Sharma Meena R, Periandythevar Parameswaran, Shapiro Bernard H
Laboratories of Biochemistry, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104-6048, USA.
Drug Metab Dispos. 2003 Sep;31(9):1074-6. doi: 10.1124/dmd.31.9.1074.
Phenobarbital (PB) induction of the CYP2B subfamily was studied in the livers and spleens of male and female rats. Animals were treated with either PB (10 mg/kg) or vehicle for 4 consecutive days. A reverse transcriptase-polymerase chain reaction (RT-PCR), quantitative Northern blotting, Western blotting, and a radioenzymatic assay were used to observe differential levels of CYP2B1 and CYP2B2 mRNAs, proteins, and catalytic activities. CYP2B2 expression was limited to the livers of PB-treated male and female rats and was not detected in spleen. Low constitutive levels of CYP2B1 mRNA were markedly induced approximately 7- to 17-fold in the livers of PB-treated male and female rats, respectively. However, using the same standard oligonucleotide probe for CYP2B1 mRNA, we observed considerably greater constitutive concentrations of the transcript in spleen than in liver. Putative splenic CYP2B1 mRNA was significantly elevated by the PB treatment, although not as profoundly as the hepatic response. In contrast, only the livers of the barbiturate-treated rats expressed CYP2B1 proteins or specific catalytic activity (androstenedione 16beta-hydroxylase). Protein and catalytic activities of the isoforms were undetectable in spleen of either male or female vehicle- and PB-treated rats. In agreement, RT-PCR was unable to demonstrate the expression of splenic CYP2B1 mRNAs. Investigating the possibility that the Northern probe for CYP2B1 was identifying a similar sequence isoform, we performed RT-PCR using primers for CYP2B12 and CYP2B15. Since neither of these isoforms was expressed in spleen, we conclude that the spurious results using the Northern probe for CYP2B1 mRNA were due to the presence of a cross-reacting, PB-responsive transcript not currently identifiable in existing databases.
在雄性和雌性大鼠的肝脏及脾脏中研究了苯巴比妥(PB)对细胞色素P450 2B亚家族的诱导作用。动物连续4天接受PB(10 mg/kg)或赋形剂处理。采用逆转录聚合酶链反应(RT-PCR)、定量Northern印迹法、蛋白质免疫印迹法和放射性酶法来观察细胞色素P450 2B1和细胞色素P450 2B2 mRNA、蛋白质及催化活性的差异水平。细胞色素P450 2B2的表达仅限于接受PB处理的雄性和雌性大鼠的肝脏,在脾脏中未检测到。在接受PB处理的雄性和雌性大鼠肝脏中,细胞色素P450 2B1 mRNA的基础水平较低,但分别显著诱导了约7至17倍。然而,使用相同的细胞色素P450 2B1 mRNA标准寡核苷酸探针,我们观察到脾脏中转录本的基础浓度比肝脏中高得多。尽管脾脏中细胞色素P450 2B1 mRNA的诱导程度不如肝脏明显,但PB处理后其假定的脾脏细胞色素P450 2B1 mRNA显著升高。相比之下,仅接受巴比妥酸盐处理的大鼠肝脏表达细胞色素P450 2B1蛋白质或特异性催化活性(雄烯二酮16β-羟化酶)。在接受赋形剂和PB处理的雄性或雌性大鼠的脾脏中,均未检测到该同工型的蛋白质和催化活性。同样,RT-PCR也未能证明脾脏中细胞色素P450 2B1 mRNA的表达。为研究细胞色素P450 2B1的Northern探针是否识别出相似的序列同工型,我们使用细胞色素P450 2B12和细胞色素P450 2B15的引物进行了RT-PCR。由于这两种同工型在脾脏中均未表达,我们得出结论,使用细胞色素P450 2B1 mRNA的Northern探针产生的虚假结果是由于存在一种交叉反应的、PB反应性转录本,目前在现有数据库中无法识别。