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Biomedical subjects

W G Stillwell

Publications and source records attributed to W G Stillwell.

At least 37 records · Page 2Linked to original sources
PubMed1987

GC/MS analysis of biologically important aromatic amines. Application to human dosimetry.

Human exposure to aromatic amines may be monitored by measuring the amount of sulfinamide adduct bound to hemoglobin. In order to develop a sensitive and selective method for measuring aromatic amines present in low concentrations the mass spectra of the pentafluoropropionamide derivatives of a series of aromatic amines were determined under various ionization conditions. With electron ionization the aromatic amine derivatives typically yield intense molecular ions with fragmentation leading to elimination of C2F5 and COC2F5. Higher molecular weight polycyclic aromatic amines, e.g., 6-aminochrysene, give prominent molecular ions as well as intense ions corresponding to M - 174 (loss of CNHCOC2F5). With positive chemical ionization using methane as reagent gas the derivatives give protonated molecular ions as the base peaks, as well as the associated ions at M + 29 and M + 41. Negative ion chemical ionization yields, primarily, peaks corresponding to the loss of HF from the molecular anions. Negative ion chemical ionization with selected ion monitoring is generally more suitable than positive chemical ionization or electron ionization for the quantitative analysis of aromatic amines present in biological samples in the mid femtomolar range. Exposure of human subjects to aromatic amines was determined via basic hydrolysis of the isolated sulfinic acid amide hemoglobin adducts. Analysis of the derivatized extracts by gas chromatography/negative ion chemical ionization/mass spectrometry demonstrated the presence of aniline, ortho-, meta-, and para-toluidine, 2-naphthylamine, and 4-aminobiphenyl. The hemoglobin adduct levels of these amines in both cigarette smokers and nonsmokers were determined.(ABSTRACT TRUNCATED AT 250 WORDS)

Amines↗
PubMed1985

Bromobenzene metabolism in isolated rat hepatocytes. 18O2 incorporation studies.

Bromobenzene metabolites have been determined in incubations of hepatocytes isolated from untreated, phenobarbital-treated, and beta-naphthoflavone-treated rats. The total formation of bromobenzene metabolites was increased 9-fold in incubations with hepatocytes isolated from phenobarbital-treated rats, and the percentage of total metabolites recovered as bromobenzene-3,4-dihydrodiol and 4-bromocatechol was more than doubled, compared to incubations using hepatocytes from untreated rats. The formation of 2-bromophenol and bromobenzene-2,3-dihydrodiol was increased more than 10-fold in incubations of hepatocytes from beta-naphthoflavone-treated rats, as compared to those of hepatocytes from untreated rats, but recovery of 4-bromocatechol was unchanged. The mechanism of 4-bromocatechol formation from bromobenzene was investigated by examining the incorporation of 18O from 18O2 and H218O into 4-bromocatechol during incubations of bromobenzene with hepatocytes from untreated and phenobarbital-treated rats. Potential metabolic precursor molecules of 4-bromocatechol were also incubated individually with isolated hepatocytes, in order to clarify their roles in 4-bromocatechol formation. The results of these studies show that 4-bromocatechol is formed in intact cells almost exclusively from bromobenzene-3,4-dihydrodiol, rather than from the bromophenols. The bromophenols are, instead, mostly conjugated. The rapid and extensive conjugation of the bromophenols by intact cells may restrict their role as precursors of 4-bromocatechol, while bromobenzene 3,4-dihydrodiol is well converted into 4-bromocatechol by hepatocytes.

Animals↗
PubMed1980

The effects of age and glutathione depletion on hepatic glutathione turnover in vivo determined by acetaminophen probe analysis.

We have validated a method to assess hepatic glutathione turnover in individual animals in vivo. This method would be applicable to man by collection of bile samples via nasoduodenal intubation. The rate of glutathione turnover was calculated from the time course of the specific activity of the glutathione-acetaminophen adduct in bile after the administration of a radiolabeled glutathione precursor and a small dose of acetaminophen. Identical results were obtained with radiolabeled glutathione or with radiolabeled cysteine, glutamic acid or glycine as the precursors. The small dose of acetaminophen administered to trap glutathione as an excretable adduct did not stimulate glutathione turnover, which reflects glutathione synthesis under steady-state conditions. No evidence for two pools of glutathione with different half-lives was found; previous reports of two glutathione pools may have failed to account for hepatic protein turnover with subsequent release of radiolabeled amino acids for glutathione synthesis. In male rats, the rate of glutathione turnover decreased from 0.52 per hr at 6 weeks of age to 0.12 per hr at 24 weeks of age. After acute depletion of glutathione by diethylmaleate, the rate of glutathione turnover promptly doubled in all age groups. Similar increases in the rate of glutathione synthesis and in the ability to stimulate glutathione production in response to acute depletion in children might explain their decreased susceptibility to acetaminophen hepatotoxicity.

Acetaminophen↗
PubMed1978

Methylthio metabolites of naphthalen excreted by the rat.

Eight methylthio metabolites have been found as urinary products of the metabolism of naphthalene in the rat. One was 1-methylthionaphthalene. A second was a methylthio analog and the dihydrodiol, and a third was naphthalene substituted with one hydroxyl and one methylthio group. Two compounds with common structural elements were found; one of these was prepared by synthesis from anti-1,2:3,4-naphthalene dioxide and one from 1 beta, 2 alpha-dithyroxy-3 alpha, 4 alpha-epoxy-1,2,3,4-tetrahydronaphthalene by reaction with 2-keto-4-methylthiobutyric acid or with methionine. Each of these compounds contained one methythio group and three hydroxyl groups substituted on a tetrahydronaphthalene structure. Two metabolites with two methylthio groups and two hydroxyl substituents on a tetrahydronaphthalene ring were also detected; one of these was prepared by synthesis from the dioxide. The most likely metabolic origin of these methylthio metabolites is through the reaction of epoxides (including the diepoxide) with a nucleophile which may be methyl mercaptan, 2-keto-4-methylthiobutyric acid, or methionine.

Animals↗
PubMed1978

Formation in vivo of deuterated methylthio metabolites of naphthalene from L-methionine (methyl-d--3).

Studies were carried out with deuterated methionine (methyl-d--3) to determine if methylthio metabolites of naphthalene were formed in vivo by reaction with methionine-derived metabolites. Rats were maintained on a methionine-free diet for nine days followed by eight days on the same diet supplemented with L-methionine-d--3 prior to administration of naphthalene. When naphthalene metabolites isolated from urine were characterized by GC and GC-MS procedures, it was found that the incorporation of deuterium into the methylthio metabolites, as well as into a catechol methyl ether, was approximately 40%. These results show that the methyl group was derived from methionine.

Animals↗
PubMed1976

Gas chromatographic-mass spectrometric-computer methods in the study of drug metabolism.

The computer-assisted interpretation of repetitively scanned mass spectra can be of great value in the analysis of a complex mixture even in the absence of a library of reference spectra. We have written a set of interpretation programs for a PDP11/45 laboratory computer. A file structure is used that combines economy of storage with ease of creation and retrieval. User interaction is by a simple command language implemented by an interpreter. The program structure is such that additional functions can be added easily.

Chromatography, Gas↗
PubMed1976

Meperidine metabolites: identification of N-hydroxynormeperidine and a hydroxy-methoxy derivative of meperidine in biological fluids.

Gas chromatographic and gas chromatographic-mass spectrometric techniques were used to identify non-acidic metabolites of meperidine (N-methyl-4-phenyl-4-carbethoxypiperidine) excreted in human, rat, and guinea pig urine. Following enzymic hydrolysis N-hydroxynormeperidine was identified in the urine of all three species in addition to the expected metabolites normeperidine and meperidine N-oxide. In rat urine the p-hydroxyphenyl metabolite of meperidine was present in appreciable amounts. Also present in small quantity was a new phenolic metabolite of meperidine containing both hydroxyl and O-methoxyl substituents in the phenyl ring of the parent drug. The latter two metabolites were excreted as conjugates in the rat.

Adult↗
PubMed1975

Metabolism of glutethimide in the human.

Gas chromatographic and gas chromatographic-mass spectrometric techniques were used to identify metabolites of glutethimide excreted in human urine. In this study three monohydroxy metabolites, a dihydrodiol and three dihydroxy metabolites were detected after ingestion of the drug. The results indicate that the phenyl ring of glutethimide is metabolized by the epoxide-dihydrodiol pathway in the human following chronic administration of the drug.

Adolescent↗