Effect of Hypophysectomy and Growth Hormone Replacement on the Modulation of P450 Expression after Treatment with the Aromatic Hydrocarbon Ethylbenzene

Abstract

Pituitary status has a significant effect on the expression of several cytochrome P450 enzymes. The goal of this study was to examine the role of pituitary input on the modulation of CYP2C11 and CYP2B after treatment with the aromatic hydrocarbon ethylbenzene (EB). Intact, hypophysectomized (HX), and HX rats supplemented with pulsatile growth hormone (GH) were treated with corn oil or EB and the effects on hepatic P450 expression were determined. Hypophysectomy caused a 50% decrease in CYP2C11 protein in untreated rats, whereas GH supplementation returned protein to control levels. EB administration also decreased CYP2C11 protein in intact rats; however, this decrease was not observed after EB treatment in HX or HX + GH groups. CYP2C11-dependent testosterone 2α-hydroxylation followed a similar pattern as CYP2C11 protein, except that the activity was only partially restored by GH replacement. CYP2B levels were also substantially influenced by hypophysectomy. Intact rats exhibited a 100-fold increase in CYP2B1 mRNA, reaching a maximum 12 h after EB administration. A much smaller response (ca. 20-fold) was observed in HX rats, reaching a maximum 24 h after EB treatment. This effect was not reversed by GH supplementation. The half-life for EB was significantly increased from 8 h in intact rats to 14 h in HX rats, suggesting higher plasma EB concentrations after EB administration to HX rats. These results indicate that CYP2C11 and CYP2B become less responsive to EB-dependent modulation in HX rats, a response that cannot be explained simply by absence of GH or by altered EB pharmacokinetics in HX animals.