Thangavel Chellappagounder, Dworakowski Wojciech, Shapiro Bernard H
Laboratories of Biochemistry, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104-6048, USA.
Drug Metab Dispos. 2006 Mar;34(3):410-9. doi: 10.1124/dmd.105.007716. Epub 2005 Dec 8.
Although in vivo expression levels of the male-specific hepatic isoforms of cytochrome P450 (P450) (CYP2C11, CYP2C13, CYP2A2, and CYP3A2) are determined by the episodic growth hormone profile secreted by male rats, these isoforms have been completely refractory to growth hormone regulation in hepatocyte culture. By using species-specific rat growth hormone, at subphysiologic in vivo concentrations administered in two daily episodic pulses, we successfully induced CYP2C11 and CYP2A2 to near normal concentrations. Whereas inductive levels of CYP2C13 were subnormal, CYP3A2 was unresponsive to all hormonal treatments, quickly declining to undetectable concentrations. In agreement with in vivo findings, we observed that induction levels of the isoforms were always greatest when the male hepatocytes were exposed to the masculine-like episodic growth hormone profile and least stimulated by the continuous feminine-like hormone profile. When administered alone, dexamethasone consistently increased isoform levels. However, when administered with growth hormone, the glucocorticoid was always antagonistic, suppressing growth hormone induction of CYP2C11, CYP2C13, and CYP2A2. Finally, the P450 isoforms were completely unresponsive to all treatments when the hepatocytes were derived from female rats, supporting earlier findings that expression levels of sexually dimorphic P450 isoforms are inherently irreversible between sexes.
尽管细胞色素P450（P450）的雄性特异性肝脏同工型（CYP2C11、CYP2C13、CYP2A2和CYP3A2）的体内表达水平由雄性大鼠分泌的间歇性生长激素谱决定，但这些同工型在肝细胞培养中对生长激素调节完全不敏感。通过使用物种特异性的大鼠生长激素，以每天两次间歇性脉冲给予亚生理体内浓度，我们成功地将CYP2C11和CYP2A2诱导至接近正常浓度。而CYP2C13的诱导水平低于正常，CYP3A2对所有激素处理均无反应，迅速降至无法检测的浓度。与体内研究结果一致，我们观察到，当雄性肝细胞暴露于类似雄性的间歇性生长激素谱时，同工型的诱导水平总是最高，而受到持续的类似雌性激素谱刺激时诱导水平最低。单独给药时，地塞米松持续增加同工型水平。然而，与生长激素联合给药时，糖皮质激素总是具有拮抗作用，抑制生长激素对CYP2C11、CYP2C13和CYP2A2的诱导。最后，当肝细胞来源于雌性大鼠时，P450同工型对所有处理均完全无反应，支持了早期的研究结果，即两性异形的P450同工型的表达水平在性别之间本质上是不可逆的。
