Disease relevance of Smx-HA

• INTERVENTIONS: Lymphocytes were assayed with tetrazolium to determine toxicity from the hydroxylamine of sulfamethoxazole [1].
• This is the first report of the formation and excretion of sulfamethoxazole hydroxylamine in patients with acquired immunodeficiency syndrome [2].
• Because of potential differences between HIV-infected patients and healthy subjects in oxidative metabolism, future studies of inhibitors of sulfamethoxazole hydroxylamine formation should be conducted in the HIV population [3].
• Compounds implicated in both drug-induced necrosis (N-acetyl-p-benzoquinone imine; NAPQI) and drug hypersensitivity (sulfamethoxazole hydroxylamine; SMX-HA) were examined and their effects on [Ca2+]i compared with those of the T cell mitogen phytohemagglutinin (PHA; 1.5 micrograms/ml) and the calcium ionophore ionomycin (2.5 microM) [4].

High impact information on Smx-HA

• In an in vivo study in six healthy volunteers the inhibition of the cytochrome P450-mediated generation of the toxic metabolite in the presence of fluconazole was shown by a 94% decrease in the area under the plasma concentration-time curve of sulfamethoxazole hydroxylamine [5].
• However, patients with liver toxicity excreted less sulfamethoxazole hydroxylamine [2].
• In this paper we report the N4-oxidation of sulfamethoxazole by activated monocytes and neutrophils (human and canine) to form sulfamethoxazole hydroxylamine and nitrosulfamethoxazole [6].
• Covalent adduct formation by sulfamethoxazole hydroxylamine was detected in normal human epidermal keratinocytes, even in the absence of cell death, and was increased with glutathione depletion [7].
• In addition, polyclonal antibodies to both NADH cytochrome b5 reductase and cytochrome b5 significantly inhibited reduction activity for sulfamethoxazole hydroxylamine [8].

Chemical compound and disease context of Smx-HA

• We measured the urine concentrations of sulfamethoxazole, sulfamethoxazole hydroxylamine, and N-sulfamethoxazole on days 3 and 10 in 15 patients with acquired immunodeficiency syndrome treated with a combination product of trimethoprim (15 mg/kg/day) and sulfamethoxazole (75 mg/kg/day) [2].
• With prior depletion of glutathione, however, normal human epidermal keratinocytes became susceptible to the toxicity of sulfamethoxazole hydroxylamine [7].
• The effect of cimetidine on the formation of sulfamethoxazole hydroxylamine in patients with human immunodeficiency virus [3].
• The hydroxylamine of sulfamethoxazole produced concentration-dependent toxicity in HIV-infected cells, with marked toxicity seen when HIV-infected cells were incubated with 400 microM of the hydroxylamine (82 +/- 8%); this was significantly greater than the toxicity seen among noninfected cells (p < 0.01) [9].

Anatomical context of Smx-HA

• In this study, we examine whether differences in the biochemical processing of sulfamethoxazole hydroxylamine (SMX-NOH) and dapsone hydroxylamine (DDS-NOH) by erythrocytes [red blood cells (RBCs)] contribute to this differential incidence [10].

Associations of Smx-HA with other chemical compounds

• Cimetidine likely caused this decrease in sulfamethoxazole hydroxylamine excretion through inhibition of CYP3A4 [3].

Gene context of Smx-HA

• We conclude that sulfamethoxazole hydroxylamine is an authentic in vivo metabolite in humans, probably formed predominantly by cytochrome P450 in the liver [11].

Analytical, diagnostic and therapeutic context of Smx-HA

• The reduction of sulfamethoxazole hydroxylamine and nitrososulfamethoxazole by plasma and the plasma redox balance in the presence of nitrososulphamethoxazole were also determined by HPLC [12].

References