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)

The hepatic expression of xenobiotic-metabolising cytochrome P450 isoforms in the genetically obese Zucker rat, a model of obesity, was compared to that of its lean littermate. Cytochrome P450 (CYP) levels were determined using diagnostic substrates and/or immunologically in Western blot analyses. When compared with the lean Zucker rat, the obese animal exhibited hyperglycaemia, hypercholesterolaemia, marked hyperinsulinaemia and hypertriglyceridaemia but was normoketonaemic. CYP3A and CYP1A2 levels were higher in the obese Zucker rat when compared with the lean littermate but, in contrast, a protein recognised by human CYP2D6 and, to a lesser extent, CYP2C11 levels were lower. Pretreatment with acetone, dexamethasone and clofibrate resulted in enhanced p-nitrophenol hydroxylase (CYP2E), erythromycin N-demethylase (CYP3A) and lauric acid hydroxylase (CYP4A) activities respectively in the liver of the lean Zucker rat but, in contrast, the obese Zucker rat was refractive to such treatment; similarly, hepatic apoprotein levels of the CYP2E and CYP4A subfamilies were increased markedly only in the lean Zucker rat. It is concluded that CYP2E, CYP3A and CYP4A subfamilies are poorly expressed in the obese Zucker rat, and this rat strain may serve as a good model for elucidating the molecular mechanisms of induction of these cytochrome P450 proteins.
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PMID:Defective expression of cytochrome P450 proteins in the liver of the genetically obese Zucker rat. 874 92

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

Dexfenfluramine has been widely used as an appetite suppressant in the treatment of obesity. It was recently shown that the apparent non-renal clearance of dexfenfluramine was significantly lower in poor metabolizers than in extensive metabolisers of debrisoquine which suggested the involvement of the polymorphically expressed enzyme, CYP2D6, in dexfenfluramine metabolism. In this study, human liver microsomes and yeast-expressed recombinant enzymes were used to examine dexfenfluramine metabolism in vitro. In human liver microsomes, the major product of dexfenfluramine was nordexfenfluramine with lesser amounts of a novel metabolite, N-hydroxynordexfenfluramine, and ketone and alcohol derivatives being formed. Eadie-Hofstee plots (v against v/[s]) of nordexfenfluramine formation between 1 and 1000 microM substrate concentration were biphasic in three of four liver microsome samples examined, with mean Km values of 3 and 569 microM for the high and low affinity enzymes, respectively. At a substrate concentration (0.5 microM) around the known therapeutic plasma concentration, there was negligible inhibition of microsomal dexfenfluramine N-dealkylation by sulphaphenazole and ketoconazole, but between 33 and 100% inhibition by quinidine, and 0-58% inhibition by 7,8-naphthoflavone in seven liver samples. In human liver microsomes, there was also a significant correlation (rs= 0.79, n = 10, P < 0.01) between dextromethorphan O-demethylation and dexfenfluramine (at 1 microM) N-dealkylation activities. Dexfenfluramine was a specific inhibitor (IC50 46 microM) of CYP2D6-mediated dextromethorphan O-demethylation in human liver microsomes but did not appreciably inhibit six other cytochrome P450 isoform-selective activities for CYP1A2, 2A6, 2C9, 2C19, 2E1 and 3A activities in human liver microsomes. Yeast-expressed recombinant human CYP2D6 metabolized dexfenfluramine with high affinity (Km 1.6 microM, Vmax 0.18 nmol min(-1) nmol P450(-1)) to nordexfenfluramine which was the sole product observed. Recombinant CYP1A2 was a lower affinity enzyme (Km 301 microM, Vmax 1.12 nmol min(-1) nmol P450(-1)) and produced nordexfenfluramine with small amounts of N-hydroxynordexfenfluramine. This is the first detailed study to examine the in-vitro metabolism of dexfenfluramine in human liver microsomes and by recombinant human P450s. We were able to identify CYP2D6 (high affinity) and CYP1A2 (low affinity) as the major enzymes catalysing the N-dealkylation of dexfenfluramine in human liver microsomes.
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PMID:Metabolism of dexfenfluramine in human liver microsomes and by recombinant enzymes: role of CYP2D6 and 1A2. 982 34

Hepatic levels of the cytochrome P450 (CYP) proteins 2E1 and 4A are often increased in obesity, diabetes and fasting. In such states of nutritional imbalance, CYPs 2E1 and 4A may play a more significant role in fatty acid oxidation. In order to more fully characterize the regulation of CYP2E1 and CYP4A in obesity and obesity-related (type II) diabetes, we analyzed the hepatic expression of CYP2E1 and CYP4A in ob/ob mice which are leptin deficient, and fa/fa Zucker rats which have defective leptin receptor function. CYP2E1 protein and mRNA were either unchanged or reduced in both models. Conversely, expression of murine Cyp4a10 and 4a14 in the obese mice, and 4A2 in the male fatty Zucker rat, were greatly increased. The levels of other CYP4As were either unchanged or reduced. These results show that CYP2E1 is not inevitably increased by obesity and diabetes and indicate differential regulation of CYP4A subfamily genes in rodent models. Further, they implicate leptin receptor signaling as a factor that may modulate expression of CYP gene products involved in fatty acid oxidation.
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PMID:Altered expression of hepatic CYP2E1 and CYP4A in obese, diabetic ob/ob mice, and fa/fa Zucker rats. 1004 3

1. The present authors have previously developed a transgenic rat carrying a chimeric gene of the mouse whey acidic protein promoter and the structural portion of human growth hormone (GH) gene. Among this (hGH-TG) rat, a line (low GH rat) missing a male-specific pulsatile GH secretary pattern due to suppression of endogenous GH secretion and having a continuous low GH (hGH and rat GH) level in the peripheral circulation was identified. The latter rat was also characterized as having severe obesity with age. This strain (low Gh rat) was used to correlate the sex-specific secretory pattern of GH with the sex-specific expression of cytochrome P450 (CYP) in rat. 2. Comparisons were made between the low GH rat and the non-transgenic rat as to the expression of liver microsomal CYP isozymes. The following enzyme activities were assessed: testosterone (T) hydroxylation and oxidation; ethoxyresorufin O-dealkylation (EROD); bunitrolol (BTL) 4-hydroxylation and T5 alpha-reduction. Protein expression of CYP1A, CYP2C11, CYP2D, CYP2E1, CYP3A2 and CYP4A1 were also assessed by Western blot analysis. 3. Enzyme activities and protein expression of CYP2C11 (T16 alpha and 2alpha-hydroxylase and 17-oxidase activities) and CYP3A2 (T6beta and 2beta-hydroxylase activities) levels, which are known to be higher in the male than in the female rat, were significantly lower in the adult male low GH rat than in the control male rat. In contrast, CYP2A1 (T7 alpha-hydroxylase) and T5-alpha-reductase activities, which are known to be specifically elevated in the female, were significantly higher in the adult male low GH rat than in the control male rat. Thus, the loss of male-specific secretory pattern of GH results in feminization of the pattern of expression of CYP and T5 alpha-reductase activity in the liver. 4. In contrast to other GH-deficient models so far studied, an increase in CYP4A1 and a decrease in CYP2E1 protein expression were observed in the low GH rat. These trends are consistent with the characteristic phenotype of obesity in the transgenic rat because CYP4A1 and CYP2E1 enhance fatty acid excretion and glyconeogenesis from fatty acids respectively.
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PMID:Characterization of hepatic cytochrome P450 isozyme composition in the transgenic rat expressing low level human growth hormone. 1064 7

A 60-year-old woman presented with a history of palpitations, headaches and severe hypertension, which was resistant to hypotensive agents. She had a 2-year history of obesity and a moon face. Her plasma adrenocorticotropic hormone level was below the limits of detection and did not respond to corticotropin-releasing hormone. Urinary-free cortisol was elevated and the circadian rhythm of serum cortisol level had completely disappeared. Imaging analysis demonstrated a unilaterally functioning mass in the left adrenal gland. Serum cortisol level in the left adrenal vein was elevated. The resected adrenal mass measured 4 x 3.5 x 2.5 cm, and ranged from yellow to tan in color. The adrenal cortex adjacent to the nodule did not demonstrate cortical atrophy. The mass was well circumscribed but not encapsulated, and consisted of multiple cortical nodules. These nodules were composed predominantly of clear cortical cells, and partly of compact cortical cells. Immunoreactivity of steroidogenic enzymes including cholesterol side-chain-cleavage P450, 3beta-hydroxysteroid dehydrogenase, 21-hydroxylase cytochrome P450, 11beta-hydroxylase cytochrome P450 and 17alpha-hydroxylase cytochrome P450 was marked in cortical nodules, but minimal in non-nodular cortex. Ultrastructural examination of nodular cortical cells also demonstrated well-developed mitochondria and smooth endoplasmic reticulum, consistent with elevated steroidogenesis in these cells.
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PMID:Adrenocorticotropin-independent unilateral adrenocortical hyperplasia with Cushing's syndrome: Immunohistochemical studies of steroidogenic enzymes, ultrastructural examination and a review of the literature. 1116 51

Insulin resistance in liver and muscle tissue, together with beta-cell secretory defects, leads to overt type 2 diabetes mellitus. In the early stages of this progressive disorder, glycaemic control can be established through diet and exercise alone. Indeed, in some patients, marked weight reduction can lead to normalized fasting blood glucose. As a consequence, pharmacological approaches to weight loss have been investigated as a new option for the management of type 2 diabetes in obese patients. The serotonin- and noradrenaline-reuptake inhibitor sibutramine has emerged as the most promising agent in the treatment of obesity, although it appears to be less effective in diabetic patients than in non-diabetic patients. Other weight-reducing agents of potential benefit include noradrenergic anorexiants, orlistat, leptin, and beta3-agonists. Insulin and insulin secretagogues, the oldest available antidiabetic drugs, have been used to compensate for beta-cell secretory defects in patients with type 2 diabetes. Repaglinide, a new, fast-acting insulin secretagogue with a short duration of action, reduces postprandial hyperglycaemia when taken shortly before meals. Other novel antidiabetic agents are currently under development, including pramlintide (an amylin analogue) and glucagon-like peptide. Pramlintide slows gastric emptying and delays glucose absorption, and glucagon-like peptide is the most potent endogenous stimulator of glucose-induced insulin release. Recent advances in type 2 diabetes therapy have seen the development of the thiazolidinediones (troglitazone, rosiglitazone, and pioglitazone), which improve insulin resistance in patients whose diabetes is poorly controlled by diet and exercise therapy. Thiazolidinediones bind to peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and act through a process involving gene regulation at a transcriptional level. Troglitazone, the first approved drug in the class, has been shown to decrease plasma glucose levels as monotherapy but is more effective in combination with sulphonylureas, metformin, or insulin. However, despite its generally good safety profile, troglitazone has been associated with severe idiosyncratic hepatocellular injury. There have been more than 150 spontaneous reports of serious hepatic events, including at least 25 instances in which patients died or required a liver transplant. Rosiglitazone, the most potent thiazolidinedione, is still in clinical development, as is pioglitazone. To date, rosiglitazone has been shown to have no reported cases of idiosyncratic drug reactions leading to jaundice or liver failure and no clinically significant drug interactions with cytochrome P450 3A4-metabolized drugs such as nifedipine. Although the available data for pioglitazone are limited to the results of short-term studies, it is reported to be safe and well tolerated. Combination therapy is increasingly important in type 2 diabetes management following failure of monotherapy because complementary mechanisms of action of the different classes of oral agents demonstrate synergistic effects when used in combination. Oral agents may also be used as adjuncts to insulin for achieving glycaemic control.
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PMID:Promising new approaches. 1122 Feb 87

Hepatic cytochrome P450 (P450) enzyme activities and gene expression can be profoundly altered in disease states. In general the levels of affected hepatic P450 enzymes are depressed by diseases, causing potential and documented impairment of drug clearance and clinical drug toxicity. However, modulation of P450s is enzyme selective and this selectivity differs among different diseases. This review will concentrate on regulation of P450s in diabetes, obesity and infectious and inflammatory disease, conditions that affect millions of people worldwide every day.
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PMID:Hepatic cytochrome P450 regulation in disease states. 1146 24

Decreased insulin sensitivity plays a major role in various human diseases. particularly type 2 diabetes mellitus, and is associated with a higher risk of atherosclerosis and cardiovascular complications. Thiazolidinediones, more commonly termed glitazones, are the first drugs to specifically target muscular insulin resistance. They have proven efficacy for reducing plasma glucose levels in patients with type 2 diabetes mellitus treated with diet alone, sulphonylureas, metformin or insulin. In addition, they are associated with some improvement of the cardiovascular risk profile. However, troglitazone, the first compound approved by the Food and Drug Administration in the US, proved to be hepatotoxic and was withdrawn from the market after the report of several dozen deaths or cases of severe hepatic failure requiring liver transplantation. It remains unclear whether or not hepatotoxicity is a class effect or is related to unique properties of troglitazone. Rosiglitazone and pioglitazone, two other glitazones, appear to have similar efficacy with regard to blood glucose control in patients with type 2 diabetes mellitus as compared with troglitazone. In controlled clinical trials, the incidence of significant (> or =3 x upper limit of normal) increases in liver enzyme levels (ALT in particular) was similar with rosiglitazone or pioglitazone as compared with placebo, whereas troglitazone was associated with a 3-fold greater incidence. In contrast to the numerous case reports of acute liver failure in patients receiving troglitzone, only a few case reports of hepatotoxicity have been reported in patients treated with rosiglitazone until now, with a causal relationship remaining uncertain. Furthermore, no single case of severe hepatotoxicity has been reported yet with pioglitazone. It should be mentioned that troglitazone, unlike pioglitazone and rosiglitazone, induces the cytochrome P450 isoform 3A4, which is partly responsible for its metabolism, and may be prone to drug interactions. Importantly enough, obesity, insulin resistance and type 2 diabetes mellitus are associated with liver abnormalities, especially non-alcoholic steatohepatitis, independent of any pharmacological treatment. This association obviously complicates the selection of patients who are good candidates for a treatment with glitazones as well as the monitoring of liver tests after initiation of therapy with any thiazolidinedione compound. While regular monitoring of liver enzymes is still recommended and more long term data are desirable, current evidence from clinical trials and postmarketing experience in the US supports the conclusion that rosiglitazone and pioglitazone do not share the hepatotoxic profile of troglitazone.
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PMID:Hepatotoxicity with thiazolidinediones: is it a class effect? 1173 45

Neonatal administration of monosodium glutamate (MSG) can produce latently expressed defects in drug metabolism and growth hormone secretion as well as stunted growth and obesity. Instead of secreting growth hormone in the masculine episodic profile, plasma hormone levels are generally undetectable in affected adult male rats. Moreover, male-specific isoforms of cytochrome P450 (P450; e.g., CYP2C11 and CYP3A2), whose combined levels comprise the bulk of the total hepatic P450 in adult male rats, are similarly undetectable in these animals. Since "signaling elements" in the masculine episodic growth hormone profile are solely responsible for the elevated characteristic male-like expression levels of CYP2C11 and CYP3A2, suppression of the isoforms in the MSG-treated rats appeared to be caused by the simple absence of the hormone from the circulation. However, the reported failures of restored physiologic masculine growth hormone profiles to correct the P450 defects suggested the occurrence of direct MSG-induced liver damage independent of the well known hypothalamic lesions produced by the amino acid. Concurrent administration of dizocilpine maleate (MK-801), a selective and highly potent noncompetitive N-methyl-D-aspartate receptor antagonist of glutamate, completely prevented the adverse effects of neonatal MSG treatment on P450 expression, growth hormone secretion, and growth parameters, indicating that the amino acid-induced defects are solely a result of neuronal (i.e., hypothalamic) damage produced at the time of MSG exposure. The irreversibility of the P450 damage is described as resulting from secondary defects initially induced by the neuronal lesions.
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PMID:Prevention of latently expressed CYP2C11, CYP3A2, and growth hormone defects in neonatally monosodium glutamate-treated male rats by the N-methyl-D-aspartate receptor antagonist dizocilpine maleate. 1213 Jul 6


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