The metabolism of 4-aminobiphenyl in rat. IV. Ferrihaemoglobin formation by 4-aminobiphenyl metabolites

Abstract

1. Rats dosed with nitrosobenzene (56 mumol/kg), 4-chloronitrosobenzene (53 mumol/kg), 3,4-dichloronitrosobenzene (53 mumol/kg), 4-ethoxynitrosobenzene (86 mumol/kg), 4-nitrosobiphenyl(nitroso-BP, 55 mumol/kg) or 2-nitrosofluorene (256 mumol/kg) had maximal ferrihaemoglobin (HbFe3+) concn of 69, 68, 69, 67, 55 and 42% after 15, 25, 48, 35, 80 and 115 min, respectively, indicating differences in solubility of the nitrosoarenes in body fluids. 2. Nitroso-BP and 3-hydroxy-4-aminobiphenyl (3-hydroxy-ABP) catalytically oxidized HbFe2+ in bovine erythrocytes in vitro; nitroso-BP was three times as active as 3-hydroxy-ABP. 3',4'-Dihydroxy-4-aminobiphenyl (3',4'dihydroxy-ABP) showed only low catalytic activity, and seven other ABP metabolites exhibited only marginal activity. 3. Nitroso-BP was inactive in solutions of purified human Hb, but 3-hydroxy-ABP catalytically oxidized HbFe2+, indicating that nitrosoarenes oxidize HbFe2+ in erythrocytes in vitro and in vivo by a mechanism different from that of o-aminophenols. The second-order rate constant for HbFe2+ oxidation by 3-hydroxy-ABP at 37 degrees C was k2 = 19.1 +/- 1.31/mol per s.

Formation and Reduction of Aryl and Heterocyclic Nitroso Compounds and Significance in the Flux of Hydroxylamines

“…Nitroso compounds have been observed in alipathic and aromatic systems before (23,25,34,35,53,54). Nitrosobenzene was produced by degradation of phenylhydroxylamine in an O 2 -dependent reaction (53).…”

“…Nitrosobenzene was produced by degradation of phenylhydroxylamine in an O 2 -dependent reaction (53). Nitrosobiphenyl was shown to oxidize ferrous hemoglobin in vitro (54). The nitroso metabolite of sulfamethoxazole reacted with GSH, Cys, or NPR (23,25).…”

“…The rapid consumption of NADPH and O 2 could also yield toxicity due to oxidative stress (depletion of GSH, etc.). Aliphatic and aromatic nitroso compounds can form complexes with hemeproteins such as P450, myoglobin, or hemoglobin (54,(59)(60)(61). The alteration of the function of some of these hemeproteins could potentially induce a variety of toxicities.…”