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

The activity of hexokinase, dehydrogenases of pentose cycle, total lactate dehydrogenase, and cytochrome-C-oxidase level was determined in the aorta of rats with hyperthyroidism caused by the intraperitoneal administration of L-thyroxin. In the administration of hormone doses approaching the physiological ones there was an increase in the activity of cytochrome-C-oxidase and a tendency to the increase of 6-phosphogluconate dehydrogenase. Elevation of the activity of all the enzymes under study, excluding lactate dehydrogenase, and in increase of the amount of extractable protein occurred in the administration of moderate thyroxin doses. An increase of hexokinase and particularly of cytochrome-C-oxidase activity was revealed in hyperthyroidism with phenomena of thyrotoxicosis. The activity of the rest of the enzymes approached control. The data obtained are discussed from the point of view of the role played by thyroid hormones in the pathogenesis of atherosclerosis.
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PMID:[Effect of thyroxine on oxidative enzymatic activity in the rat aorta]. 21 88

Silymarin is the flavonoids extracted from the seeds of Silybum marianum (L) Gearth as a mixture of three structural isomers: silybin, silydianin and silychristin, the former being the most active component. Silymarin protects liver cell membrane against hepatotoxic agents and improves liver function in experimental animals and humans. It is generally accepted that silymarin exerts a membrane-stabilizing action preventing or inhibiting membrane peroxidation. The experiments with soybean lipoxygenase showed that the three components of silymarin brought about a concentration-dependent non-competitive inhibition of the lipoxygenase. The experiments also showed an analogous interaction with animal lipoxygenase, thus showing that an inhibition of the peroxidation of the fatty acid in vivo was self-evident. Silybin almost completely suppressed the formation of PG at the highest concentration (0.3 mM) and proved to be an inhibitor of PG synthesis in vitro. In our experiments, silybin at lower dose (65 mg/kg) decreased liver lipoperoxide content and microsomal lipoperoxidation to 84.6% and 68.55% of those of the scalded control rats respectively, and prevented the decrease of liver microsomal cytochrome p-450 content and p-nitroanisole-O-demethylase activity 24 h post-scalding. Effects of silymarin on cardiovascular system have been studied in this university since 1980. P. O silymarin 800 mg/kg/d or silybin 600 mg/kg/d reduced plasma total cholesterol, LDL-C and VLDL-C. They however, enhanced HDL-C in hyperlipemic rats. Further studies showed that silymarin enhanced HDL-C but didn't affect HDL-C, a property of this component which is beneficial to treatment of atherosclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Advances in pharmacological studies of silymarin. 184 18

Cerebrotendinous xanthomatosis (CTX) is a rare familial disorder characterized by progressive neurological dysfunction, atherosclerosis, and xanthomas with sterol storage in the nervous system, vessels, and tendons. Increased serum cholestanol, derived from intermediates of cholesterol catabolism, may possibly be a major cause of the disease. An examination was made of the cDNA encoding cytochrome P450 sterol 27-hydroxylase (CYP27) in hepatic mitochondria, considered a defective enzyme inducing CTX, in a Japanese housewife afflicted with CTX and her family. The proposita and one of her brothers, who also had CTX symptoms and hypercholestanolemia, were found to be homozygotic, carrying a point mutation in the CYP27 gene at Arg104 (CGG) to Trp104 (TGG). The mutant position has a 100% conserved positive charge in all known vertebrate cytochrome P450s and even in bacterial cytochrome P450cam. The mother of the proposita and another brother were both free of CTX symptoms and were heterozygotic for the mutation, although their plasma cholesterol increased moderately. An increase in plasma cholestanol alone would, thus, not appear to be a direct cause of sterol storage in CTX, while CTX is strongly suggested to be caused by defects in both alleles of the CYP27 gene.
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PMID:A point mutation in the bile acid biosynthetic enzyme sterol 27-hydroxylase in a family with cerebrotendinous xanthomatosis. 800 21

The hypothesis that cytochrome P450IA2 (CYPIA2) and/or N-acetyltransferase 2 (NAT2) may be involved in the pathogenesis of peripheral arterial disease was investigated in 90 Australian patients with significant disease and 81 matched control subjects. CYPIA2 and NAT2 phenotypes were determined from urinary metabolite patterns after an oral dose of caffeine. NAT2 phenotype was similar (chi 2 = 0.01; p = 0.98) in both atherosclerotic patients (43.3% rapid) and control subjects (42.0% rapid). CYPIA2 metabolism as measured by the median ratio of (1,7-dimethylxanthine + 1,7-dimethyluric acid)/caffeine was significantly induced by smoking in both patients with atherosclerosis (ratio of 6.5 in nonsmokers and 12.4 in smokers; p < 0.05) and control subjects (ratio of 8.2 in nonsmokers and 14.8 in smokers; p < 0.05), but values in atherosclerotic and control nonsmokers and smokers were similar. Probit transformation of the data revealed a trimodal distribution of ratios in control subjects who were nonsmokers, with 5% classified as poor metabolizers (homozygous rapid) and 95% as extensive metabolizers. The distribution of ratios in control subjects who were smokers was unimodal, whereas among the patients with arterial disease, both smokers and nonsmokers exhibited a bimodal pattern with 8.2% to 16% poor metabolizer and 84% to 91.8% extensive metabolizer phenotypes. When data from both nonsmokers and smokers were combined, the overall proportion of subjects who were poor metabolizers was not significantly different (chi 2 = 1.82; p = 0.18) between control subjects (3.8%) and patients with atherosclerosis (10.6%). Thus biotransformation of environmental or dietary aromatic or heterocyclic amines by NAT2 or CYPIA2 is unlikely to have a significant role in the cause or pathogenesis of peripheral arterial disease.
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PMID:Acetylation phenotype and cytochrome P450IA2 phenotype are unlikely to be associated with peripheral arterial disease. 837 27

It is now known that human exposure to certain chemicals e.g. benzene, halocarbons, ketones, nitrosamines, etc. can result in adverse health effects that are often not easily recognised as manifestations of chemical toxicity. These are inflammatory states, such as hepatitis, nephritis, scleroderma, and lupus, due to production of reactive oxygen species (ROS) through activation of cytochrome P4502E1 by the chemical, or by metabolism of the chemical to reactive intermediates and neoantigens which initiate immunotoxic effects. Intracellular glutathione (GSH), vitamins C, E and A protect against this ROS toxicity and inflammation; fasting and consumption of alcohol exacerbate it. Chronic inflammatory states may subsequently develop, including rheumatoid disease, atherosclerosis, diabetes, infertility and birth defects, multiple system organ failure (MSOF), Alzheimer's disease, and cancer.
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PMID:Chemical-induced inflammation and inflammatory diseases. 897 63

Atherosclerosis and its clinical manifestations are still one of the most important civilization problems. New questions arise: is it really an inevitable process? Are there any rational methods to prevent the development of atherosclerotic changes or to facilitate its regression? The aim of the work was to evaluate the influence of bioflavonoids extracted from milk thistle (Sylibum marianum L), troxerutin (O-(beta-hydroxy-ethyl)-ruozid and lecithin, administered together and as a single therapy, on the experimental atherosclerosis development in rabbits. Sixty male mixed-breed rabbits were randomly assigned to 6 equal groups: I--control, II--fed on fat-rich diet (FR/DB), III--fed on FR-diet and sylimaryn concentrate (S), IV--animals fed on FR-diet and troxerutin (T), V--rabbits fed on FR-diet and soya bean lecithin (L), VI--animals fed on FR-diet and sylimaryn-phospholipid complex (SF). The whole experiment lasted 12 weeks. Following tests have been performed: electrocardiographic, biochemical, pathomorphological (including macroscopic and microscopic evaluations of aorta). Biochemical analysis included: cholesterol concentration (total, low density lipoprotein fraction cholesterol and high density fraction cholesterol), triglycerides, b-lipoproteins, phospholipids, fibrinogen, trace elements (calcium, magnesium, zinc and copper) and dimalonic aldehyde concentration. Concentrations of ascorbyl free radical, total cholesterol, triglycerides, P-450 cytochrome and phospholipids in liver have been estimated. Evident normalization of lipid metabolism and inhibition of atherosclerotic changes have been observed in the group of animals fed on SF complex. Concentrations of total cholesterol, LDL-cholesterol fraction, phospholipids and triglycerides decreased in serum. Decrease of serum dimalonic aldehyde was followed by increase of ascorbyl free radicals concentration in liver. Significant increase of serum zinc has been also noted, which exceeded values observed in control group. Concentration of P-450 cytochrome increased in liver microsomes. Sylimaryn and lecithin showed less anti-atherosclerotic activity, and troxerutin displayed the least anti-atherosclerotic activity (Tab. 1-2, Fig. 1-2). On the basis of the achieved results the following conclusions were drawn: 1) Sylimaryn and lecithin have anti-atherosclerotic activity in rabbits. 2) Sylimaryn-phospholipid complex shows the strongest anti-atherosclerotic activity. 3) The achieved results allow us to undertake clinical trials using SF-complex in prevention and treatment of atherosclerosis.
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PMID:[The effect of bioflavonoids and lecithin on the course of experimental atherosclerosis in rabbits]. 947 22

Low density lipoprotein (LDL) oxidation is a major contributor to foam cell formation during early atherogenesis. Several oxygenases have been implicated in the process of LDL oxidation in the arterial wall, where the environment is relatively low in antioxidants, but the exact mechanism for LDL oxidation in vivo is not known. In the present study we sought to determine the ability of cytochrome P450 2E1 (P450 2E1) and other P450s, located in the liver and in other tissues, to oxidize LDL. Upon incubation of LDL (0.1 mg of protein/ml) with purified, reconstituted rabbit P450 2E1 in the presence of NADPH and the NADPH-cytochrome P450 reductase, time- and P450 2E1 concentration-dependent LDL oxidation was observed, as analyzed by determining the formation of peroxides, thiobarbituric acid reactive substances (TBARS), and conjugated dienes. Within 1 h of initiating the reaction, almost maximal oxidation was observed. NADPH, and active P450 2E1 enzyme were required for LDL oxidation to occur. The rate of P450 2E1-induced LDL oxidation was also dependent on the lipoprotein concentration. P450 2E1 could also oxidize pure phospholipids and cholesteryl ester, the major lipids in LDL. In the presence of catalase or superoxide dismutase (SOD), LDL oxidation was completely blocked, suggesting that hydrogen peroxide and superoxide are involved in P450 2E1-induced LDL oxidation. The ability of P450 2E1 to oxidize LDL was not unique to this enzyme, and could be observed with some other purified, cytochromes P450 in the reconstituted system such as rat P450 2B1 and human P450 3A4. Finally, microsomal membranes obtained from rats that were induced to express high levels of P450s 2B1, 2E1, and 1A1/2 were able to oxidize LDL, whereas little oxidation was seen with microsomes that were induced to express 3A2. We thus conclude that LDL can be oxidized by some cytochrome P450s and, as some of these enzymes are present in liver and in arterial wall, they may have a physio/pathological relevance to LDL oxidation and atherogenesis.
Atherosclerosis 1999 Apr
PMID:Microsomal cytochromes P450 catalyze the oxidation of low density lipoprotein. 1021 53

The plasma ACTH and cortisol levels do not change during aging. On the other hand, the plasma dehydroepiandrosterone sulfate (DHEA-S) changes remarkably during aging. Before puberty, the plasma DHEA-S level both in males and females is very low, however, it rapidly increases at puberty, and thereafter significantly decreases both linearly and age-dependently. Cytochrome P450c17 has two enzyme activities, 17-alpha-hydroxylase and 17,20-lyase. Cortisol is synthesized by 17-alpha-hydroxylase, and DHEA is synthesized by 17,20-lyase. The mechanism of dissociation of cortisol and DHEA synthesis in aging depends on another regulator of 17,20-lyase of cytochrome P450c17 such as cytochrome P450 reductase. We demonstrated significant decrease in cytochrome P450 reductase activity in bovine aged adrenal glands. We clarified the beneficial effects of DHEA as an anti-aging steroid based on both in vitro and in vivo experiments, such as the stimulatory effect of immune system, anti-diabetes mellitus, anti-atherosclerosis, anti-dementia (neurosteroid), anti-obesity and anti-osteoporosis. It is very important to identify the mechanism of action of DHEA. We clarified the conversion of DHEA to estrone by cytochrome P450 aromatase in primary cultured human osteoblasts. We indentified high affinity of DHEA binding with K(d)=6.6 nM in antigen and DHEA stimulated human T lymphocytes. We searched for the target genes that are specifically induced in activated T lymphocytes in the presence of DHEA by subtractive hybridization screening for differentially expressed transcripts. The double blind, randomized human replacement therapies utilizing DHEA are also reviewed.
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PMID:Mechanism of action of anti-aging DHEA-S and the replacement of DHEA-S. 1204 59

There is substantial evidence that cytokines induce apoptosis of vascular smooth muscle cells (VSMCs) in atherosclerosis. Its regulation, however, is not completely defined. The aim of this study is to investigate whether proteasome activity is related with apoptosis in VSMCs by tumor necrosis factor-alpha (TNF-alpha). Rat aorta smooth muscle cells were treated with TNF-alpha and proteasome inhibitor MG132 and then cell death was determined by morphology, viability, and DNA fragmentation. MG132 or TNF-alpha alone did not induce cell death. In contrast, co-treatment of TNF-alpha and proteasome inhibitor induced death and DNA degradation in VSMCs, suggesting proteasome inhibitor enhanced death activity of TNF-alpha. The death was not blocked by ascorbic acid but by nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine. Both caspase-3 and -8 were activated during the death by the proteasome inhibitor and TNF-alpha. The death was effectively blocked by the caspase-3 inhibitor z-DEVD-fmk, suggesting a role of caspase-3 in the death. Nonetheless, there were no significant alterations in the level of Bcl-2, Bcl-X(L), Bax and Bak by the proteasome inhibitor, nor any evidence of cytochrome (cyt) c release into cytosol from dying cells, suggesting that cyt c is not involved. These results suggest that proteasome inhibition potentiates TNF-mediated death in VSMCs in a cyt c-independent pathway. The present study proposes a new mechanism by which VSMCs undergo death by cytokines.
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PMID:Enhancement of TNF-alpha-mediated cell death in vascular smooth muscle cells through cytochrome c-independent pathway by the proteasome inhibitor. 1256 Jan 2

Benzo[a]pyrene (BP), a polycylic aromatic hydrocarbon (PAH), is a potent atherogen and carcinogen in laboratory animals. Since genotoxic mechanisms may contribute to the development of atherosclerosis by PAHs, we have tested the hypotheses that: 1) BP induces DNA adducts in mouse aortic smooth muscle cells (SMCs); 2) 3-hydroxybenzo[a]pyrene (3-OH-BP) and benzo[a]pyrene-3,6-quinone (BPQ) are proximate genotoxic metabolites; and 3) cytochrome P4501B1 (CYP1B1) mediates the activation of BP and its metabolites to ultimate genotoxic intermediates. Cultured mouse aortic SMCs were treated with BP, 3-OH-BP, or BPQ for 24 h, and DNA adduct formation was analyzed by (32)P-postlabeling. In some experiments, cells were pretreated with the CYP1B1 inhibitor 1-ethynylpyrene (EP) prior to exposure to BP or its metabolites. BP, 3-OH-BP, and BPQ induced formation of several DNA adducts that were not observed in dimethylsulfoxide-treated cells. Re- and cochromatography experiments indicated that 3-OH-BP and BPQ were proximate genotoxic metabolites of BP. DNA adduct formation was strongly inhibited by EP, a specific inhibitor of CYP1B1. BP treatment of SMCs resulted in induction of aryl hydrocarbon hydroxylase (AHH) activity and CYP1B1, but not CYP1A1, apoprotein. EP also blocked AHH induction by BP. In conclusion, the results of this study support the hypothesis that in SMCs, which are target sites for the development of atherosclerosis, the major bioactivation pathway of BP entails CYP1B1-mediated formation of the 3-OH-BP and BPQ, which are proximate genotoxic metabolites that may in turn get transformed to ultimate DNA-binding metabolites, which may contribute to atherogenesis by PAHs.
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PMID:Role of cytochrome P4501B1 in benzo[a]pyrene bioactivation to DNA-binding metabolites in mouse vascular smooth muscle cells: evidence from 32P-postlabeling for formation of 3-hydroxybenzo[a]pyrene and benzo[a]pyrene-3,6-quinone as major proximate genotoxic intermediates. 1264 94


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