Shimada M, Murayama N, Nagata K, Hashimoto H, Ishikawa H, Yamazoe Y
Division of Drug Metabolism and Molecular Toxicology, Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Arch Biochem Biophys. 1997 Jan 1;337(1):34-42. doi: 10.1006/abbi.1996.9764.
A spontaneous dwarf rat derived from a colony of Sprague-Dawley (SD) strain has no detectable level of growth hormone (GH) in pituitary, although it contained other hormones like prolactin and ACTH. Hepatic profile of cytochrome P450 (P450) differed clearly between dwarf and normal SD rats. A male-specific form of P450, CYP2C11, was detected in dwarf male rat livers, while the level was one-third of the normal SD livers. This P450 was also detected in dwarf females. Other male-specific CYP3A2 and CYP3A18 were also contained in both sexes of dwarf rats, whereas a female-specific form, CYP2C12, was not detectable in dwarf females. Phenobarbital-inducible CYP2B1 and CYP2B2 were constitutively expressed in dwarf rats, although substantially absent in normal SD rats. To assess the role of GH on hepatic P450 expression, GH was given to dwarf rats for 7 to 9 days. The intermittent injection (mimicking the male secretory pattern) resulted in the elevation of CYP2C11 to a level as observed in normal SD males. Continuous infusion of GH (mimicking the female secretory pattern) evoked CYP2C12 in livers of both sexes of dwarf rats, whereas the treatment decreased levels of CYP3A2, CYP3A18, and CYP2B1. These results clearly demonstrate that specific defect of GH, but not pituitary, cause the clear changes in hepatic P450 forms including sex-specific forms. The present study provides evidence further to strengthen the principal role of GH on the regulation of expression of P450 in rat livers.
一只源自斯普拉格-道利（SD）品系群体的自发性侏儒大鼠，其垂体中未检测到生长激素（GH）水平，不过它含有催乳素和促肾上腺皮质激素等其他激素。侏儒SD大鼠和正常SD大鼠肝脏中的细胞色素P450（P450）谱明显不同。在侏儒雄性大鼠肝脏中检测到一种雄性特异性的P450形式，即CYP2C11，但其水平仅为正常SD大鼠肝脏的三分之一。这种P450在侏儒雌性大鼠中也被检测到。其他雄性特异性的CYP3A2和CYP3A18在侏儒大鼠的雌雄两性中也都有，而一种雌性特异性形式CYP2C12在侏儒雌性大鼠中未被检测到。苯巴比妥诱导的CYP2B1和CYP2B2在侏儒大鼠中组成性表达，而在正常SD大鼠中基本不存在。为了评估GH对肝脏P450表达的作用，给侏儒大鼠注射GH 7至9天。间歇性注射（模拟雄性分泌模式）导致CYP2C11升高至正常SD雄性大鼠中观察到的水平。持续输注GH（模拟雌性分泌模式）在侏儒大鼠的雌雄两性肝脏中都诱发了CYP2C12，而该处理降低了CYP3A2、CYP3A18和CYP2B1的水平。这些结果清楚地表明，GH的特异性缺陷而非垂体缺陷导致了肝脏P450形式包括性别特异性形式的明显变化。本研究进一步提供了证据，以强化GH在大鼠肝脏中对P450表达调控的主要作用。
