Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutathione transferases (GST) are detoxifying enzymes who act with many endogenous and exogenous substances such as polycyclic aromatic hydrocarbons (PAH). The GST activity towards trans-stilbene oxide (GST-tSBO) is inherited in an autosomal dominant fashion and can be separated in high (GST-positive) and low (GST-negative) phenotypes when measured in blood. Human fibroblast cultures were established from males matched for age, smoking habits and clinical manifestations of atherosclerosis. Matched pairs of GST-negative and GST-positive fibroblasts were studied. There was a very strong correlation between the levels of GST-tSBO in peripheral blood and in cultured fibroblasts within the same individual. When fibroblasts were exposed to benzo(a)pyrene (BP) or dimethylbenzanthracene (DMBA) GST-negative cells produced relatively more collagen than GST-positive cells. GST-negative fibroblasts showed a greater cell death than GST-positive fibroblasts as well among controls as after exposure to PAH. It is concluded that lack of GST-tSBO is easily discriminated in cultured skin fibroblasts. GST-negative and GST-positive fibroblasts showed different susceptibility towards some toxic stimuli that might be of importance in atherogenesis.
 ...
PMID:Human fibroblasts lacking trans-stilbene oxide active glutathione transferase exhibit increased cell death when exposed to polycyclic aromatic hydrocarbons. 160 25

It is very important to elucidate the causative agents of atherosclerosis because coronary heart disease and cerebrovascular disease are the main causes of death in the developed countries. The evidence for a monoclonal origin of atherosclerotic plaques in humans prompted the study of the involvement of mutagens/carcinogens in the development of atherosclerosis. Polycyclic hydrocarbons, including 7,12-dimethylbenz[a]anthracene and benzo[a]pyrene, were shown to act as initiators and/or accelerators in atherosclerotic plaque formation in the chicken, pigeon and mouse. Radiation and oxygen radicals were also demonstrated to be involved in the development of atherosclerosis in animals.
 ...
PMID:International Commission for Protection Against Environmental Mutagens and Carcinogens. ICPEMC Working Paper 7/1/3. Animal studies suggesting involvement of mutagen/carcinogen exposure in atherosclerosis. 223 25

The mutagenic activation of benzo[a]pyrene (BaP) after exposure to aorta smooth muscle cells of different origin was examined. Three test systems with different genetic endpoints--sister-chromatid exchange (SCE), gene mutation at the hypoxanthine guanine phosphoribosyl transferase (HGPRT) locus and unscheduled DNA synthesis (UDS)--were used. Treatment of rat and rabbit aorta smooth muscle cells with BaP (1-6 micrograms/ml) resulted in a significant increase of SCEs, HGPRT mutations and UDS. So smooth muscle cells are capable of converting BaP to metabolites with a DNA-damaging action. In order to investigate the relation between the formation of mutagenic BaP metabolites and the susceptibility to atherosclerosis we compared the mutagenic potential of BaP using aorta smooth muscle cells of different species (rat, rabbit) and locations (thoracic and abdominal aorta). Rabbits and abdominal aortas are more susceptible to atherosclerosis than rats and thoracic aortas. The SCE, HGPRT and UDS assays revealed that smooth muscle cells of different origin possessed the same metabolic potential towards BaP. There was no correlation between the mutagenic potency of BaP metabolites and the susceptibility to atherosclerosis. As smooth muscle cells have a low metabolic capacity towards BaP, probably other factors in addition to the metabolic capacity of smooth muscle cells are responsible for species and tissue differences in susceptibility to atherosclerosis.
 ...
PMID:A comparative study on the metabolic activation of 3,4-benzo[a]pyrene to mutagens by aorta smooth muscle cells of rat and rabbit. 234 94

Cytochrome P-450-dependent mixed function oxidase activity is present in vascular tissue; however, as far as we could determine, the distribution of monooxygenase activity across the blood vessel wall has not previously been assessed. The aryl-hydrocarbon hydroxylase activity was examined by metabolism of benzo[a]pyrene in microsomes prepared from intimal and smooth muscle cell scrapings of the hog thoracic aorta. Microsomes of intimal cells comprising 95% endothelial cells showed an approximately 2.5-fold increase in aryl-hydrocarbon hydroxylase activity compared with that in microsomes prepared from medial smooth muscle cells. Michaelis-Mentin kinetics for the intimal enzyme yielded an apparent Km value of 11.11 microM and an apparent Vmax of 3-OH benzo[a]pyrene of 40 pmol/mg protein/10 min. Aryl-hydrocarbon hydroxylase activity was dependent on nicotinamide adenine dinucleotide phosphate and was inhibited by 7,8 benzoflavone, SKF 525A, and carbon monoxide. The localization of cytochrome P-450-dependent mixed function oxidase primarily to the intimal surface of the aorta may indicate a role for this enzyme system in vasoregulation and the pathogenesis of atherosclerosis.
 ...
PMID:Presence of cytochrome P-450-dependent monooxygenase in intimal cells of the hog aorta. 407 22

The frequency of atherosclerotic lesions of the abdominal aorta has been reported to increase significantly in chickens exposed to benzo[a]pyrene and 7,12-dimethylbenz[a,h]anthracene. The present studies were performed to determine in another experimental model frequently used in atherosclerotic studies (i.e. White Carneau Pigeons) whether these and other chemical carcinogens enhance atherosclerosis. The induction and enhancement of atherosclerotic lesions were observed in pigeons treated with 7,12-dimethylbenz[a,h]anthracene, benzo[a]pyrene and 3-methylcholanthrene. The number and size of plaques in the aorta were frequently greater in pigeons treated with the higher concentration (i.e. 100 mg/kg) of these 3 polycyclic aromatic hydrocarbons. Benzo[e]pyrene and 2,4,6-trichlorophenol were ineffective in the induction or enhancement of atherosclerosis in the pigeons. The results of the present and previous studies suggest that the polycyclic aromatic hydrocarbons (excluding benzo[e]pyrene) may be the only potential atherogens in avian atherosclerosis. This relationship may be associated with how these hydrocarbons are transported in the plasma (i.e. by lipoproteins) as demonstrated by the present distribution studies.
 ...
PMID:The effectiveness of chemical carcinogens to induce atherosclerosis in the white Carneau pigeon. 608 78

Atherosclerosis-susceptible White Carneau (WC-2) pigeons were compared with atherosclerosis-resistant Show Racer (SR-39) pigeons in terms of hepatic and aortic biotransformation and bioactivation of benzo[a]pyrene (B[a]P). Following pretreatment of the two strains with 3-methylcholanthrene (MC, 40 mg/kg), WC-2 hepatic 9000 X g supernatant fractions (S-9) exhibited consistently greater increases in the production of specific B[a]P metabolites when compared with uninduced controls than did the corresponding SR-39 preparations. Analyses of organic solvent-extractable metabolites with h.p.l.c. revealed that inducer pretreatment resulted in significantly greater increases (18- versus 7-fold) in the generation of B[a]P-7,8-dihydrodiol by WC-2 versus SR-39 hepatic S-9. Similar differences in inducibility were found for most other metabolites appearing in the h.p.l.c. profiles. Hepatic monooxygenase systems were induced in both strains following treatment of pigeons with a mixture of polychlorinated biphenyls (Aroclor 1254, 500 mg/kg); WC-2 birds again demonstrated greater responsiveness. Bioactivation of B[a]P to mutagenic (but not cytotoxic) products by hepatic S-9 was more effective in preparations from MC-pretreated WC-2 versus SR-39 pigeons when assessed with Salmonella typhimurium tester strains. Aortic homogenates from MC-pretreated pigeons displayed even greater inducibility differences than were observed with hepatic preparations. Inducer-mediated increases in the formation of B[a]P-7,8- and B[a]P-9,10-dihydrodiols were approximately 10- and 12-fold greater in WC-2 than SR-39 aortic preparations, respectively. The results document marked differences in biotransformation and bioactivation of carcinogenic hydrocarbons by atherosclerosis-susceptible and resistant pigeons and are reminiscent of the metabolic differences observed in carcinogenesis-susceptible and resistant strains of mice. It is suggested that these pigeon strains might offer a promising system in which to further study the role of target tissue biotransformation in the atherogenic actions of polynuclear aromatic hydrocarbons.
 ...
PMID:Carcinogenesis and atherogenesis: differences in monooxygenase inducibility and bioactivation of benzo[a]pyrene in aortic and hepatic tissues of atherosclerosis-susceptible versus resistant pigeons. 630 25

For 9 days, 12 volunteers ate each day 8 oz of hamburgers and 6 oz of steak barbecued over charcoal. This was followed by a mean rise in high density lipoprotein (HDL) cholesterol of 25%. In addition there was a reduction in total cholesterol (the fall in total less the HDL fraction, which reflects mainly low density lipoprotein cholesterol was 20%). These changes were not seen when 6 of the subjects later ate the same quantity of meat under the same conditions except that it had been cooked in an electric oven. Benzo(a)pyrene and other polycyclic aromatic hydrocarbons have previously been shown to be produced in meat cooked over charcoal, and it is suggested that the resulting induction of the polycyclic hydrocarbon-dependent type of cytochrome P450 is responsible for inducing enzyme activity involved in lipid metabolism. Despite the beneficial effect that such changes in lipids might have on the risk of coronary heart disease, these findings should not be seen as a guide to long-term changes in cooking practice in view of the possible carcinogenic effects of benzo(a)pyrene produced in this way.
Atherosclerosis 1983 Aug
PMID:The effect on blood lipids of eating charcoal-grilled meat. 631 Dec 28

Known cytochrome P450-dependent oxygenase inhibitor ketoconazole (5-50 microM) blocked the murine macrophage-mediated modification of human low density lipoprotein (LDL) as measured by production of thiobarbituric acid-reactive substance, stimulation of [125I]LDL degradation in a fresh set of macrophages and LDL electrophoretic mobility, in a dose-dependent manner with complete inhibition at 30-40 microM. When resident macrophages were incubated with LDL in the presence of metyrapone, methoxsalen and alpha-naphthaflavone at concentrations that have been shown to inhibit the cytochrome P450-dependent oxygenases, there was no change in LDL modification. Induction of benzo[alpha]pyrene hydroxylase activity in macrophages by 24 h incubation with benzo[alpha]pyrene was accompanied by a 1.5-fold increase of LDL modification which has been leveled down by ketoconazole as well as methoxsalen and alpha-naphthaflavone. Furthermore, ketoconazole effectively diminished cell-free LDL oxidation induced by iron, but not copper ions, and reduced the spontaneous and zymosan-stimulated lucigenin-amplified chemiluminescence of macrophages. The data allow us to suggest that ketoconazole inhibits LDL oxidation by acting as an iron chelator and/or inhibitor of prooxidant forms of iron-containing enzymes.
Atherosclerosis 1995 Apr 07
PMID:Ketoconazole inhibits oxidative modification of low density lipoprotein. 760 80

Aberrant smooth muscle cell proliferation is a focal point in the genesis and progression of atherosclerosis. To date, limited information is available on the molecular and cellular basis of the atherogenic response and the potential contribution of environmental chemicals to the overall process. This review highlights major findings in this laboratory on the mechanism(s) responsible for the acquisition of a proliferative phenotype in vascular smooth muscle cells following repeated cycles of treatment with allylamine and benzo(a)pyrene, known atherogenic chemicals. These agents share the ability to induce and promote aberrant proliferative behavior in smooth muscle cells, but appear to interfere with distinct molecular targets.
 ...
PMID:Growth-related signaling as a target of toxic insult in vascular smooth muscle cells: implications in atherogenesis. 763 34

Over the past several decades emphasis has been given to the elucidation of mechanisms involved in the onset and progression of cardiovascular disorders. Stroke, hypertension, and atherosclerosis continue to rank as primary causes of death in the western world. In the case of atherosclerosis, the preferential localization of atheroma to large- and medium-sized blood vessels and the sequence of events leading to plaque development have been well defined. Damage to luminal endothelial and/or medial smooth muscle cells, migration of inflammatory cells, diffusion or local delivery of mediators within the vessel wall, proliferation of vascular smooth muscle cells, and cellular accumulation of lipids are now recognized as hallmarks of the pathologic process. Although these events have been established with a fair degree of certainty, the mechanisms responsible for initiation of the atherosclerotic process are not yet completely understood. Environmental chemicals have come under increasing scrutiny as evidence continues to accumulate suggesting that toxic insult plays an important role in the initiation and/or progression of atherosclerotic disorders. This review focuses on various aspects of xenobiotic-induced vascular injury with emphasis on the toxic effects of allylamine and benzo[a]pyrene in smooth muscle cells, the primary cellular component of atherosclerotic lesions. Both of these chemicals modulate growth and differentiation programs in aortic smooth muscle cells and have been implicated in the development of atherosclerotic-like lesions in laboratory animals. The major findings from recent studies examining the cellular and molecular basis of toxicant-induced phenotypic modulation of vascular smooth muscle cells to a proliferative state and the role of oxidative metabolism, phospholipid turnover, protein kinase C, ras-related signal transduction, and matrix interactions in the vasculotoxic response to allylamine and benzo[a]pyrene are discussed.
 ...
PMID:Responses of vascular smooth muscle cells to toxic insult: cellular and molecular perspectives for environmental toxicants. 799 Jan 68


1 2 3 4 5 Next >>