Regulation of liver zinc metabolism and metallothionein by cAMP, glucagon and glucocorticoids and suppression of free radicals by zinc.

Abstract

Regulation of metallothionein synthesis and concomitant changes in the kinetics of zinc metabolism are influenced by dibutyryl cAMP, epinephrine, glucagon and dexamethasone in both intact rats and isolated rat liver parenchymal cells. Liver metallothionein levels were elevated many fold and were directly related to the transient hypozincemia produced following administration of these hormones or Bt2cAMP. Incubation of monolayer cultures of liver cells with these agents caused changes in both rapidly taken up 65Zn2+ and slow 65Zn2+ exchange; and increased metallothionein levels up to 7 fold. Using a 32P-labeled oligonucleotide, corresponding to a 21 base sequence of the metallothionein gene as a hybridization probe, metallothionein mRNA levels were found to be increased by each hormone and cAMP in isolated liver cells and intact rats. This indicates metallothionein gene expression is regulated by cAMP in addition to metals and glucocorticoids. Free radical damage to isolated liver cells caused by t-butylhydroperoxide or 3-methylindole increased malondialdehyde production which could be reduced by addition of Zn2+ to the culture medium. This suggests zinc uptake influenced the extent of lipid peroxidation. Spin-trapping techniques using electron spin resonance showed zinc also reduced free radical formation by the isolated hepatocytes. The concentration of metallothionein in liver cells seems to be related to cellular functions of zinc and coordinately regulated by glucagon through changes in cAMP levels and glucocorticoids.