Furukawa T, Manabe S, Watanabe T, Sharyo S, Mori Y
Medicinal Safety Research Laboratories, Sankyo Co., Ltd., Shizuoka, Japan.
Toxicol Appl Pharmacol. 1999 Dec 15;161(3):219-24. doi: 10.1006/taap.1999.8808.
Daily fluctuations have been observed in the hepatic cytochrome P450 monooxygenase activities of rodents. It was confirmed in our previous study that the P450 activities assessed by measurement of 7-alkoxycoumarin O-dealkylase (ACD) showed obvious daily fluctuations in male rats with high values during the dark period. However, there is still very little information about the daily fluctuation of P450 activities in female rats. In the first experiment of the present study, the daily fluctuation of ACD activities in female rats was examined. The results indicated the absence of any apparent daily fluctuation in the hepatic ACD activities of the females, so the study confirmed a sex difference in the daily rhythm of the ACD activities. In the second experiment using hypophysectomized (Hpx) rats, it was investigated whether this sex difference in daily rhythm was attributable to growth hormone (GH) release, an activity which is known to affect the sex difference in the expression of P450 isoforms. It was found that the Hpx rats, given subcutaneous injections of GH twice during the light period to mimic a male pattern of GH secretion, showed obvious light-dark fluctuation in ACD activities with high values in the dark period, and similar results were obtained in sham-operated males. Conversely, the Hpx rats given continuous infusion of GH to mimic a female pattern of GH secretion did not show the light-dark fluctuation in ACD activities, and similar results were obtained in sham-operated females. In conclusion, there is a sex difference in the daily rhythm of the hepatic P450 activities in rats and this difference is apparently influenced by the difference in the patterns of GH secretions.
已观察到啮齿动物肝脏细胞色素P450单加氧酶活性存在每日波动。我们之前的研究证实，通过测量7-烷氧基香豆素O-脱烷基酶（ACD）评估的P450活性在雄性大鼠中表现出明显的每日波动，在黑暗期值较高。然而，关于雌性大鼠P450活性的每日波动的信息仍然非常少。在本研究的第一个实验中，检测了雌性大鼠ACD活性的每日波动。结果表明，雌性大鼠肝脏ACD活性不存在任何明显的每日波动，因此该研究证实了ACD活性每日节律存在性别差异。在使用垂体切除（Hpx）大鼠的第二个实验中，研究了这种每日节律的性别差异是否归因于生长激素（GH）释放，已知该活性会影响P450同工型表达的性别差异。发现Hpx大鼠在光照期皮下注射两次GH以模拟雄性GH分泌模式，其ACD活性在黑暗期表现出明显的明暗波动且值较高，假手术雄性大鼠也获得了类似结果。相反，持续输注GH以模拟雌性GH分泌模式的Hpx大鼠未表现出ACD活性的明暗波动，假手术雌性大鼠也获得了类似结果。总之，大鼠肝脏P450活性的每日节律存在性别差异，这种差异显然受GH分泌模式差异的影响。
