Department of Molecular Life Sciences, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.
Department of Regenerative Medicine, Center for Matrix Biology and Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.
Lab Invest. 2018 Nov;98(11):1500-1511. doi: 10.1038/s41374-018-0088-6. Epub 2018 Jul 3.
The adult liver performs many metabolic functions for maintaining homeostasis. There are several sex differences in liver function and disease pathogenesis. One important function of the liver is drug metabolism, where cytochrome p450s (CYPs) in hepatocytes are the main enzymes involved. The toxicity of various drugs and chemicals differs with sex due to differences in hepatocytic CYP expression. However, the molecular mechanism regulating sex-related differences in drug metabolism remains unknown. In this study, we identified transcriptional regulator B-cell lymphoma 6 (Bcl6) as an important factor in sex-biased differential CYP expression. Microarray analysis of livers derived from liver-specific Bcl6-knockout mice showed that Bcl6 is required for sex-biased CYP expression patterns in the liver. Additionally, quantitative PCR analysis revealed that hepatocytic expression of male-biased genes, such as Cyp2d9, Cyp2u1, Cyp4a12a/12b, and Cyp7b1, in liver-specific Bcl6-knockout male mice significantly decreased to levels similar to those observed in wild-type female mice. Conversely, hepatocytic expression of female-biased genes, such as Cyp2a4/2a5, Cyp2b9, Cyp3a41, and Cyp17a1, significantly increased in liver-specific Bcl6-knockout male mice. Deletion of Bcl6 caused female-like expression of CYPs in male livers. These results suggest that Bcl6 is a key regulator of sex-related differential regulation of drug metabolism. Moreover, serum sex hormone levels and fertility did not change in liver-specific, Bcl6-knockout mice. Hepatocytic Bcl6 regulates sex-related differential CYP expression in the liver without changing the sex of the whole body. Thus, this mouse model is useful for analyzing liver-specific sex-dependent regulation of drug metabolism and pathogenesis.
成年肝脏具有许多维持内稳态的代谢功能。肝脏功能和疾病发病机制存在多种性别差异。肝脏的一个重要功能是药物代谢，其中肝细胞中的细胞色素 P450s（CYPs）是主要涉及的酶。由于肝实质细胞 CYP 表达的差异，各种药物和化学物质的毒性存在性别差异。然而，调节药物代谢性别相关差异的分子机制尚不清楚。在这项研究中，我们确定转录调节因子 B 细胞淋巴瘤 6（Bcl6）是肝 CYP 表达性别偏倚差异的重要因素。来自肝特异性 Bcl6 敲除小鼠的肝脏的微阵列分析表明，Bcl6 是肝脏性别偏倚 CYP 表达模式所必需的。此外，定量 PCR 分析显示，肝特异性 Bcl6 敲除雄性小鼠中雄性偏倚基因（如 Cyp2d9、Cyp2u1、Cyp4a12a/12b 和 Cyp7b1）的肝细胞表达显著降低至与野生型雌性小鼠相似的水平。相反，肝特异性 Bcl6 敲除雄性小鼠中雌性偏倚基因（如 Cyp2a4/2a5、Cyp2b9、Cyp3a41 和 Cyp17a1）的肝细胞表达显著增加。Bcl6 的缺失导致雄性肝脏中 CYP 的雌性样表达。这些结果表明 Bcl6 是调节药物代谢性别相关差异的关键调节剂。此外，肝特异性 Bcl6 敲除小鼠的血清性激素水平和生育能力没有改变。Bcl6 在肝细胞中调节肝脏中与性别相关的差异 CYP 表达，而不改变整个身体的性别。因此，这种小鼠模型可用于分析肝脏特异性性别依赖性药物代谢和发病机制的调节。
