Induction of Several Acute-Phase Protein Genes by Heavy Metals: A New Class of Metal-Responsive Genes

Acute-phase reactants, metallothioneins, and heat-shock proteins are the products of three families of genes that respond to glucocorticoids and cytokines. Metallothioneins and heat-shock proteins, however, are also stimulated by heavy metals, whereas very little is known about the effect of heavy metals on acute-phase-reactant genes. We have studied the effect of heavy metals (Hg, Cd, Pb, Cu, Ni, and Zn) and Mg on the acute-phase reactants α₁acid glycoprotein, C-reactive protein, α₁antitrypsin and α₁anti-chymotrypsin. α₁-Acid glycoprotein and C-reactive protein mRNA levels were increased severalfold in livers of heavy-metal-treated Balb/c mice. The strongest induction was mediated by Hg, followed in order of response by Cd > Pb > Cu > Ni > Zn > Mg. None of the metals affected the mRNA levels of albumin, α₁-antitrypsin, and α₁antichymotrypsin. Furthermore, failure to repress albumin, a negative acute-phase reactant, indicated that the induction of these genes was not due to a metal-mediated inflammatory response. The metals also induced α₁acid glycoprotein and C-reactive protein in adrenalectomized animals, indicating that induction by the heavy metals is not mediated by the glucocorticoid induction pathway. Sequence analysis has revealed a region of homology to metal-responsive elements in the α₁acid glycoprotein and C-reactive protein promoters. Additionally, an α₁-acid glycoprotein expression vector, pAGP(−595)CAT, responded to Hg and Cd when transfected into human HepG2 cells. Our studies indicate that the induction of α₁-acid glycoprotein and C-reactive protein by heavy metals may be regulated by these metal-responsive elements at the level of transcription.