Inhibition of glutathione S-transferase zeta and tyrosine metabolism by dichloroacetate: A potential unifying mechanism for its altered biotransformation and toxicity

Dichloroacetate (DCA) inhibits its own metabolism and is converted to glyox ylate by glutathione S-transferase zeta (GSTz). GSTz is identical to maleyl acetoacetate isomerase, an enzyme of tyrosine catabolism that converts male ylacetoacetate (MAA) to fumarylacetoacetate and maleylacetone (MA) to fumar ylacetone. MAA and MA are alkylating agents. Rats treated with DCA for up t o five days had markedly decreased hepatic GSTz activity and increased urin ary excretion of MA. When dialyzed cytosol obtained from human liver was in cubated with DCA, GSTz activity was unaffected. In contrast, DCA incubation inhibited enzyme activity in dialyzed hepatic cytosol from rats. Incubatio n of either rat or human hepatic cytosol with MA led to a dose dependent in hibition of GSTz. These data indicate that humans or rodents exposed to DCA may accumulate IMA and/or MAA which inhibit(s) GSTz and, consequently, DCA biotransformation. Moreover, DCA-induced inhibition of tyrosine catabolism may account for the toxicity of this xenobiotic in humans and other specie s. (C) 1999 Academic Press.