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)

Cholesterol 7 alpha-hydroxylase is the rate limiting enzyme in bile acid biosynthesis and plays an important role in cholesterol homeostasis. The Golden Syrian hamster has been used as an animal model for the study of atherosclerosis and cholesterol gallstone disease. We have screened a lambda DASH II hamster liver genomic library using a rat cDNA as a hybridization probe. A 14-kb genomic clone has been isolated and characterized by restriction mapping and Southern blot hybridization. The clone contained the full-length gene encoding cholesterol 7 alpha-hydroxylase together with an upstream sequence of approximately 5 kb. DNA sequencing and analysis of about 11 kb of the gene revealed that the hamster CYP7 gene consists of six exons and five introns, which have the same structures and sizes as predicted in the rat and human CYP7 genes. The nucleotide and deduced amino acid sequences of the hamster cholesterol 7 alpha-hydroxylase have a high sequence identity of about 90% to the rat and 82% to the human sequences. Particularly, exons 2, 5, and 6 are highly conserved among these species, thus reflecting the presence of some domains that are crucial for the activity of this unique enzyme. The putative cholesterol-binding region, an aromatic amino acid region, and the P450 heme-binding region are completely conserved. Comparison of the 250-bp 5'-flanking sequence to the corresponding region in the rat and human genes revealed a high degree of homology ranging between 71% and 82%. Next to the canonical TATA and CCAAT boxes are many consensus sequences (LF-A1, LF-B1, TGT3) for liver-specific or -enriched transcription factors (HNF4, HNF1, and HNF5, respectively) and an imperfect direct repeat of thyroid hormone responsive element (TRE), which is located between TGT3 and LF-B1. These sequence motifs are completely conserved among the rat, human, and hamster CYP7 genes. Several modified sterol regulatory element (SRE)-like sequences are located in the upstream flanking region and in the first intron. This highly conserved proximal promoter may play important roles in the transcription activity and in the regulation of the CYP7 gene by physiological agents, such as bile acids and steroid/thyroid hormones. This is the first report describing the complete nucleotide sequence and confirming the structure of a CYP7 gene.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Genomic cloning, sequencing, and analysis of the hamster cholesterol 7 alpha-hydroxylase gene (CYP7). 810 53

Reactive oxygen species (ROS) are cytotoxic, causing inflammatory disease, including tissue necrosis, organ failure, atherosclerosis, infertility, birth defects, premature aging, mutations and malignancy. ROS are produced in the metabolism of drugs and industrial chemicals by (i) one-electron peroxidase oxidations to form cation radicals, (ii) cytochrome P450 metabolism to free radical products, (iii) stabilisation of the ROS-generator, CYP2E1, and (iv) futile cycling of other cytochromes P450. ROS production initiates inflammation which unless quenched may result in chronic inflammatory disease states, e.g. hepatitis, nephritis, myositis, scleroderma, lupus erythematosus, multiple system organ failure. Quenching of ROS is affected by the redox buffer, glutathione (GSH), and the antioxidants, ascorbic acid, tocopherols, retinoids, in conjunction with the redox enzymes, GSH reductase, GSH peroxidase, catalase and superoxide dismutase. Many industrial workers with symptoms of systemic inflammation, resulting from exposure to toxic chemicals, are diagnosed as having rheumatoid arthritis, virus infections, or other microbial lesions, largely because many physicians are unaware that exposure to certain chemicals can initiate inflammatory disease states.
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PMID:Chemical toxicity and reactive oxygen species. 911 92

Steroid sulphates such as oestrone sulphate (OE1S) and dehydroepiandrosterone sulphate (DHEAS) have been suggested to be of biological importance in different disease states such as breast cancer and atherosclerosis. Previous studies have shown that drugs such as aminoglutethimide and rifampicin that induce P450-dependent mixed-function oxygenases selectively suppress plasma OE1S levels. The aim of this study was to evaluate the influence of treatment with carbamazepine, an antiepileptic drug known to stimulate mixed-function oxygenases, on plasma levels of OE1S and DHEAS. We measured plasma OE1S and DHEAS together with other plasma oestrogens and androgens in male epileptic patients before and during carbamazepine monotherapy. Patients treated with valproate monotherapy acted as a control group. Treatment with carbamazepine decreased plasma OE1S levels from a mean value of 810.8 to 411.6 pmol/l (mean suppression to 50.7% of pretreatment levels, P < 0.001). Similarly, the ratio of OE1S to OE1 fell to 59.9% of pretreatment levels (P < 0.001)). DHEAS decreased from a mean level of 4.9 mumol/l before treatment to 3.0 mumol/l during carbamazepine therapy (mean reduction to 62.7% of pretreatment levels (P < 0.001), while the ratio of DHEAS to DHEA fell to 63.0% of pretreatment values (P < 0.01). No significant change in plasma levels of the other oestrogens or androgens measured was observed. Treatment with valproate caused a slight decrease in FSH levels (P < 0.05), but no change in any of the other hormones measured was observed. Studies are warranted to evaluate the possible effects of long-term treatment with carbamazepine on the risk of developing endocrine-sensitive tumours and cardiovascular disease and also the possible effects of alterations in plasma DHEAS on epileptic activity.
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PMID:Differential effect of carbamazepine and valproate monotherapy on plasma levels of oestrone sulphate and dehydroepiandrosterone sulphate in male epileptic patients. 916 21

The objective of the present study was to investigate the expression of major xenobiotic-metabolising cytochrome P450 proteins, and of other enzyme systems, in hepatic and extrahepatic tissues of rabbits rendered atherosclerotic by the dietary administration of 1% cholesterol diets for 8 weeks. Individual cytochrome P450 proteins were monitored using diagnostic substrates and immunologically in Western blot analysis. The activity of all hepatic isoforms studied was depressed in the atherosclerotic animals; when, however, apoprotein levels were determined immunologically, no major differences were evident between the control and the atherosclerotic rabbits. In vitro studies indicated that neither cholesterol nor palm oil inhibited cytochrome P450 activity. The effects of cholesterol treatment leading to atherosclerosis on kidney, heart and lung cytochrome P450 activities were isoform- and tissue-specific; no change was evident in the heart activities, but in the lung and kidney cytochrome P450 activities were clearly modulated by the treatment with cholesterol. Apoprotein levels did not always parallel the changes in activities. Western blot analysis of aortic cytochromes P450 revealed that administration of cholesterol-rich diets enhanced CYP2B and CYP3A apoprotein levels. Cholesterol feeding to rabbits gave rise to a marked decrease in hepatic glutathione S-transferase activity but did not influence glutathione reductase or total glutathione levels. The same treatment had no effect on catalase, glutathione peroxidase and superoxide dismutase. It is concluded that treatment of rabbits with cholesterol-rich diets leading to atherosclerosis gives rise to profound changes in the expression of cytochrome P450 proteins in the liver and other tissues; possible mechanisms are discussed.
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PMID:Marked inhibition of hepatic cytochrome P450 activity in cholesterol-induced atherosclerosis in rabbits. 967 66

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 beverage tea, from the top leaves of the plant Camellia sinensis is one of the most widely used beverages in the world, second only to water. Black and green tea have mostly similar actions. The active components are polyphenols, mainly epigallocatechin gallate in green tea, and the tea leaf polyphenol oxidase mediated oxidation to oolong and black tea, yielding other polyphenols, theaflavin and thearubigins. There is 40-50 mg caffeine in a 160-ml cup of tea. The chemopreventive effects of tea depend on: (1) its action as an antioxidant; (2) the specific induction of detoxifying enzymes; (3) its molecular regulatory functions on cellular growth, development and apoptosis; and (4) a selective improvement in the function of the intestinal bacterial flora. The oxidation of LDL cholesterol, associated with a risk for atherosclerosis and heart disease, is inhibited by tea. Many of cancers are caused by lifestyle elements. One is cigarette and tobacco use, leading to cancer in the oral cavity, esophagus and lung, inhibited by tea. Mice administered a tobacco nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), developed significantly fewer lung tumors than controls when given green tea or its major polyphenol, epigallocatechin gallate (EGCG). Tea suppressed the formation of 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative DNA damage, in the lung DNA of mice given NNK. Gastric cancer, caused by a combination of Helicobacter pylori and salted foods, is lower in tea drinkers. Western nutritionally-linked cancers of the breast, colon, prostate and pancreas can be inhibited by tea. The formation of genotoxic carcinogens for these target organs during the cooking of meats, heterocyclic amines, and their effects were decreased by tea. Tea inhibited the formation of reactive oxygen species and radicals and induced cytochromes P450 1A1, 1A2 and 2B1, and glucuronosyl transferase. The higher formation of glucuronides represents an important mechanism in detoxification. The developmental aspects and growth of cancers through promotion are decreased by tea. The regular use of a widely available, tasty, inexpensive beverage, tea, has displayed valuable preventive properties in chronic human diseases.
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PMID:Mechanisms of chronic disease causation by nutritional factors and tobacco products and their prevention by tea polyphenols. 1206 77

Universally, the general population is exposed to a variety of "toxic" substances. Some of these are from manufactured goods and some from air and water pollution. Toxins are also normally found in many foods; however, unless the exposure is overwhelming, we are many times (even unknowingly) protected by the foods we eat. A judicious choice of food will counteract noxious agents. Therefore, the diet can be a major factor in determining who does and who does not show toxic symptoms following exposure. This review will cover three aspects. The first will be on protectors against metal toxicity. For example, whereas humans can consume fish that have absorbed mercury from contaminated bay water, selenium can act as a natural antagonist for mercury poisoning. (Naturally, too much selenium itself can be detrimental!) Some vegetables can accumulate cadmium from contaminated soil, and zinc from a variety of nuts is an antagonist of cadmium toxicity. Nitrites in preserved meats can be converted into nitroamines by saliva or mild stomach acid. Vitamin C found in oranges and bell peppers can inhibit that conversion. In addition, calcium antagonizes both lead and aluminum toxicity. The second aspect is on oxidants and antioxidants. Oxidative stress can lead to some cancers, atherosclerosis, and adverse effects of aging. Antioxidants are the best protectors of the damage caused by reactive oxygen species (ROS). The most effective antioxidants are found in highly colored fruits and vegetables such as carrots, tomatoes, and berries, called carotenoids. Flavonoids (polyphenols), another class of effective antioxidants that negate ROS, may or may not be colored. The third aspect is on gaps in current knowledge. Many foods naturally contain chemicals that are, in larger concentrations, quite toxic or carcinogenic. Biotransformations (detoxification mechanisms) involving type I and type II enzymes are known. Some foods do modify these enzymes either positively or negatively. Grapefruit contains a substance that inhibits an isoform of P450, making some cardiac drugs, as substrates, more toxic. There is inadequate information on what specific components are in a variety of foods that are associated with cancer prevention. The experimental carcinogenic compound (and suspected as a human carcinogen) found in overcooked, burnt, and fried meats and fish, namely IQ (2-amino-3-methyl-3H-imidazo[4,5f]quinoline, will be used as a prototype for what needs to be known about foods that will affect toxins.
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PMID:Can nutrition affect chemical toxicity? 1239 88

Cystathionine beta-synthase (CBS) deficiency causes severe hyperhomocysteinemia and other signs of homocystinuria syndrome, in particular a premature atherosclerosis with multiple thrombosis. However, the molecular mechanisms by which homocysteine could interfere with normal cell function are poorly understood in a whole organ like the liver, which is central to the catabolism of homocysteine. We used a combination of differential display and cDNA arrays to analyze differential gene expression in association with elevated hepatic homocysteine levels in CBS-deficient mice, a murine model of hyperhomocysteinemia. Expression of several genes was found to be reproducibly abnormal in the livers of heterozygous and homozygous CBS-deficient mice. We report altered expression of genes encoding ribosomal protein S3a and methylthioadenosine phosphorylase, suggesting such cellular growth and proliferation perturbations may occur in homozygous CBS-deficient mice liver. Many up- or down-regulated genes encoded cytochromes P450, evidence of perturbations of the redox potential in heterozygous and homozygous CBS-deficient mice liver. The expression of various genes involved in severe oxidative processes was also abnormal in homozygous CBS-deficient mice liver. Among them, the expression of heme oxygenase 1 gene was increased, concomitant with overexpression of heme oxygenase 1 at the protein level. Commensurate with the difference in hepatic mRNA paraoxonase 1 abundance, the mean hepatic activity of paraoxonase 1, an enzyme that protects low density lipoprotein from oxidation, was 3-fold lower in homozygous CBS-deficient mice. Heterozygous CBS-deficient mice, when fed a hyperhomocysteinemic diet, have also reduced PON1 activity, which demonstrates the effect of hyperhomocysteinemia in the paraoxonase 1 activity.
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PMID:Altered gene expression in liver from a murine model of hyperhomocysteinemia. 1279 73

Harmful free-radicals, such as superoxide anion (a reactive oxygen species: ROS) are produced during aerobic respiration in all tissues because of only partial reduction of some oxygen molecules in mitochondria: this is due to one-electron reduction of each atom of oxygen, instead of four-electron reduction per molecule of oxygen to form water. Similarly, in liver, and many other tissues such as lung and brain, an electron transfer chain from NADPH to water occurs (with insertion of one oxygen atom into xenobiotic substrates) that uses cytochromes P450 (EC 1.14.14.1) as the electron acceptor. Here, futile recycling of electrons, in the absence of substrate produces the superoxide anion (*O2')--see above. Reactive oxygen species (ROS) and reactive sulfur species (RSS) may act in unison to damage biomolecules. For example, damage to biomolecules can occur by attack on phospholipid membranes, and also the targeting of DNA results in mutagenicity and associated carcinogenicity-related mutagenic damage. Free radical injury to low density lipoprotein (LDL) has been identified in the causation of atherosclerosis implicated in arterial disease, which can lead to heart attack and strokes.
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PMID:Dietary alkyl thiol free radicals (RSS) can be as toxic as reactive oxygen species (ROS). 1532 13

Endothelium-derived nitric oxide (NO) is critically involved in the regulation of a wide variety of vascular functions. It had been hypothesized that a deficiency of vascular NO might be involved in the accelerated atherosclerosis and dramatic cardiovascular mortality observed in patients with chronic renal failure. At present it is difficult to measure authentic NO in vivo. An alternative is to study NO by its effect on vascular tone by using the forearm blood flow technique. In this way, studies demonstrated an unimpaired availability of NO under baseline conditions but a profound reduction of agonist-induced endothelium-dependent vasodilatation in uremic patients. Further investigation showed that the latter phenomenon is mainly attributable to a reduced availability of vascular NO upon agonist stimulation, while the NO-independent mechanism(s) appear(s) to be intact in this setting. Explanations for this finding include an uncoupling of NO synthase induced by cofactor deficiency, and/or a reduced NO availability caused by high levels of oxidative stress. Recent data suggest only a minor role for cytochrome-P450 2C9-dependent pathways in this context. Future studies have to show which mechanisms are most relevant, and whether they are sensitive to therapeutic intervention.
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PMID:Nitric oxide in chronic renal failure. 1584 8


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