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)

Aryl 4-monooxygenase [aniline, reduced-flavoprotein:oxygen oxidoreductase (4-hydroxylating); EC 1.14.14.1] activity was searched for and found in homogenates of aorta walls from rabbits, rhesus monkeys, and humans. Specific activities were comparable to activities observed in several other extrahepatic tissues of rabbits and monkeys and in epidermal tissues from mice, but were one to two orders of magnitude lower than those observed in corresponding preparations of hepatic tissues. Cytochrome P-450 also could be detected in low concentrations in microsomal fractions of aortic wall homogenates. The monooxygenase activity found in the aorta could play a significant role in the etiology and pathogenesis of atherosclerosis in humans by catalyzing the conversion of environmental promutagens to mutagenic initiators and/or cytotoxic factors, thus leading to development of benign, smooth muscle tumors of the inner lining of artery walls.
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PMID:Aryl 4-monooxygenase and cytochrome P-450 in the aorta: possible role in atherosclerosis. 82 48

We report the identification and partial characterization of polymorphisms among inbred strains of mice affecting several aspects of the expression of apolipoproteins B and E (apoB and apoE), the major proteins of low density lipoproteins (LDL) and very low density lipoproteins (VLDL). These polymorphisms include differences in the levels of the lipoproteins and apolipoproteins on both chow and high fat diets, differences in their response to a high fat diet challenge, and differences in the relative levels of the two molecular weight species of apoB. Although most strains exhibited a large increase in plasma LDL and VLDL in response to a high fat diet, the levels of apoB and apoE mRNA were either unaffected or, in some cases, decreased slightly. Also, the levels of apoB and apoE mRNA were not correlated among strains with the levels of the apolipoproteins in plasma, suggesting that genetic control occurs primarily at the level of lipoprotein catabolism. Elucidation of the precise mechanisms involved in the differences will require genetic analysis. Toward this end, we have identified DNA polymorphisms for apoB and apoE and have used these in segregation analysis to determine the chromosomal locations of the apoB and apoE structural genes in mice. The gene for apoB, designated Apob, resides in the proximal region of chromosome 12 linked to genes for ribosomal RNA and aryl hydrocarbon hydroxylase. The gene for apoE, designated Apoe, is located on chromosome 7, linked to genes for glucose phosphate isomerase and peptidase 4. Previously, we mapped the structural genes for apolipoproteins A-I and A-II to mouse chromosomes 9 and 1, respectively, and thus, the four loci encoding mammalian apolipoproteins have now been located in the mouse. These loci are homologous to the loci encoding apolipoproteins in humans as judged by the conservation of linked markers. A correlation was observed between a unique apoB allele and "responsiveness" to a high fat diet challenge. There were no obvious associations of apoB, apoE, or LDL/VLDL phenotypes or genotypes with diet-induced atherosclerosis among strains surveyed. These results clarify the organization and regulation of the genes for apoB and apoE, and they provide information about the naturally occurring polymorphisms affecting their expression.
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PMID:Genetic factors controlling structure and expression of apolipoproteins B and E in mice. 303

Cholesterol regulates hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity by feedback inhibition. It has been suggested that oxidized derivatives of cholesterol (oxysterols) play an important role, as an intracellular mediator, in the feedback inhibition of cholesterol biosynthesis. We, therefore, investigated the role of intracellular oxysterols in the regulation of HMG-CoA reductase activity. Rats were fed with food (control), cholesterol, clofibrate as a potentiator of the microsomal monooxygenase cytochrome P-450 enzyme system, ketoconazole as a strong inhibitor of the system, or butylated hydroxytoluene (BHT) as an antioxidant. We analyzed and compared hepatic microsomal oxysterol levels among the groups. The results of this study indicated that the oxysterol level, especially 7beta-hydroxycholesterol and 7-ketocholestrol, in the liver was lowered by the administration of ketoconazole and BHT, and HMG-CoA reductase activity was increased in response to these agents. However, there was no change in the HMG-CoA reductase activity, after the administration of clofibrate. We conclude that reduced levels of oxysterol may release the inhibitory effect on the HMG-CoA reductase enzyme and lead to up-regulation of the enzyme.
Atherosclerosis 1997 Jun
PMID:Reduction of oxysterol levels up-regulates HMG-CoA reductase activity in rat liver. 919 77

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

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