Eugene B. Hansen
National Center for Toxicological Research
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Xenobiotica | 1988
Carl E. Cerniglia; Eugene B. Hansen; Kenneth J. Lambert; Walter A. Korfmacher; Dwight W. Miller
1. Strains of the fungus Cunninghamella elegans ATCC 9245 and 36112 were tested for their ability to transform the antihistamines methapyrilene (I), thenyldiamine (II) and tripelennamine (III). 2. Antihistamine metabolites were isolated by h.p.l.c., and identified by their 1H-n.m.r. and mass spectral properties. 3. All three drugs were transformed by both C. elegans strains to N-oxidized and N-demethylated derivatives. Metabolism during 96 h of incubation amounted to 85% for (I), 64% for (II), and 83% for (III). Metabolites soluble in organic solvents amounted to 62% to 86% of the total metabolism; approximately 88% to 95% of the organic-soluble metabolites were N-oxide derivatives of each antihistamine.
Xenobiotica | 1997
Donglu Zhang; Eugene B. Hansen; Joanna Deck; Thomas M. Heinze; Allison L. Henderson; Walter A. Korfmacher; Carl E. Cerniglia
1. Metabolites formed during incubation of the antihistamine cyproheptadine hydrochloride with the zygomycete fungus Cunninghamella elegans in liquid culture were determined. The metabolites were isolated by hple and identified by mass spectrometric and proton nmr spectroscopic analysis. Two C elegans strains, ATCC 9245 and ATCC 36112, were screened and both produced essentially identical metabolites. 2. Within 72 h cyproheptadine was extensively biotransformed to at least eight oxidative phase-I metabolites primarily via aromatic hydroxylation metabolic pathways. Cyproheptadine was biotransformed predominantly to 2-hydroxycyproheptadine. Other metabolites identified were 1- and 3-hydroxycyproheptadine, cyproheptadine 10,11-epoxide, N-desmethylcyproheptadine, N-desmethyl-2-hydroxycyproheptadine, cyproheptadine N-oxide, and 2-hydroxycyproheptadine N-oxide. Although a minor fungal metabolite, cyproheptadine 10,11-epoxide represents the first stable epoxide isolated from the microbial biotransformation of drugs. 3. The enzymatic mechanism for the formation of the major fungal metabolite, 2-hydroxycyproheptadine, was investigated. The oxygen atom was derived from molecular oxygen as determined from 18O-labelling experiments. The formation of 2-hydroxycyproheptadine was inhibited 35, 70 and 97% by cytochrome P450 inhibitors metyrapone, proadifen and 1-aminobenzotriazole respectively. Cytochrome P450 was detected in the microsomal fractions of C. elegans. In addition, 2-hydroxylase activity was found in cell-free extracts of C. elegans. This activity was inhibited by proadifen and CO, and was inducible by naphthalene. These results are consistent with the fungal epoxidation and hydroxylation reactions being catalysed by cytochrome P450 monooxygenases. 4. The effects of types of media on the biotransformation of cyproheptadine were investigated. It appears that the glucose level significantly affects the biotransformation rates of cyproheptadine; however it did not change the relative ratios between metabolites produced.
Xenobiotica | 1995
Eugene B. Hansen; B. P. Cho; Walter A. Korfmacher; Carl E. Cerniglia
1. Two strains of the filamentous fungus Cunninghamella elegans (ATCC 9245 and ATCC 36112) were screened for their ability to metabolize three alkylamine-type antihistamines; brompheniramine, chlorpheniramine and pheniramine. 2. Based on the amount of parent drug recovered after 168 h of incubation, C. elegans ATCC 9245 metabolized 60, 45 and 29% of brompheniramine, chlorpheniramine and pheniramine added respectively. The results from strain ATCC 36112 were essentially identical to those of strain ATCC 9245. 3. The metabolic products of N-oxidation and N-demethylation were isolated by reversed-phase hplc and identified by analysing their mass and proton nmr spectra. For all three antihistamines, the mono-N-demethylated metabolite was produced in the greatest amounts. The chloro- and bromo-substituents appeared not to affect the route of metabolism but did influence the relative amounts of metabolites produced. 4. Circular dichroism spectra of the metabolites and the unmetabolized parent antihistamines showed each to be a racemic mixture of the (+) and (-) optical isomers. In addition, comparison of the metabolism of racemic chlorpheniramine to that of optically pure (+) chlorpheniramine showed no significant differences in the ratios of metabolites produced. There was therefore no metabolic stereoselectivity observed by the fungal enzymes.
Rapid Communications in Mass Spectrometry | 2000
Steve Bajic; Daniel R. Doerge; Lin Lu; Eugene B. Hansen
A critical limitation of electrospray ionization (ESI) liquid chromatography/mass spectrometry (LC/MS) sources is the susceptibility to blockage of interface orifices due to the deposition of involatile components from the sample and/or mobile phase. These components, including salts, buffers, and ion-pairing agents, can be essential to the performance of the chosen analytical method. We report here the performance enhancements provided by a novel atmospheric pressure ionization (API) source in the analysis of erythromycin A (ERY) using mobile phases that contain involatile components. The enhanced robustness of the new source is derived from the use of a continuous flow of aqueous solvent at the sampling cone orifice that maintains unobstructed ion transmission. The ESI mass spectral responses measured for ERY, using an LC separation that incorporates 10 mM sodium phosphate with and without 10 mM octane sulfonate, were monitored by repeated injections over 13-15 h total analysis time. Minimal effects on ESI mass spectral responses (integrated peak area) or chromatographic performance (peak shape, retention time) were observed during these studies. In the absence of the aqueous cleaning flow, complete loss of mass spectral responses and total blocking of the sampling cone was observed in less than 30 min. Responses for ERY spiked into chicken and beef liver, and catfish muscle at or below the regulatory level of interest (100 ppb), were quantified by internal standard calibration using this procedure. These results demonstrate the ability of a novel API-MS ion source to perform analyses that require the use of involatile mobile phase additives.
Applied Microbiology and Biotechnology | 2000
Joanna D. Moody; Thomas M. Heinze; Eugene B. Hansen; Carl E. Cerniglia
Abstract Two strains of the filamentous fungus Cunninghamella elegans (ATCC 9245 and ATCC 36112) were grown in Sabouraud dextrose broth and screened for the ability to metabolize the ethanolamine-type antihistamine diphenhydramine. Based on the amount of parent drug recovered after 7 days incubation, both C. elegans strains metabolized approximately 74% of the diphenhydramine, 58% of this being identified as organic extractable metabolites. The organic extractable metabolites were isolated by reversed-phase high-performance liquid chromatography and identified by analyzing their mass and nuclear magnetic resonance spectra. Desorption chemical ionization mass spectrometry (DCIMS) with deuterated ammonia was used to differentiate possible isobaric diphenhydramine metabolites and to probe the mechanisms of ion formation under ammonia DCIMS conditions. C. elegans transformed diphenhydramine by demethylation, oxidation, and N-acetylation. The major metabolites observed were diphenhydramine-N-oxide (3%), N-desmethyldiphenhydramine (30%), N-acetyldidesmethyldiphenhydramine (13%), and N-acetyl-N-desmethyldiphenhydramine (12%). These compounds are known mammalian metabolites of diphenhydramine and may be useful for further toxicological studies.
Journal of the American College of Toxicology | 1993
Kenneth L. Dooley; Eugene B. Hansen; Winslow G. Sheldon; Frederick A. Beland
Aconiazide, a hydrazone derivative of isoniazid, has been proposed for the treatment of tuberculosis. As a first step toward assessing the safety of this drug, the effects of a daily oral 14-day treatment on weight gain, pathology, and several hematologic and clinical chemistry parameters were determined in Fischer 344 (F344) rats. Dosage-related changes in body weight were observed and these became significant at dosages of 500 mg aconiazide/kg body weight. Pathologic lesions involved the sciatic nerve, liver, and bone marrow, with the incidence typically becoming significantly elevated at dosages of 500 mg aconiazide/kg body weight. Aconiazide treatment caused statistically significant changes in certain clinical chemistry and hematologic parameters; however, the values of these were still within the normal range reported for rats of a comparable age. The plasma concentrations of aconiazide were dosage-related, tended to be higher in females, and did not increase with repeated dosing.
Journal of the American College of Toxicology | 1995
Frederick A. Beland; Kenneth L. Dooley; Eugene B. Hansen; Winslow G. Sheldon
Aconiazide, a hydrazone derivative of isoniazid, has been proposed for the treatment of tuberculosis. The toxicity of aconiazide was assessed by treating male and female Fischer 344 (F344) rats daily by gavage for 6 months at doses up to 400 mg/kg body wt. For comparison, the toxicity of isoniazid was determined following treatment in an identical manner at equimolar doses. Aconiazide resulted in only one death during the 6-month experiment, whereas isoniazid caused a significant increase in morbidity and mortality. Each drug induced significant dose-related decreases in body weight in both sexes, and isoniazid caused a significant decrease in liver weight in male rats. Isoniazid also induced centrilobular hepatic necrosis in male rats, a lesion not observed upon aconiazide treatment. Plasma drug levels were ≥10-fold greater in rats administered isoniazid as compared to aconiazide. The higher levels of free drug observed with isoniazid may contribute to greater toxicity of isoniazid compared to aconiazide.
Electrophoresis | 1998
Chun‐Sheng Liu; Xing-Fang Li; Devanand M. Pinto; Eugene B. Hansen; Carl E. Cerniglia; Norman J. Dovichi
Journal of Agricultural and Food Chemistry | 1997
Wenhong Luo; Eugene B. Hansen; Catharina Y. W. Ang; Joanna Deck; James P. Freeman; Harold C. Thompson
Journal of Chromatographic Science | 1993
Walter A. Korfmacher; Joseph Bloom; Mona I. Churchwell; Timothy A. Getek; Eugene B. Hansen; Kevin T. McManus