PubMed Health⌕ Search

Biomedical subjects

J T MacGregor

Publications and source records attributed to J T MacGregor.

At least 55 records · Page 3Linked to original sources
PubMed1987

Formation of a diazonium cation intermediate in the metabolism of sulphamethazine to desaminosulphamethazine in the rat.

14C-Sulphamethazinediazonium tetrafluoroborate (14C-SDTFB) when orally administered to rats was converted primarily to 14C-labelled desaminosulphamethazine (desaminosulmet) and methanol-insoluble residues in the gastrointestinal tract (gut). 14C-labelled sulphamethazine (sulmet), N4-acetylsulmet, the N4-glucose conjugate of sulmet and other unidentified products were also observed in the tissues and urine of rats given 14C-SDTFB. 2. When 14C-sulmet, nitrite and dimethylaniline were simultaneously administered to a rat by the oral route, one of the 14C-labelled products formed in the stomach was isolated and identified as 4-dimethylaminophenyl [4-(N-4,6-dimethyl-2-pyrimidinyl)sulphamidophenyl] diazene, providing evidence that 14C-sulmet was diazotized in the stomach of the animal. 3. SDTFB was weakly mutagenic when evaluated by the Ames test. 4. The methanol-insoluble 14C-labelled residues in the gut of rats dosed orally with 14C-SDTFB and 14C-sulmet + nitrite were partially converted to 14C-labelled desaminosulmet, sulmet, N4-acetylsulmet and other unidentified products when fed to recipient rats.

Aniline Compounds↗
PubMed1986

Assessment of cytogenetic damage by quantitation of micronuclei in human peripheral blood erythrocytes.

The incidence of micronuclei (Howell-Jolly bodies) in peripheral blood erythrocytes of splenectomized and nonsplenectomized humans was evaluated as an index of genotoxic exposure. Subjects with intact spleens had very low frequencies of micronucleated cells among circulating erythrocytes, even when these individuals were exposed to known clastogenic agents used in cancer therapy (no micronuclei were seen in 100,000 cells). After splenectomy, the frequency of micronuclei among erythrocytes of untreated subjects rose slowly and after 4 mo established a steady-state level of approximately 2.0/1000, a value similar to that reported for human bone marrow (Goetz et al. Relationship between experimental results in mammals and man: cytogenetic analysis of bone marrow injury induced by a single dose of cyclophosphamine. Mutat. Res., 31: 247-254, 1985; and Hogstedt et al. Micronuclei and chromosome aberrations in bone marrow cells and lymphocytes of humans exposed mainly to petroleum vapors. Hereditas, 94: 179-187, 1981. Chemotherapy increased these levels, with individual samples from patients on daily treatment often having values greater than 5 times higher than control levels. The frequency of micronucleated erythrocytes rose as the duration of clastogenic exposure increased and returned to near base-line levels approximately 4 mo after treatment was discontinued. These findings suggest that it will be possible to use analyses of circulating erythrocytes to assess genotoxic exposures among splenectomized human populations. The ease of sample preparation and scoring should make it possible to monitor individuals with greater statistical power than is feasible with conventional cytogenetic techniques.

Antineoplastic Agents↗
PubMed1985

Mutagenicity tests of lipid oxidation products in Salmonella typhimurium: monohydroperoxides and secondary oxidation products of methyl linoleate and methyl linolenate.

Nine hydroperoxy and hydroperoxy-epidioxy oxidation products derived from either autoxidation (AO) or photosensitized oxidation (PO) of methyl linoleate (MLo) or methyl linolenate (MLn) were tested for mutagenic activity by the Salmonella typhimurium his+ reversion assay using strains TA100, TA98, TA102, TA97 and TA1537. All nine oxidation products, monohydroperoxides from AO-MLn (I) or from PO-MLn (II), dihydroperoxides from PO-MLo (III), AO-MLn (IV) or PO-MLn (V), hydroperoxy epidioxides from PO-MLo (VI), AO-MLn (VII) or PO-MLn (VIII) and hydroperoxy bis-epidioxides from PO-MLn (IX), were weakly mutagenic in strains TA97 and/or TA100. The hydroperoxy epidioxides (VI-IX) exhibited significantly greater activity in strain TA97 than did the monohydroperoxides (I, II) or the dihydroperoxides (III-V). In strain TA100, all of the oxidation products tested exhibited similar activity. No major differences between products derived from autoxidized and photooxidized MLn (I v. II, IV v. V, VII v. VIII) were obtained. Rat-liver S-9 reduced the toxicity of all oxidation products to the tester strains. The greatest mutant yields were usually obtained in the presence of S-9, but mutagenic potency was sometimes greater without S-9. The structural feature common to all of the mutagenic oxidation products was the presence of a hydroperoxy group, suggesting that this characteristic is responsible for the observed mutagenicity, either directly or through a common degradative pathway to reactive products of lower molecular weight.

Animals↗
PubMed1984

The persistence of micronucleated erythrocytes in the peripheral circulation of normal and splenectomized Fischer 344 rats: implications for cytogenetic screening.

Micronucleated erythrocytes are selectively removed from the peripheral circulation of normal rats. Splenectomy prevents this selective removal. In normal rats treated daily for 20 days with 0.2 mg/kg triethylenemelamine (TEM), micronucleated normochromatic (mature) erythrocytes did not accumulate in peripheral blood. In these same animals, the frequencies of micronucleated cells among polychromatic (newly formed) erythrocytes increased from 0.21 to 5.25 per thousand in peripheral blood and from 1.75 to 31.5 per thousand in bone marrow. Since both control and induced frequencies in peripheral blood were approximately 15% of those in bone marrow, the removal appears to be equally efficient for cells containing either spontaneously occurring or clastogen-induced micronuclei. In splenectomized rats treated daily for 11 days with 0.2 mg/kg TEM, the frequency of micronucleated normochromatic erythrocytes (NCEs) in the peripheral blood rose rapidly to 9 times the control value and remained elevated for 50-55 days, indicating a life span approximately equivalent to that of normal erythrocytes. Among splenectomized rats exposed to either 0.15 mg/kg triethylenemelamine, 6.5 mg/kg cyclophosphamide, or 300 mg/kg urethane for periods exceeding the erythrocyte life span, the incidences of micronucleated NCEs in the peripheral blood rose steadily from a control value of 1.0 per thousand to maximum values of 15.0, 12.7 and 8.9 per thousand, respectively. During these extended exposures, the mean frequencies of micronucleated polychromatic erythrocytes (PCEs) in peripheral blood increased from a spontaneous value of 0.9 per thousand to 23.0, 13.0 and 6.6 per thousand, respectively, reflecting the frequencies among PCEs in the bone marrow and approximating the maximum values among NCEs in the peripheral blood. Thus, the frequency of micronucleated erythrocytes in the peripheral blood of splenectomized rats can be used as an index of both acute and cumulative chromosomal damage, while in normal rats the use of peripheral blood for cytogenetic monitoring is restricted by the selective removal of these micronucleated cells.

Animals↗
PubMed1984

Density-gradient enrichment of newly-formed mouse erythrocytes. Application to the micronucleus test.

To facilitate scoring micronuclei in peripheral blood erythrocytes, we have developed a centrifugation method to concentrate polychromatic and newly-formed normochromatic erythrocytes from microliter quantities of blood in a Percoll density gradient. Erythrocytes were separated into two discrete bands in a continuous gradient generated in situ in a microhematocrit capillary tube. The upper band contained white blood cells and a mixture of polychromatic and young normochromatic erythrocytes with a density of 1.080-1.082 g/ml. More than 75% of the polychromatic erythrocytes in samples of normal blood were recovered in the upper band. Older normochromatic erythrocytes migrated to the lower band. The frequency of polychromatic erythrocytes was increased from approximately 2% in whole blood to 60-80% in the upper band. After clastogen treatments, the elevated frequencies of micronuclei in the upper band polychromatic erythrocytes were similar to those in unfractionated blood. The frequencies of micronucleated normochromatic erythrocytes in the upper band were higher than those in whole blood at 48, 72 and 96 h after clastogen treatment, consistent with the expectation that the low-density normochromatic cells are newly derived from polychromatic erythrocytes. This density-gradient centrifugation technique enhances the efficiency of scoring micronuclei in the acute peripheral blood micronucleus test.

Animals↗
PubMed1984

Mutagenicity of flavones, chromones and acetophenones in Salmonella typhimurium. New structure-activity relationships.

28 flavones and 11 structurally-related flavonoids, chromones, and acetophenones, were tested for mutagenicity in the Salmonella typhimurium his reversion assay. 7 flavones, all of which were hydroxy- or methoxy-substituted at position 8, were moderate to strong mutagens in strain TA100 in the presence of rat liver S9 mix. In each case, the response of strain TA98 was either not significant or was very much weaker than that observed in strain TA100. The activation by S9 is not mediated by the microsomal cytochrome P450 system, since activation was not diminished when microsomes were removed by centrifugation at 100 000 X g. The observed strain specificity and structural requirements for activity indicate a mutagenic mechanism different from that associated with previously reported mutagenic flavonols (3-hydroxy-flavones) which are most active in strain TA98. The most mutagenic flavone investigated, 5,7,8-trihydroxy-flavone (norwogonin), had a potency of 17 revertants/nmole. Simplification of the chemical structures to hydroxy-substituted chromone and acetophenone systems revealed similar strain specificity, hydroxylation requirements, and S9 dependence within these structural classes, suggesting a similar activation pathway and mutagenic mechanism. The greatest mutagenic potency was observed within the flavone series, but significant potency was retained by similarly hydroxylated chromones and acetophenones. No mutagenic activity was observed in the absence of the aryl ketone moiety.

Acetophenones↗
PubMed1983

A rapid screen for cumulative chromosomal damage in mice. Accumulation of circulating micronucleated erythrocytes.

The frequency of micronuclei in normochromatic peripheral blood erythrocytes was found to be a useful index of cumulative chromosomal damage in repeatedly exposed mice. Although approximately 5 weeks of continuous treatment is required to reach the maximum steady state level, significant elevations in this index were achieved after only 5 daily exposures to non-lethal doses of all six genotoxins tested. The frequencies of micronucleated cells per 1000 normochromatic erythrocytes in weanling mice after 5 daily intraperitoneal (i.p.) injections of each test agent were: triethylenemelamine (0.5 mg/kg), 13.7; mitomycin C (2 mg/kg), 7.1; cyclophosphamide (22 mg/kg), 6.6; colchicine (1 mg/kg), 4.0; nitrogen mustard (0.4 mg/kg), 3.6; 7,12-dimethylbenz[a]anthracene (5 mg/kg), 6.6. Controls averaged 1.2 per 1000. During extended exposure to nitrogen mustard (5 i.p. injections of 0.4 mg/kg per week), the incidence of micronucleated erythrocytes rose steadily to a value of 12.0 per 1000, approaching the steady state after about 5 weeks of treatment. These results indicate that the measurement of micronuclei in peripheral blood erythrocytes is an effective and rapid method for estimating chromosomal damage in subchronically or chronically exposed animals. In practical application, routine blood smears taken during 90-day subchronic toxicity tests could be scored for micronuclei in less than 1 day, providing an economical estimate of in vivo chromosomal damage.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1983

Genetic effects of the flavonols quercetin, kaempferol, and galangin on Chinese hamster ovary cells in vitro.

The genotoxicity of selected flavonols was evaluated by multiple endpoints in Chinese hamster ovary (CHO) cells. Chromosomal aberrations, sister-chromatid exchange (SCE), and forward mutation at 4 gene loci were measured in a single population of cells exposed to quercetin, kaempferol, or galangin for 15 h with and without metabolic activation. The incidence of chromosomal aberrations was significantly increased by quercetin in the absence of activation and by kaempferol and galangin with and without activation. Flavonol treatment affected SCE and mutation at the hgprt, aprt, or Na+/K+-ATPase loci only marginally, but significantly increased mutation frequencies at the tk locus. The response at the tk locus suggests that the CHO cells may behave similarly to L5178Y cells, in which the tk locus is thought to reflect chromosomal lesions in addition to point mutation. These results indicate that, at least under the conditions examined, flavonols induce chromosomal aberrations in CHO cells, but have little effect on point mutation or SCE.

Animals↗
PubMed1983

In vivo exposure to plant flavonols. Influence on frequencies of micronuclei in mouse erythrocytes and sister-chromatid exchange in rabbit lymphocytes.

No consistent increases in the micronucleus frequency were observed in bone marrow or peripheral blood erythrocytes from mice treated with quercetin, rhamnetin, neohesperidin dihydrochalcone, or hesperetin dihydrochalcone under various exposure and sampling conditions. Over the dose range of 100-1000 mg/kg, quercetin failed to increase significantly erythrocyte micronucleus frequencies either (1) in bone marrow of male mice at 6 h after the second of 2 i.p. or oral doses given 24 h apart, or at 48, 96 or 192 h after a single i.p. or oral dose, or (2) in peripheral blood of male or female mice sampled for 7 consecutive days following a single i.p. dose. Feeding 5% or 10% quercetin for 8 days also failed to increase the micronucleus frequency in bone marrow erythrocytes of female or male mice. Hesperetin dihydrochalcone and neohesperidin dihydrochalcone, at p.o. doses of 100-1000 mg/kg, did not increase the micronucleus frequency in bone marrow erythrocytes 6 h after the second of 2 doses 24 h apart, nor did rhamnetin at 48 or 96 h after a single i.p. dose of 1000 mg/kg. Galangin, in contrast, did significantly increase the micronucleus frequency in bone marrow and blood erythrocytes under certain conditions, but the largest increases were only between 2 and 3 times control values and these were observed at highly toxic doses. Rabbits given up to 250 mg/kg quercetin i.p. showed no treatment-related increase in the sister-chromatid-exchange frequency in peripheral blood lymphocytes sampled at 1 and 7 days after treatment. These results fail to confirm published data which report a markedly increased frequency of micronuclei in bone marrow erythrocytes from quercetin-treated mice, show no quercetin-related alterations in the sister-chromatid-exchange frequency in rabbit lymphocytes, and indicate that clastogenesis in bone marrow erythroblasts due to oral or i.p. administration of the flavonols studied is at most very weak.

Animals↗
PubMed1983

Negative Ames tests of epoxide fatty methyl esters derived from hemolysis of linoleic acid hydroperoxides.

Five isomeric epoxyhydroxyene and epoxyoxoene fatty esters derived from hemolytic decomposition of linoleic acid hydroperoxide were tested for mutagenicity by the "Ames' top-agar incorporation method using S-9 mix derived from livers of male rats pretreated with Aroclor 1254. The epoxide fatty esters tested--methyl trans-12,13-epoxy-erythro-11-hydroxy-cis(trans)-9-octadecenoate and methyl trans-12,13-epoxy-threo-11-hydroxy-cis(trans)-9-octadecenoate (each composed of approximately 80% cis-9-ene and 20% trans-9-ene), methyl trans-12,13-epoxy-9-oxo-(trans-10-octadecenoate, methyl trans-12,13-epoxy-9-hydroxy-trans-10-octadecenoate and methyl cis-12,13-epoxy-9-oxo-trans-10-octadecenoate--had structural characteristics similar to certain potent mutagens. However, these esters were not mutagenic in Salmonella typhimurium strains TA100, TA98 or TA1537 at concentrations up to 2000 micrograms/test plate. Under the same test conditions, the methyl ester of hydroperoxy linoleic acid, from which these epoxides were derived, was weakly mutagenic in strain TA100 and possibly also in strain TA98.

Animals↗
PubMed1983

Micronuclei in circulating erythrocytes: a rapid screen for chromosomal damage during routine toxicity testing in mice.

Micronuclei in circulating erythrocytes provide a convenient measure of genetic damage resulting from chromosomal breakage or anaphase lag in bone marrow erythroblasts. The assay is easily integrated with acute, subchronic, or chronic toxicity tests. Scoring micronucleated erythrocytes in blood rather than bone marrow permits repeated sampling, simplifies sample preparation, and provides a more favorable cell population for scoring. Micronucleated erythrocytes accumulate during repeated exposures to clastogens and reach a maximum steady-state frequency after about five weeks of continuous treatment. Measurement of micronuclei in peripheral blood is therefore ideally suited for inclusion with routine subchronic toxicity tests. The same smear made for differential white blood cell counts at or near the end of the study can be scored for micronucleated erythrocytes, minimizing the effort required for this additional information and also permitting retrospective evaluation of completed studies.

Animals↗