Sequential enzyme-catalyzed metabolism of 4-nitrotoluene to S-(4-nitrobenzyl)glutathione.
[14C]-4-Nitrotoluene was metabolized by rat liver postmitochondrial supernatant containing NADPH, reduced glutathione and a sulfate activating system to 4-nitrobenzyl alcohol, 4-nitrobenzyl sulfate, and S-(4-nitrobenzyl) glutathione. Formation of both sulfur-containing metabolites was dependent on the presence of a sulfate activating system. These results suggest that the glutathione conjugate was derived from 4-nitrobenzyl sulfate. Reaction of 4-nitrobenzyl sulfate with glutathione was not detected in pH 7.4 buffer, but rat liver cytosol catalyzed the formation of the glutathione conjugate from 4-nitrobenzyl sulfate. These results show that 4-nitrotoluene is metabolized in rat liver by sequential side chain oxidation, sulfation, and glutathione conjugation. Furthermore, they indicate that, unlike certain other arylmethyl sulfates, 4-nitrobenzyl sulfate is not highly reactive.
D000818:Animals; D003600:Cytosol / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D014050:Toluene / Q000031:analogs & derivatives* / Q000378:metabolism
D014050:Toluene; C038391:S-(4-nitrobenzyl)glutathione; C017572:4-nitrotoluene; D005978:Glutathione