Hepatic microsomal cytochrome p-450-dependent N-demethylation of methylguanidine.
Cytochrome P-450-dependent N-demethylation of methylguanidine, a uremia toxin, was investigated. Methylguanidine was stoichiometrically converted into equal amounts of guanidine and formaldehyde by aerobic incubation with phenobarbital-induced microsomes and NADPH. The guanidine formation in the incubation mixture followed Michaelis-Menten kinetics and required the presence of molecular oxygen and NADPH. Methimazole, a non-formaldehyde-producing substrate specific for FAD-containing monooxygenase, did not inhibit significantly formaldehyde formation, suggesting that microsomal FAD-containing monooxygenase does not play a significant role in N-demethylation of methylguanidine. The direct involvement of cytochrome P-450 in the N-demethylation is supported by the observations that addition of methylguanidine to purified cytochrome P-450 preparation caused a type I spectral change and that inhibitors of cytochrome P-450, such as carbon monoxide and metyrapone, markedly decreased the rate of demethylation. Neither superoxide anion nor hydrogen peroxide was directly involved in the demethylation reaction. In addition, guanidine formation was observed in the reconstituted system containing purified cytochrome P-450. Thus, these findings indicate that the hepatic microsomal mixed function oxidase system catalyzes N-demethylation of methylguanidine to guanidine.
D000818:Animals; D002384:Catalysis; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006146:Guanidines / Q000378:metabolism*; D008297:Male; D008760:Methylguanidine / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000502:physiology*; D010089:Oxidoreductases, N-Demethylating / Q000302:isolation & purification / Q000502:physiology*; D010634:Phenobarbital / Q000494:pharmacology; D011817:Rabbits
D006146:Guanidines; D008760:Methylguanidine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010089:Oxidoreductases, N-Demethylating; D010634:Phenobarbital