Stephen P . Spielberg

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The use of 96-well microtiter plates and a programmable microplate reader to measure glutathione reductase in an assay based on reduction of 5,5'-dithiobis(2-nitrobenzoic acid) by GSH generated from an excess of GSSG is described. Samples are prepared in 96-well plates and absorbance at 415 nm with a reference wavelength of 595 is determined every 30 s for(More)
The N4-hydroxylation of sulfamethoxazole (SMX) to its hydroxylamine (SMX-HA) metabolite is the first step in the formation of reactive metabolites responsible for mediating hypersensitivity reactions associated with this compound. In rat hepatic microsomes, the NADPH-dependent oxidation of SMX to SMX-HA was increased 3-fold by pretreatment of rats with(More)
Arene oxide metabolites of aromatic anticonvulsants (phenytoin, phenobarbital, and carbamazepine) may be involved in the pathogenesis of hypersensitivity reactions. We investigated 53 patients with clinical sensitivity to anticonvulsants by exposing their lymphocytes in vitro to drug metabolites generated by a murine hepatic microsomal system. The diagnosis(More)
Potentially serious idiosyncratic reactions associated with sulfamethoxazole (SMX) include systemic hypersensitivity reactions and hepatotoxicity. Covalent binding of SMX to proteins subsequent to its N-hydroxylation to form N4-hydroxysulfamethoxazole (SMX-HA) is thought to be involved in the pathogenesis of these reactions. A polyclonal antibody was(More)
N4-oxidation of sulfonamides has been implicated in the pathogenesis of idiosyncratic reactions to these antimicrobials. In vitro toxicity assays employing mononuclear leukocytes as target cells have shown that the toxicity of sulfamethoxazole hydroxylamine (SMX-HA) is inhibited by exogenous glutathione, suggesting that conjugation with glutathione is an(More)
Systemic caffeine clearance and urinary metabolite profiles were determined in 15 subjects with diverse exposure histories to cytochrome P-450 inducers (cigarette smoke) and inhibitors (oral contraceptive steroids). A correlation was observed between caffeine clearance and a urinary ratio based on the molar recovery of paraxanthine 7-demethylation products(More)
Individual differences in metabolism of the sulfonamides may predispose patients to idiosyncratic reactions. Sulfonamides are metabolized by N-acetylation (mediated by a genetically polymorphic enzyme) and oxidation to potentially toxic metabolites. We examined 6 patients who had severe reactions to sulfonamides and compared them with 20 controls.(More)
The purpose of this study was to determine the molecular basis in the dog for an unusual and absolute deficiency in the activity of cytosolic N-acetyltransferase (NAT), an enzyme important for the metabolism of arylamine and hydrazine compounds. NAT activity towards two NAT substrates, p-aminobenzoic acid and sulfamethazine, was undetectable in dog liver(More)
Human lymphocytes incubated with a mouse hepatic microsomal drug metabolizing system were used to study the cytotoxicity of four anticonvulsants. In vitro toxicity assessed by trypan blue dye exclusion was significantly greater for compounds with relatively high clinical toxicity (mephenytoin and phenacemide) than those with only rare cytotoxic(More)