Biomedical subjects

S D Nelson

Publications and source records attributed to S D Nelson.

273 records · Page 16Linked to original sources

PubMedDate not supplied

The formation and toxicity of catechol metabolites of acetaminophen in mice.

Acetaminophen is metabolized to a catechol, 3'-hydroxy-4'-hydroxyacetanilide (3-hydroxyacetaminophen), by mouse liver microsomes, and to both catechol and methylated catechol metabolites by the mouse in vivo. Although 3-hydroxyacetaminophen is less hepatotoxic in mice than acetaminophen itself, 3-methoxyacetaminophen is as hepatotoxic as acetaminophen and is subject to a glutathione threshold effect. However, neither metabolite is formed in sufficient amounts to account for the hepatotoxicity caused by acetaminophen in the mouse. Mouse liver microsomes catalyze the oxidation of acetaminophen to the catechol in an apparent cytochrome P-450-mediated reaction that is induced by phenobarbital and inhibited by piperonyl butoxide, but is surprisingly not altered by cobaltous chloride. Lineweaver-Burk analysis of the oxidation carried out by liver microsomes from control animals gave curvilinear plots that may indicate catalysis by two enzyme sites with apparent Km values of 0.011 and 0.271 mM, and apparent Vmax values of 87 and 162 pmol/mg/min, respectively. Neither an isotope effect nor an NIH shift were measurable in the microsomal metabolism of selectively deuterated analogs of acetaminophen to 3-hydroxyacetaminophen. These results, coupled with results of previous investigations with 18O2 and epoxide hydrolase, indicate that a mechanism different from either direct insertion or epoxidation is involved in the formation of the catechol metabolite of acetaminophen.

Acetaminophen↗

PubMedDate not supplied

The microsomal metabolism and site of covalent binding to protein of 3'-hydroxyacetanilide, a nonhepatotoxic positional isomer of acetaminophen.

Incubations of 3'-hydroxyacetanilide (3HAA) with hepatic microsomal preparations from phenobarbital-pretreated mice led to the formation of three products of aromatic hydroxylation, viz. 2',5'-, 3',4'-, and 2',3'-dihydroxyacetanilide, which were identified by GC/MS techniques and quantified by GLC analysis. NADPH-dependent covalent binding of radioactivity from [14C]3HAA to microsomal protein took place at almost four times the rate at which [14C]acetaminophen became irreversibly bound to protein under the same experimental conditions. This binding was inhibited by the addition to incubation media of ascorbate, glutathione, and the soluble proteins bovine serum albumin and bovine alpha s1-casein, but not by superoxide dismutase. Radioactivity from [14C]3HAA also became covalently bound to the added soluble proteins, the extent of which was greatest when the proteins contained a high content of free -SH groups. From an analysis of the effect of ascorbate and glutathione on both the covalent binding of 14C to protein and the production of the noncovalently bound products of 3HAA metabolism, it is concluded that reactive intermediates most likely derive from further oxidation of the primary 3HAA metabolites to electrophilic semiquinone and/or quinone species. Sulfhydryl groups appear to be the principal sites on protein at which covalent binding of these reactive metabolites of 3HAA takes place, a feature shared by the reactive species generated during acetaminophen metabolism.

Acetaminophen↗

PubMedDate not supplied

Drug and defibrillator interactions.

We reviewed the interactions of drugs and defibrillators, with emphasis on implantable cardioverter defibrillators. Articles were identified by searching MEDLINE from 1966 to the present; additional sources were identified from reference lists in these articles. Drugs have the potential for both beneficial and harmful interactions with electrical therapy. Beneficial interactions include reductions in the energy required to defibrillate the heart and in the occurrence of arrhythmia resulting in decreased shock frequency, prolonged device longevity, and improved patient comfort. Potentially harmful interactions include altering the detection of ventricular tachycardia; altering the pacing threshold, resulting in interference with bradycardia or antitachycardia pacing; development of incessant ventricular tachycardia; and increasing the energy required to defibrillate the heart. As the use of implantable cardioverter defibrillators increases, pharmacists should be aware of the potential for drug-device interactions.

Animals↗