Drug residue formation from ronidazole, a 5-nitroimidazole. VIII. Identification of the 2-methylene position as a site of protein alkylation.
Ronidazole protein-bound adducts were generated by the in vitro anaerobic incubation of [2-methylene-14C]ronidazole with microsomes from the livers of male rats. Acid hydrolysis of the protein adducts yielded an imidazole ring fragment bearing the radiolabel and an amino acid residue derived from the proteins. This fragment has been identified as carboxymethylcysteine by co-chromatography of the amino acid and its dansyl derivative with known standards under a variety of conditions. The carboxymethylcysteine was estimated to represent at least 15% of the radioactivity derived from the protein-bound adducts and provides unequivocal evidence that nucleophilic attack by protein cysteine thiols occurred at the 2-methylene position of ronidazole.
Alvaro
R F
RF
Department of Animal and Exploratory Drug Metabolism, Merck Sharp and Dohme Research Laboratories, Rahway, NJ 07065.
Wislocki
P G
PG
Miwa
G T
GT
Lu
A Y
AY
D000478:Alkylation; D000818:Animals; D002233:Carbocysteine / Q000737:chemistry; D004350:Drug Residues; D006868:Hydrolysis; D008297:Male; D008862:Microsomes, Liver / Q000737:chemistry / Q000187:drug effects; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000187:drug effects; D051381:Rats; D012385:Ronidazole / Q000737:chemistry*; D013329:Structure-Activity Relationship
D011506:Proteins; D002233:Carbocysteine; D012385:Ronidazole