Interference with Growth Hormone Stimulation of Hepatic Cytochrome P4502C11 Expression in Hypophysectomized Male Rats by 3-Methylcholanthrene

Abstract

Cytochrome P450 2C11 (CYP2C11) is a sexually dimorphic liver enzyme whose expression is regulated by the male pulsatile pattern of growth hormone (GH) secretion. Hepatic CYP2C11 expression is down-regulated by polycyclic aromatic hydrocarbons such as 3-methylcholanthrene (MC). An attractive hypothesis as to the mechanism of CYP2C11 down-regulation by aromatic hydrocarbons is the disruption of normal GH signaling by exposure to these compounds. To evaluate the effects of MC on the ability of GH to stimulate hepatic CYP2C11 expression, our approach was to employ GH replacement in male Fischer 344 rats made GH-deficient by hypophysectomy (hypx). Groups of hypx rats received the following treatments: vehicle; GH alone (twice daily, 125 μg/kg sc, days 1–6); MC alone (20 mg/kg gavage, days 1, 3, and 5); and both GH and MC. Rats were euthanized on day 7. As a positive control response, pronounced induction of hepatic CYP1A1 apoprotein was observed in all MC-treated rats. CYP2C11 expression in hypx rats receiving GH alone was increased at the mRNA, apoprotein, and catalytic activity (testosterone 16α-hydroxylation) levels, with mRNA and apoprotein levels approaching that of intact male rats. The inability of GH to fully restore CYP2C11 catalytic activity was attributed to the lowered NADPH-cytochrome P450 reductase apoprotein and catalytic activity observed in all hypx rats. CYP2C11 expression in hypx rats receiving both GH and MC was significantly lower at the mRNA, apoprotein, and catalytic activity levels than that observed in hypx rats treated with GH alone, but significantly higher at the mRNA, apoprotein, and catalytic activity levels than that observed in vehicle-treated hypx rats and in hypx rats treated with MC alone. These data suggest that MC interferes with the ability of GH to stimulate CYP2C11 expression. Thus, disruption of GH signaling by aromatic hydrocarbons may represent a mechanism contributing to the suppression of CYP2C11 gene expression.