Feminization of Hepatic Cytochrome P450s by Nominal Levels of Growth Hormone in the Feminine Plasma Profile

The feminine profile of continuous growth hormone secretion was restored at various concentrations to hypophysectomized, thyroxine-supplemented female rats to determine the minimum signaling concentrations of the hormone required to maintain female-like expression levels of gender-dependent hepatic cytochrome P450s (P450s). Rat growth hormone was infused by intraperitoneally implanted osmotic minipumps, and the resulting circulating concentrations and profiles were determined by radioimmunoassay of serially collected plasma samples. Restoration of feminine growth hormone profiles at 3% of physiological concentration completely suppressed male-specific CYP2C11, CYP2C13, CYP2A2, and CYP3A2. Although significant levels of female-dependent isoforms were expressed at this growth hormone concentration, their full expression required, somewhat higher plasma concentrations of the hormone; CYP2A1 and 5 alpha-reductase were increased to normal female levels with only 6-12% of physiological concentrations of the hormone, normal expression levels of CYP2C12 required approximately 12-25% physiological hormone levels, and CYP2C7 required approximately 25-50% of the normal growth hormone profile to attain female-like expression levels. When determined, protein and specific catalytic activities were in agreement with mRNA levels, supporting the conclusion that growth hormone regulates gender-dependent expression of P450 isoforms by transcription initiation. There was little effect of gender, hypophysectomy, or growth hormone replacement on CYP2C6, growth hormone receptor, and growth hormone-binding protein mRNAs. In contrast, insulin-like growth factor-1 mRNA was sexually dimorphic (male > female), virtually disappeared after hypophysectomy, and was restored to female-like levels with plasma growth hormone concentrations equaling 12-25% of normal. These findings demonstrate the effectiveness of nominal growth hormone concentrations (undetectable by available radioimmunoassay) in an otherwise feminine plasma profile to maintain female-like expression levels of gender-dependent P450s.