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Biomedical subjects

A Gold

Publications and source records attributed to A Gold.

At least 73 records · Page 4Linked to original sources
PubMed1989

Bacterial mutagenicity of new cyclopenta-fused cata-annelated polycyclic aromatic hydrocarbons, and identification of the major metabolites of benz[j]acephenanthrylene formed by Aroclor-treated rat liver microsomes.

Three novel cyclopenta-fused polycyclic aromatic hydrocarbons were synthesized, benz[d]aceanthrylene, benz[k]aceanthrylene, and benz[j]acephenanthrylene, and evaluated for mutagenic activity in the Ames Salmonella typhimurium plate incorporation assay. The two benzaceanthrylene derivatives were active at low S9 concentrations in strain TA98 (4 and 27 rev/nmole respectively), as had been predicted from the calculated delta Edeloc/beta values of the carbocations derived from opening of the cyclopenta-fused epoxide rings, but the majority of this mutagenicity appeared to be due to free-radical decomposition products of spontaneous endo-peroxide formation. These compounds were therefore not further investigated. Benz[j]acephenanthrylene was also an indirect-acting frameshift mutagen (8-12 rev/nmole in strain TA98), but unlike most of the previously assayed cyclopenta-fused polycyclic aromatic hydrocarbons exhibited no peak of activity at low S9 protein concentration. The principal metabolites formed from this compound by microsomes from Aroclor-treated rat liver were benz[j]acephenanthrylene-4,5-dihydro-4,5-diol (necessarily derived from hydration of benz[j]acephenanthrylene 4,5-oxide) and benz[j]acephenanthrylene-9,10-dihydro-9,10-diol (precursor to benz[j]acephenanthrylene-9,10-dihydrodiol 7,8-oxide, the bay-region diol-epoxide). Consideration of the reduced activity of this compound compared to the related structure chrysene, the S9 dependence curves, and the predicted delta Edeloc/beta values of the postulate active species, suggests that in contrast to most other cyclopenta-fused polycyclic aromatic hydrocarbons, bay-region diol-epoxide formation plays a greater role than epoxidation of the cyclopenta-fused ring in the metabolic activation of benz[j]acephenanthrylene.

Animals↗
PubMed1989

DNA adduct formation, metabolism, and morphological transforming activity of aceanthrylene in C3H10T1/2CL8 cells.

Aceanthrylene (ACE), a cyclopenta-fused polycyclic aromatic hydrocarbon (CP-PAH) related to anthracene, has been studied for its ability to be metabolized, to form DNA adducts, and to morphologically transform C3H10T1/2CL8 mouse embryo fibroblasts in culture. Although ACE has been previously shown to be a strong mutagen in Salmonella typhimurium strains TA89 and TA100, it did not transform C3H10T1/2 cells (0.4-16 micrograms/ml) under 2 treatment protocols: treatment (for 24 h) 1 day after seeding the cells; treatment (for 24 h) 5 days after seeding the cells. Both protocols are effective in detecting the morphological transforming activity of PAH and CP-PAH and the latter protocol has been shown to be effective in detecting chemicals which are active in the first protocol only with the additional treatment of the cells with a tumor promoter. ACE is metabolized by C3H10T1/2 cells to ACE-1,2-dihydrodiol (the cyclopenta-ring dihydrodiol) at a rate of 450 pmoles ACE-1,2-dihydrodiol formed/h/10(6) cells. ACE-7,8-dihydrodiol and ACE-9,10-dihydrodiol, identified as major Aroclor-1254-induced rat liver microsomal metabolites from their UV, NMR, and mass spectral data, were not identified in incubations of C3H10T1/2 cells with ACE. ACE-DNA adducts in C3H10T1/2 cells were isolated, separated, identified, and quantitated using the 32P-postlabeling method. ACE forms 4 major adducts and each was identified as an ACE-1,2-oxide/2'-deoxyguanosine adduct. The level of adduction was 2.18 pmoles ACE adducts/mg DNA after a 24-h incubation of ACE (16 micrograms/ml) with C3H10T1/2 cells. ACE-DNA adduct persistence and repair were evaluated in C3H10T1/2 cells using a hydroxyurea block after ACE treatment. ACE-DNA adducts were not repaired under the conditions used in the morphological transformation studies. Thus, ACE provides an interesting example of a mutagenic PAH which is metabolized by C3H10T1/2 cells to active intermediates, forms relatively stable and persistent 2'-deoxyguanosine adducts in C3H10T1/2 cells, and yet induces no detectable morphological transforming activity under the experimental conditions used.

Animals↗
PubMed1989

Effect of oral administration of haloperidol on plasma thyrotropin concentrations in men.

To investigate the effects of neuroleptics on plasma thyrotropin (TSH) concentrations, haloperidol tablets were administered orally to 34 normal male volunteers. Seventeen of the subjects received 4 mg; the other 17 received 10 mg. Plasma samples were collected at baseline and 1, 3, 4, 6, 14, 24, 36, 48, 72 and 96 hr after drug administration. Plasma TSH was assayed by a double antibody radioimmunoassay procedure. A significant change in plasma TSH occurred for all subjects (p less than 0.001). By multivariate analysis of variance, the dose x time interaction was not significant. However, a significant dose x time interaction was detected in a univariate analysis. After haloperidol 10 mg a statistically significant rise in TSH occurred at 3-4 hr, which corresponded to the time of attainment of maximal plasma haloperidol concentrations. A significant but modest correlation between plasma haloperidol and TSH was present at 3 hr (0.373; p less than 0.05). TSH concentrations at 14 hr after the 10 mg dose were not significantly correlated with simultaneous or peak plasma haloperidol concentrations. Consequently, only the release of TSH occurring at 3-4 hr after the 10 mg dose was attributed to the drug's effects.

Adolescent↗
PubMed1988

Porphinatoiron-mediated oxidation of polycyclic aromatic hydrocarbons.

Although porphinatoiron complexes have been used extensively as biomimetic catalysts for oxidation of aliphatic and olefinic hydrocarbons, few oxidations of polycyclic aromatic hydrocarbons (PAH) have been reported. In all cases, heterogeneous iodosobenzene/tetraphenylporphinatoiron(III) systems were employed, oxidations were inefficient and control experiments demonstrating the requirement for catalyst were not described. The current study investigates the oxidation of pyrene, benzo[a]pyrene and benzanthracene in a homogeneous m-chloroperoxybenzoic acid/bifacially hindered porphinatoiron system in which the peroxyacid was shown to be unreactive in the absence of catalyst. Pyrene and benzo[a]pyrene were oxidized efficiently, with pyrene yielding mixtures of 1.6- and 1.8-quinones and benzo[a]pyrene yielding mixtures of phenols and quinones. Benzanthracene was oxidized less efficiently, primarily at the meso positions, to give 7.12-quinone. Initial oxidation of meso carbons of benzo[a]pyrene (confirmed by the presence of the 6-hydroxy derivative as a product) and benzanthracene indicates that PAH-to-catalyst charge transfer may be an important oxidation pathway. Oxidation of pyrene was performed by addition of pyrene to observable oxo iron(V) species as well as in a catalytic reaction where excess peroxyacid was added to a solution of pyrene and catalyst and oxo iron(V) is not generated as an observable intermediate. Yields (based on oxidant consumed), were identical under both conditions, strongly supporting oxo iron(V) as a common intermediate.

Benz(a)Anthracenes↗
PubMed1987

Analysis of cyclopentafused isomers of benz(a)anthracene in wood smoke.

A previously-unidentified peak occurring in chromatograms of the polycyclic aromatic hydrocarbon fraction from wood smoke particulate extracts analysed by capillary gas chromatography on a DB-5 column was found to correspond in retention index and molecular mass either to benzo(a)fluoranthene or to benzo(1)aceanthrylene, one of a series of four novel and highly mutagenic cyclopentafused isomers of benz(a)anthracene. Detailed subfractionation, and re-analysis on a liquid crystal capillary column, indicated that the identity of this peak was most likely to be benzo(a)fluoranthene, a compound not previously reported in woodsmoke.

Benz(a)Anthracenes↗
PubMed1987

Morphological transforming activity and metabolism of cyclopenta-fused isomers of benz[a]anthracene in mammalian cells.

4 isomeric cyclopenta-derivatives of benz[e]anthracene (benz[a]aceanthrylene, benz[j]aceanthrylene, benz[l]aceanthrylene, and benz[k]acephenanthrylene) were examined for their ability to morphologically transform C3H10T1/2CL8 mouse-embryo fibroblasts. All of these polycyclic aromatic hydrocarbons studied except benz[k]acephenanthrylene transformed C3H10T1/2CL8 cells to both type II and type III foci in a concentration-dependent fashion. Benz[j]aceanthrylene was the most active, equivalent in activity to benzo[a]pyrene on a molar basis, in producing dishes of cells with transformed foci (94% at 1.0 microgram/ml). Benz[e]aceanthrylene, and benz[l]aceanthrylene produced 58% and 85% of the dishes with foci respectively at 10 micrograms/ml. Metabolism studies with [3H]benz[j]aceanthrylene in C3H10T1/2CL8 cells in which unconjugated, glucuronic acid conjugated, and sulfate conjugated metabolites were measured indicated that the dihydrodiol precursor to the bay-region diol-epoxide, 9,10-dihydroxy-9,10-dihydrobenz[j]aceanthrylene, was the major dihydrodiol formed (55%). Smaller quantities of the cyclopenta-ring dihydrodiol, 1,2-dihydroxy-1,2-dihydrobenz[j]aceanthrylene (14%), and the k-region dihydrodiol, 11,12-dihydroxy-11,12-dihydrobenz[j]aceanthrylene (5%) were also formed. Similar studies with [14C]benz[l]aceanthrylene indicated that the k-region dihydrodiol, 7,8-dihydroxy-7,8-dihydrobenz[l]aceanthrylene was the major metabolite formed (45%). The cyclopenta-ring dihydrodiol, 1,2-dihydroxy-1,2-dihydrobenz[l]aceanthrylene and 4,5-dihydroxy-4,5-dihydrobenz[l]aceanthrylene were formed in minor amounts (less than 6%). Therefore, metabolism at the cyclopenta-ring of B(j)A and B(l)A is a minor pathway in C3H10T1/2CL8 cells in contrast to previously reported studies with cyclopenta[cd]pyrene in which the cyclopenta-ring dihydrodiol was the major metabolite. These results suggest that routes of metabolic activation other than oxidation at the cyclopenta-ring such as bay region or k-region activation may play an important role with these unique polycyclic aromatic hydrocarbons in C3H10T1/2CL8 cells.

Animals↗
PubMed1987

Mutagenic activity of nitro-substituted cyclopenta-fused polycyclic aromatic hydrocarbons towards Salmonella typhimurium.

Cyclopenta-fused isomers of pyrene and benz[a]anthracene, nitrated on the etheno bridge, were synthesized and tested in the Ames plate-incorporation assay. Since enzymatic reduction, if it occurs in these compounds, would form arylhydroxylamines which in turn would form highly stabilized arylnitrenium ions, we hoped to test the hypothesis that the direct-acting mutagenic activity of nitroPAH is correlated with the degree of stabilization of the electrophilic intermediate. We found that these compounds are mutagenic (1-9 rev/nmole in Salmonella typhimurium TA98) and do not require S9 activation. However, this activity is substantially lower than that of other nitroPAH of comparable size such as 1-nitropyrene (250-300 rev/nmole). The reasons for this comparative lack of activity are discussed with reference to current theories regarding structure-activity relationships of nitroPAH.

Animals↗
PubMed1987

Synthesis and bacterial mutagenicity of the cyclopenta oxides of the four cyclopenta-fused isomers of benzanthracene.

Many polycyclic aromatic hydrocarbons containing peripherally fused cyclopenta rings are believed to be activated primarily by epoxidation of the cyclopenta ring. The cyclopenta epoxides of a series of four cyclopenta benzanthracene derivatives, benz[e]aceanthrylene-5,6-oxide, benz[j]aceanthrylene-1,2-oxide, benz[l]aceanthrylene-1,2-oxide and benz[k]acephenaceanthrylene-4,5-oxide were synthesized from their parent hydrocarbons by formation of the bromohydrin followed by dehydrobromination, and characterized by u.v.-vis, and 1H n.m.r. spectroscopy and mass spectrometry. The mutagenicity of these compounds was investigated in the Ames plate incorporation assay with Salmonella typhimurium strain TA98. All the oxides were active without exogenous metabolic activation (170-320 His+ revertants per nanomole) and also toxic above 0.5 microgram/plate. Addition of S9 protein did not increase, and generally decreased, the mutagenicity of the oxides, while toxicity was largely unchanged. These results are consistent with the postulated role of cyclopenta oxides as major contributors to the mutagenicity of the parent compounds in the Ames assay.

Animals↗
PubMed1987

Why is plasma angiotensin-converting enzyme activity elevated in hyperthyroidism?

The elevation in plasma angiotensin-converting enzyme (ACE) levels observed in patients with hyperthyroidism is unexplained. In this study three hypotheses were investigated. Results from a study using rats treated with thyroid hormones indicated that the increased ACE was not due to increased cleavages of enzyme from lung endothelia. Data from patients with specific tissue damage argue against a nonspecific release of ACE from damaged cells. Data from cultured cell experiments, however, strongly support a direct effect of thyroid hormones upon ACE synthesis and secretion.

Animals↗