Activation of microsomal glutathione transferase activity by reactive intermediates formed during the metabolism of phenol.
The activity of microsomal glutathione transferase was increased 1.7-fold in rat liver microsomes which carried out NADPH dependent metabolism of phenol. Known phenol metabolites were therefore tested for their ability to activate the microsomal glutathione transferase. The phenol metabolites benzoquinone and 1,2,4-benzenetriol both activated the glutathione transferase in microsomes 2-fold independently of added NADPH. However, NADPH was required to activate the enzyme in the presence of hydroquinone. Catechol did not activate the enzyme in microsomes. The purified enzyme was activated 6-fold and 8-fold by 5 mM benzenetriol and benzoquinone respectively. Phenol, catechol or hydroquinone had no effect on the purified enzyme. When microsomal proteins that had metabolized [14C]phenol were examined by SDS polyacrylamide gel electrophoresis and fluorography it was found that metabolites had bound covalently to a protein which comigrated with the microsomal glutathione transferase enzyme. We therefore suggest that reactive metabolites of phenol activate the enzyme by covalent modification. It is discussed whether the binding and activation has general implications in the regulation of microsomal glutathione transferase and, since some reactive metabolites might be substrates for the enzyme, their elimination through conjugation.
Wallin
H
H
National Institute of Public Health, Department of Environmental Medicine, Oslo, Norway.
Morgenstern
R
R
D000818:Animals; D016227:Benzoquinones; D004789:Enzyme Activation; D005982:Glutathione Transferase / Q000032:analysis* / Q000378:metabolism; D006873:Hydroquinones / Q000494:pharmacology; D008297:Male; D008861:Microsomes / Q000201:enzymology*; D008970:Molecular Weight; D019800:Phenol; D010636:Phenols / Q000378:metabolism*; D011809:Quinones / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D016227:Benzoquinones; D006873:Hydroquinones; D010636:Phenols; D011809:Quinones; C013038:hydroxyhydroquinone; D019800:Phenol; C004532:quinone; D005982:Glutathione Transferase; C031927:hydroquinone