Oxidative conversion of isothiocyanates to isocyanates by rat liver.
This report describes the oxidative metabolism of isothiocyanates to isocyanates catalyzed by rat liver microsomes. Incubation of 2-naphthylisothiocyanate, microsomes, and NADPH yielded either N,N'-di-naphthylurea or, on inclusion of 2-aminofluorene in the incubations, N-2-naphthyl-N'-2-fluorenylurea. These ureas were formed by the production of the known genotoxicant, 2-naphthylisocyanate, which reacted with its hydrolysis product, 2-aminonaphthalene, to yield the symmetrical urea, or with 2-aminofluorene to form the mixed urea. Formation of N,N'-di-2-naphthylthiourea was also observed because 2-aminonaphthalene reacted with the substrate. Urea formation was dependent on the microsomes, NADPH, and oxygen. Use of microsomes from rats previously treated with Aroclor 1254 increased urea formation greater than 10-fold. The enzyme activity was inhibited by alpha-napthoflavone, flavone, or CO, and slightly inhibited by metyrapone, 7-ethoxycoumarin, or SKF-525A. It was not inhibited by methimazole or paraoxon, suggesting that neither flavin-containing monooxygenase nor hydrolytic enzyme was involved. These data are consistent with a cytochrome P450-dependent, oxidative desulfuration of 2-naphthylisothiocyanate to yield 2-naphthylisocyanate. Further studies with the isomeric 1-naphthylisothiocyanate and the dietary benzylisothiocyanate showed that they can also be metabolized to their isocyanates, as evidenced by the trapping of isocyanates with 2-aminofluorene to form the mixed ureas.
Lee
M S
MS
Department of Chemical Carcinogenesis, Michigan Cancer Foundation, Detroit 48201.
D015058:1-Naphthylisothiocyanate / Q000378:metabolism; D015081:2-Naphthylamine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001128:Argon / Q000378:metabolism; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism; D004790:Enzyme Induction; D005449:Fluorenes / Q000378:metabolism; D017953:Isocyanates / Q000378:metabolism*; D007536:Isomerism; D017879:Isothiocyanates / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D009153:Mutagens / Q000378:metabolism; D010084:Oxidation-Reduction; D010261:Paraoxon / Q000378:metabolism; D051381:Rats; D014508:Urea / Q000031:analogs & derivatives / Q000378:metabolism
D002273:Carcinogens; D005449:Fluorenes; D017953:Isocyanates; D017879:Isothiocyanates; D009153:Mutagens; C092586:N-2-naphthyl-N'-2-fluorenylurea; C092587:di-2-naphthylurea; C012177:2-aminofluorene; D015058:1-Naphthylisothiocyanate; D001128:Argon; D014508:Urea; D015081:2-Naphthylamine; C031287:2-naphthylisothiocyanate; D010261:Paraoxon