the genetic basis for phenobarbital induction in mice depends on the target gene, and that more than one regulatory step would by involved in this response pathway.
本研究旨在探讨遗传背景对小鼠细胞色素P-450 2b-9、细胞色素P-450 2b-10和2型醛脱氢酶mRNA的苯巴比妥诱导性的影响。我们通过半定量特异性逆转录-PCR分析，在五个近交系小鼠品系（A/J、BALB/cByJ、C57BL/6J、DBA/2J和SWR/J）中分析了两种细胞色素P-450 mRNA的基础表达和苯巴比妥诱导性。雄性小鼠组成性表达细胞色素P-450 2b-9和细胞色素P-450 2b-10 mRNA，但观察到它们对苯巴比妥的反应存在一些差异。在所有这些小鼠品系中，苯巴比妥诱导细胞色素P-450 2b-10 mRNA，而根据小鼠的品系和性别，它对细胞色素P-450 2b-9表达可能有正向或负向影响。具体而言，苯巴比妥增加了C57BL/6J雄性小鼠中细胞色素P-450 2b-9的表达，而在DBA/2J小鼠中则降低了其表达。有趣的是，地塞米松能够模拟苯巴比妥对这两个品系中两种细胞色素P-450的作用。除了C57BL/6J品系外，2型醛脱氢酶mRNA总是被苯巴比妥诱导。遗传分析表明，对于细胞色素P-450 2b-9和2型醛脱氢酶基因，来自C57BL/6J×DBA/2J杂交的F1动物中，苯巴比妥诱导型表型分别为半显性或隐性性状。本研究表明，小鼠中苯巴比妥诱导的遗传基础取决于靶基因，并且该反应途径涉及多个调控步骤。
