Suppression of constitutive cytochrome P450 gene expression by epidermal growth factor receptor ligands in cultured rat hepatocytes.

In rat hepatocytes cultured on Matrigel, incubation with epidermal growth factor (EGF) or transforming growth factor-alpha for 24 hr suppressed the constitutive expression of cytochrome P450 (CYP) 2C11 mRNA by 60-70%. The growth factors were maximally effective at concentrations of 10-30 ng/ml. These agents also suppressed the expression of CYP2C11 protein measured 48-72 hr after addition to the medium. Significant suppression of CYP2C11 mRNA was first seen 8 hr after EGF addition to the medium, was maximal by 16 hr, and persisted for at least 36 hr. The suppression of CYP2C11 mRNA by EGF was comparable in magnitude with that produced by interleukin (IL)-1, but greater than that by IL-6. The suppressive effects of EGF and IL-1 on CYP2C11 mRNA were additive, suggesting that the signaling pathways for suppression of CYP2C11 by EGF and IL-1 are different.