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)

Cytochrome P450IIE1 (IIE1) is a microsomal xenobiotic-activating enzyme that is inducible not only by various chemical agents but also by fasting and diabetes. Using a rat model that mimics human obesity, we have found that hepatic IIE1 levels are also increased by this common clinical disorder. Liver microsomes from rats made obese by feeding with an energy-dense diet displayed elevated aggregate P450 content (+28%) and enhanced catalytic activities associated with IIE1, including low-Km N-nitrosodimethylamine demethylation (+66%), aniline hydroxylation (+52%), p-nitrophenol hydroxylation (+170%), and acetaminophen-cysteine conjugate formation (+28%). In contrast, obesity had no significant effect on cytochrome b5 content, P450 reductase activity, benzphetamine demethylation, or erythromycin demethylation, with the latter two reactions being linked with rat IIC11 and IIIA1, respectively. The enhancement of IIE1-dependent drug-metabolizing activities noted in liver microsomes from obese rats was paralleled by a similar increase (111%) in hepatic IIE1 protein content in these animals, as assessed on immunoblots developed with anti-hamster IIE1 IgG. Anti-IIE1-inhibitable rates of microsomal p-nitrophenol metabolism, a reaction highly correlated with IIE1 content (r = 0.88, p less than 0.01), were over 3-fold higher in obese rats than in nonobese controls, providing additional evidence for the obesity-related increase of hepatic IIE1. The induction of IIE1 by the pathophysiological condition of obesity may provide a biochemical basis for the increased incidence of occult liver disease and certain cancers noted in obese individuals.
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PMID:Induction of cytochrome P450IIE1 in the obese overfed rat. 200 76

Changes in the components of hepatic microsomal electron transport systems and in drug hydroxylase activities were investigated in ventromedial hypothalamus (VMH) lesioned obese rats. Eight weeks after electrolysis of the bilateral VMH, the content of cytochrome P450 per mg microsomal protein (0.79 +/- 0.07 nmol/mg protein) was significantly higher (P less than 0.02) than that in the sham-operated rats (0.59 +/- 0.02). Cytochrome P450 per whole liver in the VMH-lesioned obese rats had also significantly increased (87 +/- 9 nmol vs 56 +/- 3, P less than 0.02). No significant differences were found in the cytochrome b5 contents, and the activities of NADPH- and NADH-cytochrome c reductases between the VMH-lesioned obese and sham-operated rats. The demethylation activities of aminopyrine (1.04 +/- 0.02 nmol/mg protein/min vs 0.94 +/- 0.02, P less than 0.05) and p-nitroanisole (0.96 +/- 0.02 vs 0.89 +/- 0.02 , p less than 0.02) and the aniline hydroxylase activity (0.22 +/- 0.01 vs 0.16 +/- 0.01, P less than 0.01) were enhanced, but 7-ethoxycoumarin O-deethylase activity was unchanged in the VMH-lesioned obese rats. These results indicate a selective increase in the content of cytochrome P450 among the components of the P450-dependent mixed function oxidase system in the liver of VMH-lesioned obese rats. Our observations suggest that drug metabolism may be enhanced in the hypothalamic obesity.
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PMID:Selective increase in cytochrome P450 content in hepatic microsomes from rats with ventromedial hypothalamic lesions. 204 15

The obese overfed rat effectively models many of the pharmacological changes in human obesity. Recent data show that the obese rat is unusually susceptible to liver damage by several metabolically activated drugs that may be more toxic in obese humans. Results of the present study suggest a specific molecular locus for this interaction. In obese rats, P450 content of liver and the microsomal concentration of P450 were elevated 88% and 31%, respectively, over nonobese controls. Increases in microsomal ethanol oxidation were of identical magnitude. The ethanol-inducible form of P450 that is responsible for microsomal ethanol oxidation, P450IIE1, bioactivates several drugs that are shown to cause increased injury in obese rats. Collectively, these findings indicate that specific forms of P450 may become up-regulated in obesity, increasing the risk of a biochemically defined spectrum of drug-induced organ injuries.
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PMID:Obesity as a risk factor for drug-induced organ injury. VI. Increased hepatic P450 concentration and microsomal ethanol oxidizing activity in the obese overfed rat. 319 41

In this study, the overfed rat was employed as a model for examining the influence of obesity on the regulation of hepatic cytochromes P450 3A and 2C11 (CYP3A and CYP2C11, respectively). These proteins represent the predominant constitutive hepatic P450 enzymes of male rats. Sprague-Dawley rats were chronically fed a standard pelleted diet or an energy-dense diet which typically results in significant increases in body weight, serum triglyceride levels and liver lipid content. Obesity did not influence baseline levels of spectral cytochrome P450 content. Similar baseline activities of CYP3A (testosterone 6 beta-hydroxylation), comparative CYP3A protein levels (Western blot) and steady-state CYP3A mRNA (slot blot), were found in rats fed either diet. Likewise, obesity did not appear to influence CYP2C11 at the enzyme activity (testosterone 2 alpha-hydroxylation) or mRNA levels. Half of the animals in each group received 20 mg phenobarbital (intraperitoneal injection) per animal every 12 hours for three consecutive days. This resulted in similar phenobarbital plasma concentrations in both groups. Phenobarbital treatment increased the concentrations of total cytochrome P450 in both lean and obese rats to the same extent. CYP3A activity, protein and mRNA levels were induced to a similar magnitude in rats fed either diet. Furthermore, obesity did not influence CYP2C11 activity or mRNA levels following administration of phenobarbital. A lack of an effect of obesity and the altered lipid environment on the regulation of CYP3A and CYP2C11 is in contrast to other enzymes studied previously. It is apparent that the consequences of obesity on hepatic cytochrome P450 may be enzyme-specific.
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PMID:Expression of the CYP3A and CYP2C11 enzymes in a nutritionally obese rodent model: response to phenobarbital treatment. 808 27

The present study determined the effect of genetic obesity and phenobarbital (PB) treatment on the expression and regulation of the hepatic cytochrome P450 enzyme (CYP2C11) in Fa/? and fa/fa Zucker rats. Hepatic CYP2C11 levels as determined by Western immunoblotting and associated enzymatic activity (testosterone oxidation at the 2 alpha position) were significantly lower in untreated fa/fa Zucker rats compared with that observed in Fa/? Zucker rats. There was no significant difference in the constitutive CYP2C11 steady-state mRNA level hybridizable to the cDNA (P450 16 alpha) or specific oligonucleotide probe (Northern and slot blot analyses) between fa/fa and Fa/? Zucker rats. The depressed constitutive CYP2C11 protein levels in fa/fa rats may be attributed to their low plasma testosterone and growth hormone levels; however, lack of differences in CYP2C11 steady-state mRNA suggest post-transcriptional regulatory mechanism(s). Treatment with PB further suppressed hepatic CYP2C11 protein levels and activities in both fa/fa and Fa/? Zucker rats in comparison with that seen in controls. The level of CYP2C11 steady-state mRNA was significantly higher after treatment with PB in Fa/? Zucker rats, while no change was observed in fa/fa animals. The mechanism by which PB treatment fails to increase CYP2C11 steady-state mRNA levels in the fa/fa Zucker rat is unknown; however, it may share a common molecular basis with the defect in nuclear transcription rate previously observed with CYP2B1/2B2.
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PMID:Expression of a male-specific cytochrome P450 isozyme (CYP2C11) in fa/fa Zucker rats: effect of phenobarbital treatment. 827 26

Neonatal exposure to monosodium glutamate (MSG) permanently blocks growth hormone (GH) secretion, which results in the development of a well-defined syndrome characterized by stunted body growth, obesity and impaired drug metabolism. We have found that restoration of the normal masculine circulating profile of GH (i.e., six daily pulses) by use of an external pumping apparatus is ineffective in restoring the normal expression of hepatic cytochrome P450 2C11, a major GH-dependent drug and steroid metabolizing enzyme that is eliminated by MSG treatment. Moreover, administering GH at two, four or seven plasma pulses per day with amplitudes ranging from physiologic to 7 times normal were similarly ineffective in restoring the expression (at both an activity and mRNA level) of the cytochrome. Additionally, multicytochrome P450-dependent hexobarbital hydroxylase was also unresponsive to GH administration in the MSG-treated rats. Because GH replacement was unable to correct the enzyme defects, our results suggest that the developmental abnormalities produced by neonatal MSG are not simply a result of a GH deficiency per se, but are due to an irreversible insensitivity of the target cell to GH.
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PMID:Irreversible suppression of growth hormone-dependent cytochrome P450 2C11 in adult rats neonatally treated with monosodium glutamate. 849 38

Polycystic ovarian syndrome (PCO) is a relatively poorly defined type of steroidogenic abnormality, dependent on an overproduction of lutropin (LH). The PCO is characterized by infertility, amenorrhea or oligomenorrhea, obesity and hirsutism. The clinical symptoms are associated with typical morphological changes of the ovaries. It has been suggested that hyperplastic secondary interstitial cells and theca cells are the main site of excess androgen production. In PCO the elevation of androgens is observed, while the estrogen level is normal or slightly decreased. In the ovarian sex steroidogenic pathways, 17 alpha-hydroxylase, which produces androgens and aromatase, which converts androgens to estrogens are important regulatory enzymes. Major components of 17 alpha-hydroxylase and aromatase are cytochromes P450 17 alpha and P450 arom. Histochemical investigations revealed increased immunoreactivity with the antibody directed against P450 17 alpha in theca cells. In this review data from literature are presented and discussed regarding endocrinological and molecular background of PCO.
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PMID:[Molecular basis of polycystic ovarian syndrome]. 868 42

The crucial role of glucocorticoids in obesity and insulin resistance and the actions of the OB protein leptin on the hypothalamic-pituitary-adrenal (HPA) axis suggest that there is an important interaction of leptin with the glucocorticoid system. Therefore, we designed a study to test the effect of leptin directly on adrenocortical steroidogenesis. Primary cultures of bovine adrenocortical cells were incubated with increasing concentrations (10-1,000 ng/ml) of recombinant mouse leptin for 24 h, and the effects of leptin on basal and ACTH-stimulated cortisol secretion were determined. The accumulation of P450 17alpha mRNA following incubation with ACTH (10 nmol/l) and leptin (10-1,000 ng/ml) was analyzed by Northern blot. Adrenocortical cells were characterized by immunohistochemical staining for 17alpha-hydroxyprogesterone. Leptin (10-1,000 ng/ml) inhibited basal and ACTH-stimulated cortisol release. At a concentration that occurs in obese individuals in vivo (100 ng/ml), it reduced basal cortisol secretion to 52.7 +/- 37% (mean +/- SE). The rise in cortisol secretion following maximal ACTH stimulation (10 nmol/l) was blunted to 55.2 +/- 27%. At more physiological concentrations of ACTH (0.1 nmol/l), the inhibition of cortisol release by coincubation with low doses of leptin (10 ng/ml) was even more pronounced, leading to a reduction to 32.8% (1,248 +/- 134 vs. 410 +/- 157 nmol/l). Addition of OB protein (10-1,000 ng/ml) led to a dose-dependent reduction of ACTH-stimulated cytochrome P450 17alpha mRNA accumulation (from 80 to 45%), suggesting that leptin regulates adrenal steroidogenesis at the transcriptional level. These data clearly demonstrate that leptin inhibits cortisol production in adrenocortical cells and therefore appears to be a metabolic signal that directly acts on the adrenal gland.
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PMID:Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland: leptin inhibits cortisol release directly. 920 Jun 62

This paper approaches the hypothesis that fatty acids contribute to hypertension by examining possible interactions of nonesterified fatty acids with renal pressure-natriuresis, peripheral vascular resistance, and the central nervous barostat, three loci where long-term regulation of blood pressure is probably controlled. By inhibiting aldosterone secretion, nonesterified fatty acids may lower blood pressure by facilitating pressure-natriuresis. Oxygenated metabolites of fatty acids appear to stimulate aldosterone secretion. In different experimental situations, fatty acids either constrict or dilate arteries. There is no evidence of an effect of fatty acids on the central nervous barostat, but they do sensitize peripheral vessels to alpha-adrenergic stimuli. Obesity and diabetes are marked by increased incidence of hypertension, and elevated levels of fatty acids or their P450 oxygenated metabolites may contribute to this association. Drugs that influence plasma fatty acids, like heparin, do not have reproducible effects on blood pressure. Experimental evidence suggests but does not prove that nonesterified fatty acids can affect the long-term set-point of blood pressure.
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PMID:Nonesterified fatty acids in the pathogenesis of hypertension: theory and evidence. 925 Jun 9

Estrogen biosynthesis in adipose tissue increases with age and obesity, and has been implicated in the development of endometrial cancer and breast cancer. In normal human adipose tissue, expression of the CYP19 gene which encodes aromatase P450, the enzyme responsible for estrogen biosynthesis, is regulated by a distal promoter, namely promoter I.4. Stimulation of expression in adipose stromal cells by members of the type 1 cytokine family, i.e. interleukin (IL)-6, IL-11, leukemia inhibitory factor (LIF) and oncostatin M (OSM), is mediated via a Jak-STAT3 signaling pathway and a GAS element upstream of promoter I.4. In contrast, aromatase expression in breast adipose tissue proximal to tumor is increased three- to four-fold to the utilization of another promoter, namely promoter II, proximal to the translation initiation site. In the present report, we show that prostaglandin (PG) E2 is the most potent factor which stimulates aromatase expression via cyclic AMP and promoter II. PGE2 acts via EP1 and EP2 receptor subtypes to stimulate both the PKC and PKA pathways. The combined stimulation of both of these pathways results in the maximal expression of promoter II-specific CYP19 transcripts. Because PGE2 is a major secretory product both of breast tumor epithelial cells and fibroblasts, as well as of macrophages infiltrating the tumor site, then this could be the mechanism whereby estrogen biosynthesis is stimulated in breast sites adjacent to a tumor, leading in turn to increased growth and development of the tumor itself.
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PMID:Transcriptional regulation of CYP19 gene (aromatase) expression in adipose stromal cells in primary culture. 936 91


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