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 (GS H)-depleting chemical, bromobenzene (BB) is associated with marked impairme nt in O- and S-methylation of BE metabolites in Syrian hamsters raises ques tions concerning the role of methyl deficiency in BE toxicity. N-Acetylmeth ionine (NAM) has proven to be an effective antidote against BE toxicity whe n given after liver GSH has been depleted extensively. The mechanism of pro tection by NAM may occur via a replacement of methyl donor and/or via an in crease of GSH synthesis. If replacement of the methyl donor is an important process, then blocking the resynthesis of GSH in the methyl-repleted hamst ers should not decrease NAM protection. This hypothesis was examined in thi s study. Propargylglycine (PPG), an irreversible inhibitor of cystathionase , was used to inhibit the utilization of NAM for GSH resynthesis, Two group s of hamsters were pretreated with an intraperitoneal (ip) dose of PPG (30 mg/kg) or saline 24 h before BBE administration (800 mg/kg, ip). At 5 h aft er BE treatment, an ip dose of NAM (1200 mg/kg) was given. Light microscopi c examinations of liver sections obtained 24 h after BB treatment indicated that NAM provided better protection (P < 0.05) in the PPG + BB + NAM group than in the BB + NAM group. Liver GSH content, however, was lower in the P PG + BE + NAM group than in the BB + NAM group. The Syrian hamster has a li mited capability to N-deacetylated NAM. The substitution of NAM with methio nine (Met; 450 mg/kg) resulted in a higher level of GSH in the BE + Met gro up than in the BE + NAM group (P < 0.05). The enhanced protection by PPG in the PPG + BB + NAM group was accompanied by higher (P < 0.05) urinary excr etions of specific O- and S-methylated bromothiocatechols than in the BE NAM group. The results suggest that NAM protection occurs primarily via a r eplacement of the methyl donor and that methyl deficiency occurring in resp onse to GSH repletion plays a potential role in BB toxicity.