Of the tetracyclines, minocycline is unique in causing a significant incidence of a lupus-like syndrome and autoimmune hepatitis. It is also unique among the tetracyclines in having a para-N,N-dimethylaminophenol ring. Many drugs that cause autoimmune reactions are oxidized to reactive metabolites by the myeloperoxidase (MPO) system of macrophages. In this study, we showed that minocycline is oxidized to reactive intermediates by MPO/H(2)O(2)/Cl(-), HOCl, horseradish peroxidase/H(2)O(2), or hepatic microsomes. When trapped with N-acetylcysteine (NAC), two adducts with protonated molecular ions at m/z 619 were isolated and analyzed by NMR. One represents attack of the aromatic D ring by NAC meta to the N,N-dimethylamino group, which implies that the reactive intermediate was a quinone iminium ion. The NMR of the other adduct, which was not observed when minocycline was oxidized by hepatic microsomes, indicates that the NAC is attached at the junction of the B and C rings. In the oxidation by HOCl, we found an intermediate with a protonated molecular ion of m/z 510 that represents the addition of HOCl to minocycline. The HOCl presumably adds across the double bond of the B ring, and reaction of this intermediate with NAC led to the second NAC adduct. We were surprised to find that the same NAC adduct was not observed after oxidation of tetracycline with HOCl, even though this part of the tetracycline structure is the same as for minocycline. We propose that one or more of these reactive metabolites are responsible for the idiosyncratic drug reactions that are specific to this tetracycline.