Furukawa T, Manabe S, Watanabe T, Sehata S, Sharyo S, Okada T, Mori Y
Laboratory Animal Science and Toxicology Laboratories, Sankyo Co., Ltd., 717 Horikoshi, Fukuroi, Shizuoka 437-0065, Japan.
Arch Toxicol. 1999 Sep;73(7):367-72. doi: 10.1007/s002040050675.
Hepatic P450 monooxygenase activities, which strongly influence the efficacy and/or toxicity of drugs, are known to fluctuate daily. We also know that the P450 activities assessed by measurement of 7-alkoxycoumarin O-dealkylase (ACD) activities fluctuate daily, with apparently high values during the dark period in male rats. However, there is little knowledge about the factors that regulate daily fluctuation of P450 monooxygenase activities. In the present study using rats, we induced lesions in the suprachiasmatic nucleus (SCN) of the brain, the known site of the body's internal clock, and examined the effects on the daily fluctuation of the ACD activities to clarify the relationship between the SCN and the daily fluctuation of P450 monooxygenase activities. In addition, adrenalectomy was performed to re-evaluate the influence of adrenal hormones on the P450 activities. Our results indicated that daily fluctuations of the hepatic ACD activities were completely eliminated in the SCN-lesioned rats. However, the ACD activities in the adrenalectomized rats showed apparent daily fluctuations with high values during the dark period and low values during the light period. Therefore, this study demonstrated that the daily fluctuation of the hepatic P450 monooxygenase activities in male rats is controlled by the SCN but remains unaffected by the adrenal hormones.
肝脏P450单加氧酶活性对药物的疗效和/或毒性有很大影响，已知其会每日波动。我们也知道，通过测量7-烷氧基香豆素O-脱烷基酶（ACD）活性评估的P450活性每日波动，在雄性大鼠的黑暗期明显较高。然而，关于调节P450单加氧酶活性每日波动的因素知之甚少。在本研究中，我们使用大鼠，损毁了大脑中已知的体内生物钟所在部位——视交叉上核（SCN），并检查了对ACD活性每日波动的影响，以阐明SCN与P450单加氧酶活性每日波动之间的关系。此外，进行了肾上腺切除术以重新评估肾上腺激素对P450活性的影响。我们的结果表明，SCN损毁的大鼠肝脏ACD活性的每日波动完全消除。然而，肾上腺切除大鼠的ACD活性在黑暗期呈现明显的每日波动且值高，在光照期值低。因此，本研究表明，雄性大鼠肝脏P450单加氧酶活性的每日波动受SCN控制，但不受肾上腺激素影响。
