Inhibition of glutathione synthesis with propargylglycine enhances N-acetylmethionine protection and methylation in bromobenzene-treated Syrian hamsters.

The finding that liver necrosis caused by the environmental glutathione (GSH)-depleting chemical, bromobenzene (BB) is associated with marked impairment in O- and S-methylation of BB metabolites in Syrian hamsters raises questions concerning the role of methyl deficiency in BB toxicity. N-Acetylmethionine (NAM) has proven to be an effective antidote against BB toxicity when given after liver GSH has been depleted extensively. The mechanism of protection by NAM may occur via a replacement of methyl donor and/or via an increase of GSH synthesis.

Alterations of DNA methylation by glutathione depletion.

One of the most consistent findings in cancer cells is an overall decrease of 5-methylcytosine content in DNA. The causes that lead to this alteration are not known. We have shown in a recent study that the methyl-donor, methionine (Met), can easily be depleted and that O- and S-methylation can be impaired in response to glutathione (GSH) depletion.

Glutathione depletion-induced thymidylate insufficiency for DNA repair synthesis.

Dietary methionine (Met) deficiency is known to divert folate away from de novo biosyntheses of purines and the pyrimidine, thymidylate, to the resynthesis of Met resulting in deoxynucleoside triphosphate imbalance. We have recently shown that Met can easily be depleted and methylation can be impaired by exposure to a model glutathione (GSH)-depleting agent, bromobenzene (BB). GSH depletion-induced Met depletion, therefore, could cause thymidylate insufficiency for DNA repair synthesis.

Methyl-donor deficiency due to chemically induced glutathione depletion.

Dietary deficiency of methionine (Met) is known to deplete cellular Met and cause DNA hypomethylation, but depletion of Met and impairment in methylation due to chemically induced glutathione (GSH) depletion has escaped recognition. In this study, the effect of GSH depletion on the Met pool and methylation capability was examined after bromobenzene (BB), a model GSH-depleting hepatotoxin, was administered to the Syrian hamster. An i.

O- and S-methylated bromothiocatechols.

Bromobenzene is metabolized by the Hartley guinea pig to two different bromothiocatechols, 4-bromo-2-hydroxythiophenol and 5-bromo-2-hydroxythiophenol. Both the thiol and phenol functional groups of thiocatechol undergo biological methylation. Methylation at the thiol group leads to the formation of (methylthio)bromophenol (S-methylated bromothiocatechol), while methylation of the phenol group leads to methoxybromothiophenol (O-methylated bromothiocatechol).