Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nonalcoholic steatohepatitis is prevalent among obese individuals with excessive caloric intake, insulin resistance, and type II diabetes. However, no animal models exist that recapitulate this important association. This study produced and characterized steatohepatitis (SH) caused by intragastric overfeeding in mice. C57BL/6, tumor necrosis factor (TNF) type I receptor-deficient, and genetically matched wild type mice were fed via an implanted gastrostomy tube a high-fat diet for 9 weeks in the increasing amount up to 85% in excess of the standard intake. Animals were examined for weight gain, insulin sensitivity, and histology and biochemistry of liver and white adipose tissue (WAT). Overfed C57BL/6 mice progressively became obese, with 71% larger final body weights. They had increased visceral WAT, hyperglycemia, hyperinsulinemia, hyperleptinemia, glucose intolerance, and insulin resistance. Of these mice, 46% developed SH with increased plasma alanine aminotransferase (121 +/- 27 vs. 13 +/- 1 U/L), neutrophilic infiltration, and sinusoidal and pericellular fibrosis. Obese WAT showed increased TNFalpha and leptin expression and reciprocally reduced adiponectin expression. The expression of lipogenic transcription factors (SREBP-1c, PPARgamma, LXRalpha) was increased, whereas that of a lipolytic nuclear factor PPARalpha was reduced in SH. SH was associated with reduced cytochrome P450 (Cyp)2e1 but increased Cyp4a. TNF type I receptor deficiency did not prevent obesity and SH. In conclusion, forced overfeeding with a high-fat diet in mice induces obesity, insulin resistance, and SH in the absence of TNF signaling or Cyp2e1 induction.
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PMID:Steatohepatitis induced by intragastric overfeeding in mice. 1617 2

The nuclear receptor constitutive androstane receptor (CAR), a key transcription factor for the expression of cytochrome P450 (CYP) 2B genes, resides in the cytoplasm under untreated conditions and translocates into the nucleus upon xenobiotic exposure. CAR forms a multiprotein complex including heat shock protein 90 in the cytoplasm as the glucocorticoid receptor, and it is likely that protein phosphatase 2A plays a critical role in the first step of CAR nuclear translocation. In addition to the xenobiotic induction of CYP2Bs, our recent studies have indicated that CAR is important for sex and strain differences and obesity/diabetes-associated changes in the expression of CYP2B genes. These results have raised the hypothesis that the expression of nuclear receptors varies depending on the physiologic condition, leading to the dysregulation of CYP expression. In obese mice fed a high-fat diet, however, hepatic CYP3A levels are drastically decreased without any significant changes in the expression of nuclear receptors including the pregnane X receptor and hepatocyte nuclear factor-4, which are known to be key transcription factors in the expression of CYP3A genes. These results indicate that it is important to investigate the mechanism of the transcriptional regulation of nuclear receptor genes as well as the activation of nuclear receptors to understand the CYP expression system fully.
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PMID:[Roles of nuclear receptors in the gene expression of drug-metabolizing enzymes under various physiological conditions]. 1667 42

Hypertension is often associated with insulin resistance or hyperinsulinemia. Metabolism of arachidonic acid by cytochrome P450 to the vasoconstrictor 20-HETE is thought to be involved in the pathogenesis of hypertension, but the relationship of 20-HETE with insulin resistance is not clearly understood. Obesity is a major determinant of insulin resistance, and we have previously demonstrated a positive relationship between BMI and 20-HETE in untreated hypertensive and normotensive individuals. The present analysis sought to determine if this relationship was related to insulin levels or insulin resistance (HOMA). We analysed 24h urinary excretion of 20-HETE, serum insulin levels and insulin resistance in 66 lean to overweight untreated hypertensive and normotensive individuals. There was a significant positive association between 20-HETE and BMI (p<0.001), and serum insulin and BMI (p=0.003). There were no associations between 20-HETE excretion and either serum insulin or insulin resistance, before or after adjustment for age, gender, BMI and BP, or when hypertensive and normotensive individuals were considered separately. The results of the present study suggest that the observed positive association between urinary 20-HETE excretion and BMI may not be related to circulating insulin levels or insulin resistance.
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PMID:20-Hydroxyeicosatetraenoic acid is not associated with circulating insulin in lean to overweight humans. 1671 8

It is well known, that patients with schizophrenia exhibit increased rates of cardiac morbidity and mortality. Frequent cardiovascular diseases are only partially explained by lifestyle, inactivity, dietary habits and nicotine abuse, but also by reduced compliance in prevention programs. On the other hand, it has been shown that particularly atypical antipsychotic agents are differentially responsible for high rates of obesity, hypertriglyceridemia, and diabetes. Therefore, a standardized evaluation of corresponding parameters is indicated in every patient. If needed, modulation of the medication regimen has to be performed. Additionally, a dietary counselling of the patient and his family should be offered. Besides pharmacological approaches to normalize dyslipidemia, specific behavioural therapy programmes are an option that may alter metabolic parameters. Threatening cardiac complications in long-term treatment of schizophrenia may also be the result of direct side effects under treatment with antipsychotics, like QT-prolongation triggering major arrhythmias. For prevention, predisposing risk factors like electrolyte disturbances, pre-existing cardiac diseases, co-medication with QT prolonging drugs and medication with potential cytochrome P450 interaction have to be taken into consideration.
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PMID:[Cardiac complications in patients with schizophrenic disorders]. 1697 9

The toxicity of germander, a herb used to treat obesity, is attributed to cytochrome P450 activation of the furan ring of its major diterpenoid component (teucrin A) into a reactive metabolite capable of adducting proteins. 1,4-Enedials have been proposed to be the reactive products of metabolism, possibly arising from a rearrangement of putative epoxide intermediates. We synthesized the enedial derivative of teucrin A as well as the enedial derived from a model furan, 3-(4-methoxy-benzyloxymethyl)-furan, by dimethyldioxirane oxidation and characterized the products of their reactions with amino acids and peptides. The reactions of the model enedial, 2-(4-methoxy-benzyloxymethyl)-but-2-enedial, with N-acetyl lysine (NAL) afforded regioisomeric N-alkyl-3-pyrrolin-2-ones, differing in the substitution on the double bond of the heterocyclic ring. Novel products formed in the reactions of the model enedial with N-acetyl cysteine (NAC) and both NAC/NAL uncovered the existence of tautomerization between the enedial and a hydroxyenal, which was manifest by the loss of 4-methoxybenzylalcohol and the incorporation of a second molecule of NAC. The reactions of teucrin A-enedial with NAC and NAL afforded analogues of the products observed with the model enedial, and the existence of the tautomeric equilibrium resulted in epimerization of the proton (H12) adjacent to the former furan ring. This work further illuminates the complex chemical behavior of unsaturated dialdehydes as an important class of toxic metabolites and lays the foundation for studies of the protein targets of teucrin A-enedial.
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PMID:Characterization of the amino acid adducts of the enedial derivative of teucrin A. 1704 Jan 2

Ischemia/reperfusion (I/R) injury is a major cause of morbidity and mortality in liver surgery and transplantation, and fatty livers are susceptible to greater I/R injury and a higher incidence of primary graft nonfunction after transplantation. Because alcohol intake and obesity are major causes of fatty liver, this study was initiated to investigate the effect of chronic ethanol consumption on hepatic microsomal cytochrome P450 (CYP) activity after I/R. Rats were fed an alcohol liquid diet or a control isocaloric diet for 4 weeks, and then subjected to 60 min of hepatic ischemia and 5 h of reperfusion. It was found that, chronic ethanol consumption significantly increased liver weight, serum triglyceride (TG), liver TG, and serum aminotransferase activities. Moreover, alcoholic fatty livers exposed to I/R showed significantly higher levels of aminotransferase activities than the controls. No significant differences in microsomal CYP content or CYP1A1 activity were found between I/R treated animals fed a control diet (the CD + I/R group) and I/R treated animals fed an ethanol containing diet (the ED + I/R group). Moreover, whereas CYP1A2 activity was decreased in the ED + I/R group versus the CD + I/R group, CYP2E1 activity was elevated. Additionally, chronic alcohol consumption up-regulated TNF-alpha and IL-6 mRNA levels immediately after I/R. In conclusion, chronic ethanol consumption was found to potentiate hepatocellular damage as indicated by abnormalities in microsomal drug metabolizing function during I/R.
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PMID:Altered activity of cytochrome P450 in alcoholic fatty liver exposed to ischemia/reperfusion. 1732 42

Dehydroepiandrosterone (DHEA), the major precursor of androgens and estrogens, has several beneficial effects on the immune system, on memory function, and in modulating the effects of diabetes, obesity, and chemical carcinogenesis. Treatment of rats with DHEA influences expression of cytochrome P450 (P450) genes, including peroxisome proliferator-activated receptor alpha (PPAR alpha)- and pregnane X receptor (PXR)-mediated induction of CYP4As and CYP3A23, and suppression of CYP2C11. DHEA treatment elevated the expression and activities of CYP3A4, CYP2C9, CYP2C19, and CYP2B6 in primary cultures of human hepatocytes. Induction of CYP3A4 in human hepatocytes was consistent with studies in rats, but induction of CYP2Cs was unexpected. The role of PXR in this response was studied in transient transfection assays. DHEA activated hPXR in a concentration-dependent manner. Because CYP2B6 induction by DHEA in human hepatocytes might involve either PXR or constitutive androstane receptor (CAR) activation, we performed experiments in primary hepatocytes from CAR knockout mice and observed that CAR was required for maximal induction of Cyp2b10 by DHEA. Furthermore, CAR-mediated Cyp2b10 induction by DHEA was inhibited by the inverse agonist of CAR, androstanol (5 alpha-androstan-3 alpha-ol). Further evidence for CAR activation was provided by cytoplasmic/nuclear transfer of CAR upon DHEA treatment. Elucidation of CAR activation and subsequent induction of CYP2B6 by DHEA presented an additional mechanism by which the sterol can modify the expression of P450s. The effect of DHEA on the activation of the xenosensors PPAR alpha, PXR, and CAR, and the consequent potential for adverse drug/toxicant interactions should be considered in humans treated with this nutriceutical agent.
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PMID:Dehydroepiandrosterone induces human CYP2B6 through the constitutive androstane receptor. 1759 76

Pharmacogenomics of serotonin are potentially relevant in research and clinical practice. There are few proven examples of the importance of pharmacogenetics of serotonin-modifying agents used in functional gastrointestinal or motility disorders. Drug metabolism is dependent on function of the cytochrome P450 enzymes, such as 2D6 and 3A4. Genetic variations in transporters and translation mechanisms have been associated with responses to treatment in irritable bowel syndrome and in obesity. Research on the impact of polymorphisms of key proteins on the pharmacokinetics and pharmacodynamics of drugs that alter serotonin-mediated signalling will assist in explaining diverse responses to those drugs and ultimately improve clinical practice, individualizing medicine.
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PMID:Pharmacogenomics and serotonergic agents: research observations and potential clinical practice implications. 1762 87

Susceptibility to sporadic colorectal cancers (CRC) is generally thought to be the sum of complex interactions between environmental and genetic factors, all of which contribute independently, producing only a modest effect on the whole phenomenon. However, to date, most research has concealed the notion of interaction and merely focused on dissociate analyses of risk factors to highlight associations with CRC. By contrast, we have chosen a combinative approach here to explore the joint effects of several factors at a time. Through an association study based on 1,023 cases and 1,121 controls, we examined the influence on CRC risk of environmental factors coanalyzed with combinations of six single nucleotide polymorphisms located in cytochrome P450 genes (c.-163A>C and c.1548T>C in CYP1A2, g.-1293G>C and g.-1053C>T in CYP2E1, c.1294C>G in CYP1B1, and c.430C>T in CYP2C9). Whereas separate analyses of the SNPs showed no effect on CRC risk, three allelic variant combinations were found to be associated with a significant increase in CRC risk in interaction with an excessive red meat consumption, thereby exacerbating the intrinsic procarcinogenic effect of this dietary factor. One of these three predisposing combinations was also shown to interact positively with obesity. Provided that they are validated, our results suggest the need to develop robust combinative methods to improve genetic investigations into the susceptibility to CRC.
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PMID:Combinations of cytochrome P450 gene polymorphisms enhancing the risk for sporadic colorectal cancer related to red meat consumption. 1762 11

Despite efforts spanning four decades, the therapeutic potential of thyroid hormone receptor (TR) agonists as lipid-lowering and anti-obesity agents remains largely unexplored in humans because of dose-limiting cardiac effects and effects on the thyroid hormone axis (THA), muscle metabolism, and bone turnover. TR agonists selective for the TRbeta isoform exhibit modest cardiac sparing in rodents and primates but are unable to lower lipids without inducing TRbeta-mediated suppression of the THA. Herein, we describe a cytochrome P450-activated prodrug of a phosphonate-containing TR agonist that exhibits increased TR activation in the liver relative to extrahepatic tissues and an improved therapeutic index. Pharmacokinetic studies in rats demonstrated that the prodrug (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane (MB07811) undergoes first-pass hepatic extraction and that cleavage of the prodrug generates the negatively charged TR agonist (3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methylphosphonic acid (MB07344), which distributes poorly into most tissues and is rapidly eliminated in the bile. Enhanced liver targeting was further demonstrated by comparing the effects of MB07811 with 3,5,3'-triiodo-l-thyronine (T(3)) and a non-liver-targeted TR agonist, 3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (KB-141) on the expression of TR agonist-responsive genes in the liver and six extrahepatic tissues. The pharmacologic effects of liver targeting were evident in the normal rat, where MB07811 exhibited increased cardiac sparing, and in the diet-induced obese mouse, where, unlike KB-141, MB07811 reduced cholesterol and both serum and hepatic triglycerides at doses devoid of effects on body weight, glycemia, and the THA. These results indicate that targeting TR agonists to the liver has the potential to lower both cholesterol and triglyceride levels with an acceptable safety profile.
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PMID:Targeting thyroid hormone receptor-beta agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index. 1787 14


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