Modified expression of cytochrome P450 mRNAs by growth hormone in mouse liver

Abstract

The expression of eight mouse hepatic cytochrome P450s (P450s) genes was investigated at the mRNA level in relation with the pattern of growth hormone (GH) administration. The constitutive expression of five sex-dependent P450s was sexually dimorphic, namely female > male for CYP2A4, CYP2B9, CYP2B10, and CYP3A41, and male > female for CYP2D9. In mice neonatally treated with monosodium l-glutamate to produce GH-deficiency, GH was found to be an essential factor with GH archetype as a determinant in the regulatory mechanism of hepatic CYP2D9 and CYP3A41 expression, and GH was shown to be a repressive factor for the constitutive expression in females. Implantation with micro-osmotic pump containing GH (to yield a constant release of GH to mimic the plasma GH profile in females) to male mice increased CYP2A4, CYP2B9, CYP2B10, and CYP3A41, but decreased CYP2D9, expression to female levels, while conversely, twice-daily administration of GH (to produce the so-called male pattern of plasma GH levels) to female mice resulted in the repression of female-specific, CYP2B9 and CYP3A41, as well as female-predominant, CYP2A4 and CYP2B10, expression, and induction of male-specific CYP2D9 expression. Thus, the sex-dependent plasma GH profile (referred to hereafter as the GH archetype) was a decisive factor for the expression of sex-specific P450 genes in adult mouse liver. On the other hand, the regulation of CYP1A2, CYP2C29, and CYP3A11 expression was either sex-independent or GH archetype-independent, considering the comparable levels between sexes of the constitutive expression and GH-inducible expression of these isoforms. Moreover, the observations suggested for the first time that the expression of CYP2B9 and CYP2A4 was not entirely GH-independent, but rather involved an imprinting GH-related factor that participated in the regulatory mechanism of P450 expression in females.