N-methylation as a toxication route for xenobiotics. II. In vivo formation of N,N'-dimethyl-4,4'-bipyridyl ion (paraquat) from 4,4'-bipyridyl in the guinea pig.
The biotransformation of 4-phenylpyridine and 4,4'-bipyridyl to N-methylated quaternary ammonium metabolites in guinea pig and rabbit has been examined. Neither animal species excreted the neurotoxin N-methyl-4-phenylpyridinium ion as a urinary metabolite after ip administration of 4-phenylpyridine. However, treatment of rabbits with 4,4'-bipyridyl resulted in the formation of N-methyl-4,4'-bipyridinium ion in the urine (1.2% of the administered dose), and ip administration of 4,4'-bipyridyl to guinea pigs afforded both N-methyl-4,4'-bipyridinium ion and N,N'-dimethyl-4,4'-bipyridinium ion (paraquat) as urinary metabolites (0.8% and 2.9%, respectively, of the administered dose). The detection of the lung toxin paraquat as a urinary metabolite of 4,4'-bipyridyl is a significant finding, in that it represents the first documented report of the formation of a toxic metabolite via the N-methylation pathway.
Godin
C S
CS
College of Pharmacy, University of Kentucky, Lexington 40536-0082.
Crooks
P A
PA
D015082:2,2'-Dipyridyl / Q000378:metabolism* / Q000652:urine; D000818:Animals; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D006168:Guinea Pigs; D008745:Methylation; D010269:Paraquat / Q000378:metabolism* / Q000652:urine; D011725:Pyridines / Q000378:metabolism*; D011817:Rabbits; D015262:Xenobiotics / Q000378:metabolism*
D011725:Pyridines; D015262:Xenobiotics; D015082:2,2'-Dipyridyl; D010269:Paraquat; C034306:4,4'-bipyridyl