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Biomedical subjects

S D Nelson

Publications and source records attributed to S D Nelson.

At least 217 records · Page 12Linked to original sources
PubMed1979

Mutagenicity and irreversible binding of the hepatocarcinogen, 2,4-diaminotoluene.

Mutagenicity of 2,4-diaminotoluene (DAT) in the Salmonella mutagenicity assay was increased with liver fractions from phenobarbital (PB) or beta-naphthoflavone (BNF) treated rats. Substitutions of the hydrogens in the methyl group of 2,4-DAT with deuterium resulted in a decrease in mutagenicity. Incubation of rat liver microsomes with tritiated 2,4-DAT in the presence of NADPH led to the formation of irreversibly bound products to microsomal protein. The rates of binding were not increased using microsomes from PB or BNF-treated rats and was not altered by deuterium substitution in the methyl group. Addition of superoxide dismutase, glutathione (GSH) or rat liver supernatant reduced 2,4-DAT irreversible binding, whereas 2,4-DAT mutagenicity was unaffected by superoxide dismutase addition. Injection of tritiated 2,4-DAT 100 mg/kg to rats lead to its irreversible binding to liver protein and ribosomal RNA and to kidney protein in vivo, again protein binding was not increased after prior treatment with PB or BNF. No irreversible interaction of tritiated 2,4-DAT with DNA either in vitro or in vivo could be demonstrated.

Animals↗
PubMed1979

Mutagenic activation of tris(2,3-dibromopropyl)phosphate: the role of microsomal oxidative metabolism.

The flame retardant tris(2,3-dibromopropyl)phosphate (Tris-BP) is converted to products which are mutagenic for Salmonella typhimurium TA 100 in the presence of rat liver microsomes, NADPH and oxygen. Other bromopropyl-compounds were also mutagenic; 2,3-dibromopropene and 2,3-dibromopropionic acid were directly mutagenic, whereas 2,3-dibromopropanol and tris(2-bromopropyl)phosphate were weakly mutagenic after addition of liver microsomes and cofactors. Typical in vivo and in vitro inhibitors of cytochrome P-450 inhibited Tris-BP mutagenicity. The effects of inducers of cytochrome P-450 on Tris-BP mutagenicity was dependent on the concentration of mutagen and microsomal protein in the assay, indicating complexity in the kinetics involved when dealing with possible multiple pathways that lead to mutagenicity. Addition of glutathione strongly inhibited Tris-BP mutagenicity. It is suggested that Tris-BP is oxidized to a reactive electrophile, possibly the 2-keto derivative, which could react with nucleophilic groups in DNA and thus lead to mutagenic events.

1-Propanol↗
PubMed1979

HLA antigen frequencies in flax byssinosis patients.

Not all workers exposed to flax dust contract byssinosis. It is not known what determines susceptibility or insusceptibility. This study is an attempt to establish whether the incidence of histocompatibility antigens is involved in susceptibility to the disease. Forty patients suffering from flax byssinosis were tissue-typed for HLA-A and -B antigens. HLA-B27 was significantly more common in the patients (22.5%) than in the controls (5.5%); P = 0.029 after correction for the number of antigens compared. HLA-A11 was present in twelve patients (30%) compared with 14% in the controls; after correction for the number of comparisons, this is not a statistically significant increase. Because HLA-B27, though significantly more common in flax byssinosis, is not necessary for its occurrence (77.5% of our patients did not have it), it is possible that the increase in the frequency of HLA-B27 is attributable to an association with other genes, perhaps those regulating the immune response or coding for antigens at other HLA loci.

Adult↗
PubMed1978

Covalent binding of 2,4-diaminoanisole and 2,4-diaminotoluene in vivo.

We have studied the activation of 2,4-diaminoanisole (2,4-DAA), a mutagenic hair-dye component, and 2,4-diaminotoluene (2,4-DAT), a hepatocarcinogen, to products which blind covalently to tissue macromolecules. Four hours after a dose of 100 mg/kg ring-labeled 3H-2,4-DAA, 0.30 nmol is found covalently bound per mg liver protein. This amount is increased by 83% after phenobarbital pretreatment, and by 43% after beta-naphthoflavone-pretreatment. Almost the same degree of binding is seen in kidneys. Subcellular fractionation of livers shows that most of the bound material is in the microsomal fraction. Similar levels of covalent protein binding is seen after administering ring-labeled 3H-2,4-DAT. No significant binding to DNA in vitro or in vivo could be demonstrated using 3H-2,4-DAA or 3H-2,4-DAT, whereas 3H-2,4-DAT is found to covalently bind to hepatic RNA.

Animals↗
PubMed1978

N-Hydroxyamide metabolites of lidocaine. Synthesis, characterization, quantitation, and mutagenic potential.

Two possible N-hydroxyamide metabolites of lidocaine were synthesized and characterized. A combined technique utilizing chemical-ionization mass spectrometry and stable isotope labeling demonstrated that these potentially carcinogenic N-hydroxyamides were neither present in human urine after oral lidocaine administration nor during intravenous infusion of lidocaine for the treatment of ventricular arrhythmias. However, small amounts of 2,6-dimethylphenylhydroxylamine were detected in the urine of all subjects. Mutagenesis assays using the Ames test showed that neither the N-hydroxyamides nor the N-hydroxyarylamine produced revertant colonies above background levels using the Salmonella tester strain TA-1538.

Animals↗
PubMed1978

HLA-antigen frequencies in patients with a Plummer-Vinson stricture.

Factors of individual susceptibility seem to be involved in the occurrence of Plummer-Vinson stricture, which is a permanent stricture of the cervical esophagus associated with long continued iron deficiency. Fifty female patients with Plummer-Vinson stricture were HLA typed and the antigen frequencies were compared with those of 75 female blood donors from the same geographic area and of the same race. A comparison was also made with the HLA antigen frequencies of a group of 200 blood donors (75 female and 125 male). There were no statistically significant differences in the HLA antigen distributions of the three groups.

Adult↗
PubMed1978

Hepatotoxicity and metabolism of iproniazid and isopropylhydrazine.

Iproniazid (1-isonicotinoyl-2-isopropylhydrazine), an antidepressant drug removed from clinical use because of hepatic injury, and isopropylhydrazine, a metabolite of iproniazid, were found to be potent hepatotoxins in rats. This animal model was used in studies in vivo and in vitro to define better the biochemical and chemical mechanism(s) by which iproniazid and isopropylhydrazine mediate hepatotoxicity. Phenobarbital, an inducer of a class of hepatic microsomal cytochrome P-450 enzymes, greatly potentiated the necrosis, whereas inhibitors of these microsomal enzymes such as cobalt chloride, piperonyl butoxide and alpha-naphthylisothiocyanate, prevented the necrosis. Bis-para-nitrophenyl phosphate, an inhibitor of esterase and amidase enzymes, prevented the necrosis caused by iproniazid but had no effect on the necrosis caused by isopropylhydrazine. Iproniazid and isopropylhydrazine labeled with tritium or carbon-14 in the isopropyl group were found to bind covalently to hepatic tissue macromolecules, and those pretreatments that increased hepatic necrosis significantly increased covalent binding, whereas those pretreatments which prevented necrosis significantly decreased covalent binding. Iproniazid labeled with tritium in the pyridine ring or carbon-14 in the carbonyl group did not bind significantly to hepatic tissue. Rats that were given iproniazid or isopropylhydrazine, labeled specifically with tritium and carbon-14 on the c-2 methine position of the isopropyl group, expired acetone and carbon dioxide labeled with carbon-14. More importantly, propane was expired and contained a ratio of 3H/14C that was identical to that in the administered iproniazid or isopropylhydrazine and also identical to the 3H/14C ratio of the metabolite that was covalently bound to hepatic tissue macromolecules. Experiments carried out with rat liver microsomes and isopropylhydrazine specifically labeled with deuterium, tritium and carbon-14 support the view that isopropylhydrazine is the metabolite of iproniazid that is oxidized by a microsomal P-450 enzyme to a species that alkylates tissue macromolecules. Some of the urinary metabolites excreted by rats that were administered hepatotoxic doses of iproniazid and isopropylhydrazine have been identified by cochromatography and isotope dilution with synthetic standards and by comparative mass spectra. Compounds excreted into the urine of rats dosed with iproniazid include iproniazid, iproniazid-1-oxide, isonicotinic acid, isonicotinoyl glycine, acetylisoniazid, isopropylhydrazine, 1-acetyl-2-isopropylhydrazine and acetone. Isopropylhydrazine, 1-acetyl-2-isopropylhydrazine, and acetone have been found in the urine of animals administered toxic doses of isopropylhydrazine.

Animals↗
PubMed1978

Decreased toxicity of the N-methyl analogs of acetaminophen and phenacetin.

The N-methyl analogs of p-hydroxyacetanilide (acetaminophen) and p-ethoxyacetanilide (phenacetin) were prepared and tested for toxicity. N-Methylacetaminophen was found to cause no hepatic necrosis in mice, rats, or hamsters in doses that caused massive hepatic necrosis in the same animals when acetaminophen was administered. Neither acetaminophen nor its N-methylated analog caused methemoglobinemia at these dose levels. Fischer rats that were administered large doses of acetaminophen (900 mg/kg s.c.) sustained necrosis in the proximal renal tubules, whereas N-methylacetaminophen caused no renal injury at higher dose levels (1800 mg/kg s.c.). N-Methylphenacetin caused no observable hepatic necrosis in 3-methylcholanthrene (3-MC) pretreated hamsters at dose levels higher than those in which phenacetin caused hepatic necrosis. Also, in contrast to phenacetin, N-methylphenacetin did not cause extensive methemoglobinemia in mice, rats, or hamsters.

Acetaminophen↗
PubMed1977

Quantification of lidocaine and several metabolites utilizing chemical-ionization mass spectrometry and stable isotope labeling.

Quantification of the suspected metabolites of lidocaine in humans was carried out using the direct insertion probe and chemicalionization mass spectrometry. Deuterated analogs of the metabolites of lidocaine were added to serial human plasma and urine samples and were used as internal standards following oral administration of 250 mg of lidocaine hydrochloride monohydrate to two male subjects and 202 mg of lidocaine free base to one male subject. The average results after analysis of the 0-24 hr urine samples, before beta-glucuronidase-sulfatase treatment, indicated the presence of seven of the possible metabolites in the following amounts (percent of administered dose based on the free base): lidocaine, 1.95; omega-ethylamino-2,6-dimethylacetanilide, 4.90; omega-amino-2,6-dimethylacetanilide, 0.88; m- and/or p-hydroxylidocaine, 0.73; m- and/or p-hydroxy-omega-ethylamino-2,6-dimethylacetanilide, 0.56; 2,6-dimethylaniline, 0.97; and 4-hydroxy-2,6-dimethylaniline, 63.5. Both N-ethyl- and N,N-diethylglycine were detected in human and Rhesus monkey urine, although quantification was not achieved.

Acetanilides↗
PubMed1977

Molecular basis for several drug-induced nephropathies.

A recent clinical advance has been the discovery that many drug-induced hepatic diseases result from the metabolic activation of chemically stable drugs to potent alkylating agents by the liver. In addition to the liver, however, the kidney also contains active enzyme systems capable of metabolically activating drugs and other chemicals. For this reason a systematic investigation of the possible role of metabolic activation in the pathogenesis of several drug-induced renal diseases has been undertaken. These laboratory results are reviewed in the light of the clinical spectrum of the renal injuries, and possible therapeutic implications of these new findings are briefly discussed. The potential use of these models of nephrotoxicity to probe a variety of physiologic and pathophysiologic mechanisms of renal function are noted.

Acetaminophen↗