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)

Elderly patients exhibit decreased clearance of multiple drugs biotransformed by the hepatic cytochromes P-450. The cytochromes P-450 are a superfamily of enzymes, which comprise a central component of phase I drug metabolism. Distinct isoforms metabolize specific drugs. In human liver microsomes, the glucocorticoid-inducible cytochrome P-450IIIA, CYP3A, catalyzes the N-demethylation of erythromycin. To examine the activity of hepatic CYP3A in elderly males and females, erythromycin N-demethylation was examined, as reflected by the recently described [14C]erythromycin breath test in 24 healthy volunteers, age 70-88. The [14C]erythromycin breath test was measured in normal elderly males and females to: (a) determine persistence of the gender-related dimorphism (evident in younger subjects) of CYP3A activity in the elderly population, (b) examine the effect of % ideal body weight, age, diet, and medication use on the activity of human hepatic CYP3A, and (c) compare breath test results obtained in normal geriatric volunteers with published results obtained in younger subjects, to determine aging-related alterations in CYP3A enzyme activity. Erythromycin N-demethylation varied fivefold among these patients. Similar to earlier studies examining erythromycin N-demethylation in younger subjects, CYP3A activity was found to vary with gender in the geriatric cohort. [14C]Erythromycin N-demethylation at 60 min was 3.14% +/- 0.75 (n = 13) in females and 2.15% +/- 0.77 (n = 11) in males (P = 0.005). In evaluating the role of % ideal body weight and % dietary fat using multivariable linear regression analyses, [14C]erythromycin N-demethylation, was found to decline significantly as % ideal body weight increased (P = 0.001). This was not confounded by gender. [14C]Erythromycin N-demethylation was not related to dietary fat intake (P less than 0.13). [14C]Erythromycin N-demethylation in the elderly volunteers was similar to values reported for subjects aged 20-60. Performance of a new non-invasive test of the human hepatic glucocorticoid-inducible CYP3A in a geriatric cohort suggests that: (a) the gender-related heterogeneity in function of the glucocorticoid inducible human CYP3A persists during normal aging, (b) that the activity of CYP3A may decrease in obesity, and (c) that the activity of CYP3A is stable throughout normal ageing.
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PMID:Hepatic cytochrome P-4503A (CYP3A) activity in the elderly. 163 Jan 56

Long-term cafeteria feeding, cold exposure, and the combination of treatments increased energy intake in female Wistar rats by 25%, 113%, and 150%, respectively, in comparison with controls (P less than 0.01). Although cafeteria feeding at room temperature markedly increased the insulin response to an intravenous glucose tolerance test (IVGTT), glucose tolerance was deteriorated (P less than 0.01). In contrast, cold exposure significantly improved glucose tolerance in the presence of a reduced insulin response in Purina- and cafeteria-fed animals. Moreover, cold exposure also decreased body weight gain and increased brown adipose tissue mass, total cytochrome-oxidase activity, and cellularity by approximately 600-800%. The results suggest that cold exposure enhances insulin sensitivity of peripheral tissues, whereas hyperphagia on a high-fat, low-protein diet leads to insulin resistance. In addition, the results demonstrate that prolonged stimulation of energy expenditure by cold exposure not only reverses the diabetogenic effects of cafeteria feeding but also improves glucose tolerance. This phenomenon could result from a combination of two factors: (1) a cold-induced prevention of obesity; and (2) an enhanced disposal of circulating glucose into peripheral tissues, including brown adipose tissue.
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PMID:Cold exposure reverses the diabetogenic effects of high-fat feeding. 300 94

Caffeine pharmacokinetics were studied in 16 obese (mean +/- s.e. mean body weight; 110 +/- 8 kg; % ideal body weight (IBW); 186 +/- 14%) and 23 normal body weight (64 +/- 3 kg; 103 +/- 3% IBW) subjects. Eight obese and four control subjects were cigarette smokers. After abstaining from caffeine for 48 h and an overnight fast, each subject ingested 162 mg caffeine orally. Concentrations of caffeine were measured in plasma samples obtained during the 24 h following the dose and pharmacokinetic variables were determined. The apparent volume of distribution was increased markedly in obese subjects (69.9 +/- 5.9 vs 43.6 +/- 2.8 l; P less than 0.001) in the absence of any change in oral clearance (135 +/- 14-obese vs 112 +/- 12 ml/min; NS), resulting in a trend toward increased elimination half-life (7.05 +/- 1.08-obese vs 5.40 +/- 0.40 h; NS). Apparent volume of distribution correlated well with percent IBW (r = 0.65; P less than 0.001). Caffeine clearance, suggested as a measure of in vivo cytochrome P-448 activity in humans, was not altered in obesity. In contrast, the extent of caffeine distribution increased in direct relation to body weight. If caffeine is used therapeutically, the loading dose should be calculated as a function of total body weight. Since clearance of caffeine is not related to body weight, these data indicate that a chronic dosing regimen to maintain a given plasma caffeine concentration should not be altered due to obesity.
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PMID:Caffeine disposition in obesity. 402 37

In response to recent studies from India suggesting that malnutrition, as assessed by anthropometric indexes, affects metabolism of oral progestogens, this study administered a mini-pill containing .35 mg of norethindrone (NET) and combination pills containing 250 or 150 mcg of d-norgestrel (d-NG) and either 50 or 30 mcg ethinyl estradiol as a single dose for fasting women of high and low income. Blood samples were collected for up to 24 hours for NET and 80 hours for the combination pills. Pharmacokinetics were evaluated by a least-squares method. Anthropometric measurements were also made. Peak NET levels occurred within 1-2 hours; half-life of plasma NET was shorter among low income, malnourished women compared with high income, well-nourished women. A direct correlation between weight/height and half-life of the drug suggests that malnutrition enhanation rate and reduces NET's half-life. Peak levels for d-NG also were reached between 1 and 2 hours after dosing. In well-nourished women, the decline in plasma d-NG was tri-exponential; malnourished women showed a biphasic curve with a neglible alpha-phase. Therefore, the lower the nutrition status, the faster the plasma clearance of these 2 orally administered compounds. Studies inn rabbits designed to elucidate this connection showed a significant elevation in specific activities of liver microsomal glucuronyl transferase and cytochrome-p450 in undernourished compared with control animals. There was also an increase in the amount (but not affinity) of uterine progesterone receptors in undernourished animals. Another study of a small group of Thai and Indian women showed positive correlation between anthropometric indexes and post peak plasma NET levels; however, an obesity study of Thai women found no such correlation.
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PMID:Influence of nutritional status on pharmacokinetics of contraceptive progestogens. 637 30

To evaluate the relationships between changes in muscle morphology and metabolic adaptation to physical training in obesity, twenty obese women were subjected to a physical training programme with three sessions a week for 3 months. Physical training resulted in lowering of plasma insulin and improved glucose tolerance. Neither body weight nor body fat changed. With physical training the percentage distribution of fast twitch oxidative (FTa) muscle fibres (m vastus lateralis) increased (from 30.3 +/- 5.1% to 35.2 +/- 4.8%, P less than 0.05) and that of fast twitch glycolytic fibres decreased (from 18.3 +/- 6.6 to 5.8 +/- 4.8%, P less than 0.05). The number of capillaries increased, mainly around slow twitch (ST) fibres (from 4.5 +/- 0.6 to 5.8 +/- 0.8, P less than 0.01) and fast twitch oxidative (FTa) fibres (from 3.9 +/- 0.7 to 4.7 +/- 0.8, P less than 0.01). The activities of oxidative enzymes (cytochrome-c-oxidase and citrate synthase) increased (P less than 0.05) while those of glycolytic enzymes (phosphofructokinase and hexokinase) decreased after physical training (P less than 0.01). Significant negative correlations between plasma insulin and number of capillaries in contact with ST fibres (r = 0.80, P less than 0.001) and FTa fibres (r = 0.62, P less than 0.001) were found before training. The capillary density around those fibres could predict 80% of the explained variance of plasma insulin levels (P less than 0.001). The changes of glucose concentration after training could be predicted by observed changes in enzyme activities. The strong associations between muscle morphology and capillarization and enzyme activities and glucose and insulin concentrations and their changes after training suggest an important regulatory role of muscle which warrants further studies.
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PMID:Relationship between muscle morphology and metabolism in obese women: the effects of long-term physical training. 640 24

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

The role of the microsomal ethanol-oxidizing system (MEOS) in hepatic ethanol metabolism is reviewed, with focus on its constitutive, ethanol-inducible cytochrome P-4502E1 (2E1). The MEOS was purified and reconstituted using 2E1, phospholipids, and cytochrome P-450 reductase and shown to oxidize ethanol to acetaldehyde, mainly as a monooxygenase and secondarily via hydroxyl radicals, with transcriptional and posttranscriptional regulation. Polymorphism of 2E1 was recognized, and enzymology (including cofactors, role of lipids, inducers, and inhibitors) as well as cellular and tissue distribution were chartered. Physiological functions involve lipid metabolism and ketone utilization in starvation, obesity, and diabetes. The most significant role of 2E1 is its adaptive response to high blood ethanol levels with a corresponding acceleration of ethanol metabolism. The associated free radical production, however, contributes to liver injury in the alcoholic. Most importantly, 2E1 has a unique capacity to activate many xenobiotics (85 of which are listed) to hepatotoxic or carcinogenic products. Induction of 2E1 also results in enhanced production of acetaldehyde, a highly reactive and toxic metabolite. The proliferation of the endoplasmic reticulum associated with 2E1 induction is also accompanied by enhanced activity of other cytochrome P-450s, resulting in accelerated metabolism of, and tolerance to, other drugs, as well as increased degradation of retinol and its hepatic depletion. Some substrates and metabolites, however, are innocuous and may eventually be used as markers of heavy drinking. Recently discovered effective 2E1 inhibitors also have great therapeutic potential.
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PMID:Cytochrome P-4502E1: its physiological and pathological role. 911 22

The insulin resistance syndrome and the polycystic ovary syndrome (PCOS) appear to have some following coincidences: the existence of subclinical acanthosis nigricans in PCOS hyperinsulinemic women, correlation of insulin levels and free testosterone, insulin-like growth factor I binding protein (IGFIBP), and sex-hormone binding globulin. Insulin and IGFI act synergically with luteinizing hormone increasing the activity of cytochrome P450c17 and its enzymatic activity in the adrenals. The decrease in IGFI level and IGFI receptors in the ovarian granulosa cells reduce the steroids aromatisation. The increased expression of IGFI receptors in the theca cells favours the androgens' synthesis. Long-term insulin therapy results in an increase in ovary volume and the blood androgens levels. The deterioration of insulin resistance in PSOC women progresses also by the reduction of type I of skeletal muscle fibres which are sensitive to insulin, and the increase of type II fibres which are resistant to insulin in hyperandrogenemia. Testosterone deteriorates the skeletal as well as hepatic insulin sensitivity by both its facilitating effect on lipolysis and the increase of free fatty acids. Abdominal obesity seen in PCOS and insulin resistance is composed by adipocytes with glucocorticoid receptors, which after cortisol stimulation activate the lipoprotein lipase and fat accumulation. Gynoid obesity with the preferential aromatisation of steroids is not evolved because of the low estrogens and progesterone levels in PCOS. Low progesterone levels (with anticortisol effect) support the development of abdominal obesity. Ultimately, the early peak of insulin secretion (4-8 min) in PCOS is higher. This fact should testify a certain diabetic disposition. (Ref. 37.)
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PMID:[The polycystic ovary syndrome and insulin resistance]. 949 Jan 71

Obesity, ultrasonic ovarian morphology, serum LH levels and LH/FSH ratio are inconstant symptoms of the polycystic ovary syndrome (PCOS) and are thus no longer essential for diagnosis. PCOS is diagnosed today by the finding of chronic anovulation and hyperandrogenism characterized by a high serum level of "free" testoterone. The other causes of hyperandrogenism, as well as anovulations due to hyperprolactinemia, high levels of FSH and abnormal thyroid function have to be ruled out. PCOS is very often associated with insulin resistance (IR) and hyperinsulinemia (hyper I). From in vitro and vivo studies and treatment of hyper I, it has been shown that the hyper I of PCOS stimulates androgen production. Hyper I of PCOS increases the activity of androgens: by first provoking an important decrease of the sex hormone binding globulin (SHBG) thus increasing the "free", bioactive testosterone level. and then by activating the cytochrome P 450 c 17 alpha enzymatic system that controls androgen production. Subsequent to metformin administration, the reduction of hyper I and androgen serum levels creates a favorable condition for the resumption of ovarian function and clomiphene citrate action. This explains the high percentage of ovulations and pregnancies.
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PMID:[Diagnosis and treatment of polycystic ovary syndrome]. 1059 43

Glucuronidation is a phase II metabolic process and one of the most common pathways in the formation of hydrophilic drug metabolites. At least 33 families of uridine diphosphate-glucuronosyltransferases have been identified in vitro, and specific nomenclature similar to that used to classify the cytochrome (CYP) P450 system has been established. The UGT1 and UGT2 subfamilies represent the most important of these enzymes in human drug metabolism. Factors affecting glucuronidation include the following: cigarette smoking, obesity, age, and gender. In addition, several drugs have been found in vitro to be substrates, inhibitors, or inducers of UGT enzymes. Induction or inhibition of both UGT and CYP isoforms may occur simultaneously. Some important drug interactions involving glucuronidation have been documented and others can be postulated. This review summarizes the relevant literature pertaining to drug glucuronidation and its implications for clinical psychopharmacology.
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PMID:Drug glucuronidation in clinical psychopharmacology. 1159 76


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