In-vitro and in-vivo formation of N-nitrosomethylcyclohexylamine from bromhexin and sodium nitrite, and DNA methylation in rats.

Abstract

After oral administration of a commercial bromhexin (N-methyl-N-cyclohexyl(2-amino-3,5-dibrombenzyl)ammonium chloride) solution (1-90 mg/kg) together with sodium nitrite (1-90 mg/kg) to female Wistar rats, ring-hydroxylated metabolites of N-nitrosomethyl-cyclohexylamine (NMCA) were excreted in urine as glucuronide/sulfate conjugates. When [14C-methyl]-bromhexin (30 mg/kg) was given intragastrically together with sodium nitrite (30 mg/kg), alkylated DNA adducts were detected in liver and oesophagus. Gastric juice of 75 healthy human volunteers (fasted, then ingesting up to 200 mg nitrate) was incubated in vitro with bromhexin (16 mg/100 ml). In only one sample, 50 ng NMCA/100 ml were formed.