Biomedical subjects

J Nickols

Publications and source records attributed to J Nickols.

16 recordsLinked to original sources

PubMed1996

Carcinogenicity tests of methyl-n-amylnitrosamine (MNAN) administered to newborn and adult rats and hamsters and adult mice and of 2-oxo-MNAN administered to adult rats.

We examined the toxicity and carcinogenicity in rodents of methyl-n-amylnitrosamine (MNAN), multiple doses of which are known to induce esophageal and nasal tumors in rats. A single i.p. injection of 50-70 mg MNAN/kg into adult rats produced a 74% incidence of esophageal squamous carcinomas (mean latency, 63 weeks). Single doses of 3.0-12.5 mg/kg of MNAN injected into newborn and 3-day-old rats and hamsters were not carcinogenic in rats and only weakly carcinogenic in hamsters. The low doses (used because larger doses produced lethal interstitial pneumonia) probably explain the low carcinogenicity, despite previous findings of extensive formation of stable hydroxy-MNANs from MNAN by the esophagus of both species at these ages, which may indicate MNAN activation. One i.p. injection of 70-100 mg MNAN/kg into adult Syrian hamsters was weakly carcinogenic for the esophagus and forestomach. Six injections of 75 mg MNAN/kg into adult hamsters induced lung and nasal cavity tumors (65 and 43% incidences, respectively), but only a few esophageal tumors. Three injections of 15 mg MNAN/kg into adult Swiss mice induced lung adenomas and esophageal papillomas in 71 and 32% incidences, respectively. These results partially agreed with previous studies on hydroxy-MNAN formation by the esophagus of these species. Six s.c. injections of 75 mg 2-oxo-MNAN/kg into adult rats induced tumors of the nasal cavity, esophagus and soft tissue at the injection site in 68, 63, and 32% incidences, respectively. This does not support the view that 2-oxo-MNAN is an active metabolite of MNAN.

Animals↗

PubMed1994

Effect of catechol and ethanol with and without methylamylnitrosamine on esophageal carcinogenesis in the rat.

Alcohol consumption and cigarette smoking are synergistic etiologic factors for squamous cell carcinoma of the esophagus in Western countries. Catechol, a constituent of cigarette smoke, was previously found to be a co-carcinogen with methyl-n-amylnitrosamine (MNAN) for esophageal tumors in rats, when it was given in the diet. Here we tested whether the inclusion of ethanol in a similar system had an additional promoting effect on esophageal carcinogenesis. Male MRC - Wistar rats were injected three times i.p. with 25 mg MNAN/kg starting from 7 weeks of age. A second group of rats was injected similarly with MNAN and treated for life with 10% ethanol and 0.2% catechol in the drinking water, starting at 6 weeks of age. One or more test chemicals were omitted in other groups. The rats were maintained until they died and were necropsied. The number of esophageal papillomas/rat was 2.18 +/- 0.36, 4.27 +/- 0.53, 2.54 +/- 0.48 and 3.21 +/- 0.52 (mean +/- SE) in groups treated with MNAN alone, MNAN + ethanol + catechol, MNAN + ethanol and MNAN + catechol, respectively. Esophageal carcinomas showed a similar trend, with the number of carcinomas/rat equal to 0.23 +/- 0.08 in the MNAN alone group and 0.50 +/- 0.14 in the MNAN + ethanol + catechol group. Tumor multiplicities for the esophageal papillomas and carcinomas were significantly (P < 0.05) greater in the MNAN + ethanol + catechol group than in the MNAN group. These findings indicate that, in the esophagus, catechol alone was not significantly co-carcinogenic with MNAN when it was given in the drinking water (unlike when given in the diet in our previous study), but that ethanol + catechol given in the water was co-carcinogenic with MNAN. Seven of 19 rats given ethanol + catechol without MNAN developed esophageal papillomas, as compared to zero incidence in untreated controls (P = 0.06). Forestomach papillomas occurred in 22% of all rats given catechol. Hence, for esophageal tumor induction, ethanol and catechol were co-carcinogenic with MNAN and appeared to be tumorigenic when given without MNAN. Ethanol and catechol could have increased the carcinogenicity because they affected MNAN metabolism. As a partial test of this possibility, the effect of feeding these compounds for 5-7 weeks separately or together was examined on 2-, 3-, 4-and 5-hydroxy-MNAN (HO-MNAN) production from MNAN by the esophagus and liver slices from freshly killed rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

Metabolism of N-nitrosomethyl-n-amylamine by microsomes from human and rat esophagus.

Asymmetric dialkylnitrosamines induce esophageal cancer in rats and hence might be involved in the etiology of this cancer in humans. As a test of this hypothesis, we examined whether nitrosamines can be activated by segments of human esophagus and by microsomes of human and rat esophagus and liver. Specimens of 8 human esophagi were removed less than 6 h after death, and segments were incubated for 6 h with 23 and 300 microM N-nitrosomethyl-n-amylamine (NMAA). Hydroxy-NMAA yields were determined by gas chromatography-thermal energy analysis and were insignificant except for those of 5-hydroxy-NMAA, which were low. Microsomes were prepared from 4 batches of human esophagi and samples with 0.6 mg protein were incubated for 20 min with NMAA and cytochrome P-450 cofactors. We determined hydroxy-NMAAs as before and aldehydes by high-performance liquid chromatography of their 2,4-dinitrophenylhydrazones. Incubation of these microsomes with 12 mM NMAA yielded mean values of 0.64 nmol formaldehyde ("demethylation"), 0.21 nmol pentaldehyde ("depentylation"), and 0.56 nmol total hydroxy-NMAAs/min/mg protein. Metabolite yields under various conditions were determined, including a demonstration that carbon monoxide inhibited 81% of NMAA demethylation, indicating that cytochrome P-450 enzymes were involved. We also examined N-nitrosodimethylamine (NDMA) demethylation by the same microsomes. Rat esophageal microsomes dealkylated NMAA and NDMA similarly to human esophageal microsomes, but with 2-6 times and twice the activity, respectively. Human and rat esophageal microsomes demethylated 6 mM NMAA 18-20 times as rapidly as they demethylated 5 mM NDMA, in contrast to liver microsomes of these species, which demethylated 6 mM NMAA only 0.9-1.4 times as rapidly as they demethylated 5 mM NDMA. However, liver microsomes of both species were more active than esophageal microsomes for NMAA depentylation. The occurrence of NMAA demethylation and (to a lesser extent) depentylation with both human and rat esophageal microsomes is important because these are the activating reactions, and suggests that both human and rat esophagus contain P-450 isozymes that specifically dealkylate asymmetric dialkylnitrosamines.

Animals↗

PubMed1991

Effects of 2,4,5-trichlorophenoxyacetic acid, pentachlorophenol, methylprednisolone, and Freund's adjuvant on 2-hydroxyethylnitrosourea carcinogenesis in MRC-Wistar rats.

A link was proposed between human non-Hodgkin's lymphoma and exposure to 2,4,5-trichlorophenoxyacetic acid (245T) and pentachlorophenol (PCP). To test this view and the hypothesis that immune suppression or stimulation could affect B-cell lymphoma (BCL) induction, we administered chronically to MRC-Wistar (MRC-W) rats of both sexes 98% pure 245T (600 mg/kg diet), 86% pure PCP (500 mg/kg diet), methylprednisolone (20 mg/kg ip weekly), and Freund's adjuvant (0.5 ml im every 3-6 wk) for 40 wk, together with 75 mg 2-hydroxyethylnitrosourea (HENU)/l drinking water, a system known to induce B-cell lymphoma. The 245T was shown to contain only 1-4 micrograms/kg each of 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and 2,3,7,8-tetrachlorodibenzofuran (TCDF), but the PCP contained 25 micrograms TCDD and 670 micrograms TCDF/kg. HENU given alone induced B-cell lymphoma and osteosarcoma as before, with higher incidences of both tumors in males than in females. The B-cell lymphoma diagnosis was confirmed by immunologic typing of cell-surface markers and by probes for gene rearrangements. Coadministration with HENU of three of the four test agents did not affect tumor incidence, but PCP acted synergistically with HENU to induce acute myelocytic leukemia. PCP given alone or with HENU induced a 40-67% incidence of liver cell adenomas in the female rats. These effects were probably not due to TCDD in the PCP. HENU induced acute myelocytic leukemia and lung tumors in Wistar rats and n-butylnitrosourea induced acute myelocytic leukemia in MRC-Wistar rats, indicating that B-cell lymphoma induction was specific to the HENU-MRC-Wistar rat model.

2,4,5-Trichlorophenoxyacetic Acid↗

PubMed1990

2-Hydroxyethylnitrosourea induction of B cell lymphoma in female Swiss mice.

Groups of 30 adult Swiss mice of both sexes from the Eppley Institute breeding colony were treated with 37.5 or 75 mg 2-hydroxyethylnitrosourea (HENU)/l citrate buffer, given as drinking water on 4 days/week from 6-8 weeks of age for life. A third group of mice was untreated. Incidences of generalized B cell lymphoma (BCL) were 67% (males) and 87% (females) for the higher dose of the nitrosourea, 29% (males) and 79% (females) for the lower dose and 0% (males) and 7% (females) for the untreated mice. Tumor latencies were 23 weeks (high dose) and 27 weeks (low dose) in the females and 6-7 weeks longer in the males. A B-cell origin of the lymphomas was indicated by the pathology and tumor distribution and was confirmed in 4 mice by immunophenotyping and in 6 mice by probes for gene rearrangements. This system may be an effective means of inducing B cell lymphoma with a carcinogen.

Animals↗

PubMed1989

Formation of hydroxy derivatives, aldehydes, and nitrite from N-nitrosomethyl-n-amylamine by rat liver microsomes and by purified cytochrome P-450 IIB1.

The metabolism was examined of the esophageal carcinogen N-nitrosomethylamylamine (NMAA) by liver microsomes and slices from adult male Sprague-Dawley rats. Hydroxylation at C-2 to C-5 of the amyl group to give stable hydroxy-NMAAs was studied by gas chromatography-thermal energy analysis to determine the products. Microsomal metabolism produced mainly 4-hydroxy-NMAA, proceeded optimally in 100 mM phosphate at pH 7.4, and showed no sex differences. Induction by phenobarbital (PB) and 3-methylcholanthrene produced effects which were similar in slices and microsomes, with PB inducing hydroxylation at all positions and 3-methylcholanthrene specifically inducing 3-hydroxylation by factors of 2- and 6-fold. Clofibrate and isoniazid treatments did not affect NMAA metabolism by liver slices. Aroclor-1254 strongly induced microsomal 2- and 3-hydroxylation. For 2- to 5-hydroxylation, Km values for uninduced microsomes were, respectively, 1.6, 1.2, 0.3, and 1.1 mM, with Vmax of 0.08, 0.26, 1.06, and 0.15 nmol/min/mg protein. With PB-induced microsomes, all 4 Km values were 0.4-0.7 mM. Liver microsomal production of nitrite and aldehydes from NMAA was determined colormetrically or (for pentaldehyde) by high-pressure liquid chromatography of the 2,4-dinitrophenylhydrazone. Uninduced microsomes produced nitrite, formaldehyde and pentaldehyde from 0.6 mM NMAA at rates that were, respectively, 0.15, 0.72, and 1.15 times that for 4-hydroxylation. PB especially induced depentylation, whereas 3-methylcholanthrene induced depentylation and denitrosation, but suppressed demethylation. A reconstituted system containing cytochrome P-450 IIB1 gave metabolite ratios similar to those in PB-induced microsomes. The results account for most of the possible primary metabolites of NMAA and demonstrate the selectivity for metabolism at each position.

Aldehydes↗

PubMed1989

Blepharospasm associated with olivopontocerebellar atrophy.

We report two cases of cranial dystonia (blepharospasm) associated with olivopontocerebellar atrophy (OPCA). The pathophysiology of blepharospasm appears to involve an increased excitability of the interneurons of the blink and corneal reflexes. It is hypothesized that blepharospasm associated with OPCA might be due to rostral brainstem lesions disrupting central dopaminergic and cholinergic pathways, resulting in disinhibition of brainstem reflexes or denervation supersensitivity of the facial nuclear complex.

Blepharospasm↗

PubMed1988

The anterior temporal electrode in the EEG of the adult.

The anterior temporal cerebral region is not well covered, electroencephalographically, by the usual EEG electrodes. Numerous attempts have been made to add anterior temporal electrodes. There has been discussion regarding the amount of additional information actually attributable to those electrodes. We systematically evaluated the abnormalities revealed by one such noninvasive set of anterior temporal electrodes, D. Silverman's T1 and T2. A total of 624 consecutive EEGs were reviewed. We conclude that, in the adult, anterior temporal electrodes can add significantly to the information contained in the routine interictal EEG.

Adult↗

PubMed1971