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 separate steps in the formation of aldosterone from cholesterol were studied in a strain of spontaneously hypertensive rats in which phenotypic obesity is inherited as a recessive trait (Koletsky rats). The obese and hypertensive state had little or no effect on side-chain cleavage of cholesterol, formation of progesterone from pregnenolone or 21-hydroxylation. Mitochondrial 18-hydroxylation of endogenous and exogenous corticosterone, however, as well as 18- and 11 beta-hydroxylation of deoxycorticosterone, were increased in obese hypertensive rats, both when compared with non-obese hypertensive siblings and when compared with healthy Sprague-Dawley rats. 18-Hydroxylation of corticosterone was increased more than 18-hydroxylation of deoxycorticosterone. In non-obese hypertensive rats, the adrenal content of mitochondrial cytochrome P-450 was lower than that in obese hypertensive rats but higher than that in rats of the conventional Sprague-Dawley strain. The results are discussed with respect to possible heterogeneity of adrenal cytochrome P-450 and to possible explanations for the changes observed.
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PMID:Adrenal hydroxylations in genetically obese and hypertensive rats. 48 14

The present study was undertaken to examine the appropriateness of the obese overfed rat and the obese Zucker rat as animal models for evaluating drug disposition changes in human obesity. It was found that 11 of 12 characteristics that control or influence drug clearance and volume of drug distribution in obese humans were qualitatively reproduced in the obese overfed rat. In contrast, existing literature shows that the obese Zucker rat resembles the obese human in only five of 12 characteristics, with meaningful discrepancies in fat-free mass, creatinine clearance, and thyroid function. Perhaps of greatest significance were changes in hepatic cytochrome P-450, which increased in proportion to total body mass in the obese overfed rat but remain unchanged in the Zucker rat. Although P-450 status in human obesity is unknown, the overfed rat model provides an opportunity for examining increased oxidative drug elimination that appears as an established feature of human obesity. In conclusion, the obese overfed rat appears to be superior to the obese Zucker rat as an animal model for evaluating the pharmacological consequences of human obesity, particularly those in which reproducing drug pharmacokinetics is an important consideration.
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PMID:Pharmacokinetic characteristics of the obese overfed rat. 270 95

The effects of chronic growth hormone deficiency on the growth hormone-dependent, sexually dimorphic hepatic drug-metabolizing enzymes were studied in adult rats of both sexes. Neonatal administration of monosodium L-glutamate produced the expected syndrome characterized by stunted growth, obesity, prolonged vaginal estrus, and an inhibition in the growth of the pituitaries, adrenals, gonads, sexual accessory organs, and kidneys. Associated with these abnormalities was a 90% reduction in the concentration of serum growth hormone in male and female rats. In contrast, the activities of hepatic aniline hydroxylase, total cytochrome P-450, and the Michaelis constants and maximal velocities for hexobarbital hydroxylase and UDP-glucuronosyltransferase were unaffected by the profound deficiency in growth hormone.
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PMID:Normal levels of hepatic drug-metabolizing enzymes in neonatally induced, growth hormone-deficient adult male and female rats. 287 66

Liver microsomes from obese and control Sprague-Dawley rats were compared for cytochrome P-450 content and the ability to metabolize various prototype substrates. Over a 40-week period, the obesity-producing energy-dense diet increased average total body mass by 50%, liver mass by 32%, and body fat mass by 292%. Spectrally detectable cytochrome P-450 per mg protein increased by 36% in hepatic microsomes from obese rats. The livers from obese rats also contained more cytochrome P-450 (87%), while microsomal protein, NADPH-cytochrome c reductase, aryl hydrocarbon hydroxylase, and UDP-glucuronosyl transferase per organ rose slightly (12-40%) but not significantly. No change in the specific activities of these enzymes occurred. Young and adult rats were transferred from pellet diet to energy-dense diet for 3 weeks to examine the influence of diet vs. obesity. This short-term dietary change increased microsomal protein per g liver as well as cytochrome P-450 per liver, per g liver, and per mg protein. Adult animals increased in body weight by 24%, making them overweight and borderline obese. However, young animals showed no increase in body or liver weight, suggesting a direct effect of the energy-dense diet on liver P-450. Dietary obesity thus increased both the relative and total amounts of liver cytochrome P-450 in rats, but not the specific activities of other enzymes. These changes in cytochrome P-450 are consistent with the increased clearance seen for several oxidized drugs in obese humans and suggest that the obese overfed rat represents a useful animal model.
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PMID:Hepatic cytochrome P-450 and in vitro drug metabolism in an overfed rat model of obesity. 314 37

The obese Zucker rodent appears to lack a significant induction response after phenobarbital pretreatment. Induction of the hepatic cytochrome P-450 system with phenobarbital is known to enhance acetaminophen hepatotoxicity. The purpose of this study was to evaluate the influence of phenobarbital enzyme induction on acetaminophen hepatotoxicity in the obese and lean Zucker rodent. A preliminary study was performed evaluating the pharmacokinetics of acetaminophen in both the obese and lean Zucker rats. Data were utilized to calculate appropriate loading doses of acetaminophen during the subsequent hepatotoxicity study. Phenobarbital enzyme-inducing regimens were administered p.o. to achieve similar steady-state phenobarbital plasma concentrations. Control rats received appropriate placebo solutions. Serum hepatic transaminase enzymes and histologic evidence of hepatocellular necrosis were utilized to evaluate hepatic damage after p.o. administration of 1300 mg of acetaminophen to both obese and lean Zucker rats. Obese Zucker control animals had approximately 2.5 times the total hepatic glutathione content compared to their lean control (164.9 +/- 43.2 vs. 65.3 +/- 18.4 mumol/whole liver). Obese Zucker animals receiving only acetaminophen showed a trend toward a reduced incidence of hepatocellular necrosis compared to similarly treated lean littermates. Obese Zucker rodents pretreated with phenobarbital had an even more pronounced resistance to acetaminophen-induced hepatocellular necrosis (P less than .01) when compared to similarly treated lean littermates. Thus, acetaminophen hepatotoxicity is reduced in the obese Zucker rat and pretreatment with phenobarbital offers further protection against hepatocellular damage. We suggest that the previously unrecognized increase in hepatic glutathione plays a major role in the resistance of the obese Zucker rat to acetaminophen hepatotoxicity.
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PMID:Phenobarbital induction and acetaminophen hepatotoxicity: resistance in the obese Zucker rodent. 368 96

In vivo and in vitro alterations in drug metabolism and the extent of enzyme induction of the hepatic microsomal cytochrome P-450 system were evaluated in obese and lean Zucker and lean Sprague-Dawley rats. Phenobarbital enzyme-inducing regimens were administered p.o. to achieve similar steady-state phenobarbital plasma concentrations. Control rats received p.o. placebo solution. No significant intra- or inter-strain differences in antipyrine clearance (milliliters per hour) or apparent volume of distribution (liters) were observed between the placebo-treated lean Sprague-Dawley, lean Zucker and obese Zucker rats. Intra- and inter-strain differences in hepatic microsomal protein and cytochrome P-450 content were observed. Compared to placebo, antipyrine clearance (milliliters per hour) after chronic phenobarbital pretreatment was increased in the Sprague-Dawley (198%) and lean Zucker rats (131%), but not significantly altered in the obese Zucker rats. Similarly, increases in hepatic weight, whole liver microsomal protein and cytochrome P-450 content were also observed in the Sprague-Dawley (34, 124 and 352%, respectively) and the lean Zucker rats (24, 96 and 249%, respectively). However, no significant alterations in these parameters were observed in the obese Zucker rats after phenobarbital treatment. Results from these in vivo and in vitro studies implicate alterations in drug metabolism and genetic differences in cytochrome P-450 content in Zucker rats relative to the Sprague-Dawley strain. Obese Zucker rats failed to exhibit a significant induction response after phenobarbital pretreatment.
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PMID:Phenobarbital in the genetically obese Zucker rat. II. In vivo and in vitro assessments of microsomal enzyme induction. 650 19

2 aspects of oral contraception (OC) were considered--the risk of arteriosclerotic cardiopathy and the interaction with other drugs. Opinions still diverge on the role of contraceptives in the etiology of myocardial infarction. In contrast to the British studies, the World Health Organization's (WHO) data and US statistics on death from cardiovascular diseases fail to show higher prevalence for OC users. Most likely the data of different countries cannot be compared due to the differing incidence of other cardiovascular morbidity and mortality risk factors such as hypertension, obesity, smoking, physical activity, and genetic predisposition. A recent study examined the prevalence of myocardial infarction in relation to the use of estroprogestinic contraceptives. Rosenberg et al. found that 156 out of 121,944 women (1.2%) had been hospitalized following myocardial infarction, and 23 of them used OCs. The authors concluded that OCs increased the risk of infarction by 1.8. Shapiro et al. studied 369 patients who suffered myocardial infarction and an adequate control group. The overall relative frequency was 4 times in OC users but it was 4.5 times in smokers and 3.9 times in nonsmokers. The smokers who did not use OCs showed a relative frequency of 7.8 times. The risk of arteriosclerotic cardiopathy depends upon the dose of both the estrogenic and progestinic components. When prescribing drugs, physicians should know whether their patients use OCs, since these hormonal steroids may interfere with the expected therapeutic effect. A phenomenon of enzymatic competition may occur which slows down the elimination of the drug, thus exposing the patient to a "relative overdose" despite the assumption of therapeutic doses. It has always been reported that the simultaneous administration of triacetiloleandomycin and OCs causes jaundice. Thus far 15 cases have been reported. OCs tend to enhance the effect of corticosteroids. Vitamin K antagonists, oral anticoagulants, are less effective in OC users. A research study conducted by Patwardhan et al. showed that caffeine is eliminated more slowly in OC users because of a mechanism of enzymatic competition with contraceptive steroids at the level of the hepatic oxygenase system linked to cytochrome P-450. ready been reported that the simultaneous administration of triacetiloleandomycin and OCs causes jaundice. Thus far 15 cases have been reported. OCs tend to enhance the effect of corticosteroids. Vitamin K antagonists, oral anticoagulants, are less effective in OC users. A research study conducted by Patwardhan et al. showed that caffeine is eliminated more slowly in OC users because of a mechanism of enzymatic competition with contraceptive steroids at the level of the hepatic oxygenase system linked to cytochrome P-450.
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PMID:Two problems in oral contraception: arteriosclerotic cardiopathy and drug interactions. 716 61

The cytochrome P-450 (P-450) enzymes are collectively responsible for the bulk of oxidation of xenobiotic chemicals, including drugs, pesticides, and carcinogens. This biotransformation can result in either increased or decreased toxicity, depending on the situation. The regulation of individual P-450 enzymes is a complex subject, with examples of induction and direct inhibition and stimulation. Nutrients and food additives can modify P-450 activities and consequently influence toxicity. P-450s also influence the toxicity of potentially harmful materials found in foods, as well as some vitamins and natural products. Some of the foodstuffs and conditions that influence P-450 in experimental animals and in humans are protein, carbohydrate, lipid, obesity and fasting, water- and fat-soluble vitamins, minerals, sulfides, isothiocyanates, indoles, ellagic acid, capsaicin, terpenes, flavones, butylated hydroxytoluene and hydroxyanisole, charbroiled foods, ethanol, and (monosodium) glutamate and aspartate. Consideration is given, when possible, to differences in responses between animal models and humans.
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PMID:Influence of nutrients and other dietary materials on cytochrome P-450 enzymes. 787 33

Human obesity is associated with a number of pathophysiologic processes, such as fatty infiltration and fibrosis of the liver. Although obesity has been shown to alter the metabolism of various xenobiotics, its effect on hepatic cytochromes P-450 is not known. In this study, the overfed rat was used as a model for examining the influence of obesity on the expression and regulation of hepatic cytochrome P-450 2B1/2B2. Sprague-Dawley rats were fed either a standard diet or an energy-dense diet for 32 weeks. The energy-dense diet resulted in a significant increase in body weight, serum triglyceride levels, and liver lipid content. Obesity did not influence baseline levels of spectral cytochrome P-450 content. Similar baseline activities of CYP2B1/2B2 (16 beta-testosterone hydroxylase and pentoxyresorufin O-dealkylation)--comparative protein levels of CYP2B1/2B2 (Western blot), and mRNA (slot blot)--were found in rats fed either diet. Half of the animals in each group were given 20 mg phenobarbital (intraperitoneal injection)/animal every 12 hr for three consecutive days. This resulted in similar phenobarbital plasma concentrations in both groups. Phenobarbital treatment increased the concentrations of cytochrome P-450 in both groups to the same extent. However, greater CYP2B1/2B2 activity was found in control rats following phenobarbital administration, whereas the amount of protein and mRNA was similar in each treated group. In conclusion, obesity did not affect the regulation of CYP2B1/2B2 enzymes. However, changes in the lipid environment associated with obesity may have affected the activity of these proteins.
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PMID:Effect of nutritional obesity on the induction of CYP2B enzymes following phenobarbital treatment. 790 36

Leptin is a hormone that is secreted by adipocytes and regulates body weight through its effect on satiety and energy metabolism. The ob/ob mouse is deficient in this protein and is characterized by obesity and other metabolic disorders. This study investigated the alterations of several hepatic cytochrome P-450 (CYP), conjugation, and antioxidant enzymes in lean and ob/ob mice and the role leptin plays in the modulation of these enzymes. Lean and ob/ob male mice were injected with leptin (100 microg) or PBS for 15 days. Liver microsomes from ob/ob mice, when compared with lean controls, displayed significantly reduced chlorzoxazone 6-hydroxylation activity (27%); however, 7alpha- and 16alpha- testosterone hydroxylation and pentoxyresorufin O-dealkylation activities were significantly higher (47%, 22%, and 39%, respectively). Leptin administration corrected alterations seen with all P-450 activities. Dealkylation of ethoxyresorufin and omega-hydroxylation of lauric acid activities from ob/ob and lean mice were not statistically different; however, leptin exposure significantly increased ethoxyresorufin activity in lean mice (14%) and decreased the activity in ob/ob mice (36%). UDP-glucuronosyl-transferase and glutathione S-transferase activities were not altered. The antioxidant enzymes, catalase (11%) and glutathione peroxidase (26%), as well as glutathione reductase (17%), were lower in the ob/ob mice and leptin treatment corrected these alterations. The results of this study demonstrate alterations in constitutive expression of CYP2B, CYP2E, CYP2A, catalase, glutathione peroxidase, and glutathione reductase in ob/ob mice that were restored to lean control values following leptin treatment. Additionally, CYP3A activity was increased following leptin treatment in ob/ob mice. The mechanism for the observed alterations may be due to direct leptin effects or via indirect alterations in insulin, corticosterone, and/or growth hormone.
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PMID:Effect of leptin on cytochrome P-450, conjugation, and antioxidant enzymes in the ob/ob mouse. 1034 99


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