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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of long-term insulin-dependent diabetes on the enzymatic activities of hepatic cytochrome P450 isozymes were determined in rats rendered diabetic by the administration of streptozotocin and killed 4, 8, and 12 weeks following treatment. The O-dealkylations of ethoxyresorufin and pentoxyresorufin were elevated in the diabetic animals throughout the study, the extent of increase being similar at all three time points. p-Nitrophenol hydroxylase activity was induced in the diabetic animals 4 weeks following treatment with streptozotocin, but the extent of increase became less pronounced with the progress of the disease. A modest increase in ethylmorphine N-demethylase activity was also observed but only in the diabetic animals killed 4 weeks after the induction of diabetes. Finally, lauric acid hydroxylase activity was elevated in the diabetic animals 4 weeks following streptozotocin administration but then declined rapidly with the duration of the disease. It is concluded that the duration of diabetes modulates the hepatic cytochrome P450 profile, with the effect being isoenzyme specific. Mechanisms that may account for these changes are discussed.
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PMID:Modulation of the rat hepatic cytochrome P450 composition by long-term streptozotocin-induced insulin-dependent diabetes. 807 47

The insulin-mimetic effects of vanadate in preventing the increase in the level and activity of several P450 proteins in streptozotocin-diabetic rats were examined, in order to extend knowledge of the insulin-like actions of vanadate from glucose metabolism to P450-dependent metabolism. The diabetic state caused by the pancreatic beta cell toxin streptozotocin results, like the diabetes of genetic origin, in major alterations in the expression of P450 isozymes. We focused our attention on the P450III and P450I isoforms, known to be altered during the onset of diabetes. We found an increase in P450IIIA1-linked erythromycin demethylase activity (to about double the control level) and in the relative levels of P450III and P450I isozymes after 2 weeks of uncontrolled diabetes. These parameters were not different from control values in rats given vanadate in drinking water for 2 weeks after streptozotocin administration or in insulin-treated rats. In summary, vanadate appears to exert insulin-mimetic actions on the P450III and P450I family proteins that have a key role in cytochrome P450-dependent metabolism.
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PMID:Insulin-mimetic effects of vanadate in preventing the increase of P450IIIA and P450IA subfamily proteins in streptozotocin-diabetic rats. 811 Oct 71

Hepatic microsomal cytochrome P450s, which are involved in the metabolism of drugs, hormones, prostaglandins and fatty acids, change when animals develop diabetes. We studied changes in cytochrome P450 isozymes in both hepatic and renal microsomes of rats with diabetes caused by streptozocin, and compared the results with changes in catalytic activities in the microsomes. In hepatic microsomes of diabetic rats, the amount of cytochrome P450 2E1, an acetone-inducible isozyme, was two and a half times that of control rats, and that of P450 4A2, a major renal isozyme, was three times that in the controls. The amounts of cytochrome P450s 2A1, 2C6, 2C7, 3A2 and 4A3 increased in hepatic microsomes of diabetic rats, and P450 2C11 decreased. Treatment with insulin restored these to the levels in the controls. The catalytic activities of aniline hydroxylation, 7-ethoxycoumarin O-dealkylation, testosterone 2 beta, 6 beta, 7 alpha, and 16 beta-hydroxylation, and omega-, (omega-1)-hydroxylation of lauric acid were high in the hepatic microsomes of diabetic rats, and testosterone 2 alpha and 16 alpha-hydroxylation activities were low. In renal microsomes of diabetic rats, cytochrome P450s 2E1, 4A2 and K-4 were induced, and omega- and (omega-1)-hydroxylation activities were high. These changes were reversed by insulin treatment. The induction and suppression of cytochrome P450 isozymes in diabetic rats were consistent with the changes in the catalytic activities. In both hepatic and renal microsomes, P450s 2E1 and 4A2 were induced, altered metabolism of ketones and fatty acids in diabetes may contribute to these changes.
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PMID:Changes in amounts of cytochrome P450 isozymes and levels of catalytic activities in hepatic and renal microsomes of rats with streptozocin-induced diabetes. 836 36

Sex differences in the diabetes-induced changes in hepatic cytochrome P450 proteins were investigated in rats treated with streptozotocin. Changes in specific cytochrome P450 proteins were monitored using diagnostic substrates and immunologically utilizing specific polyclonal antibodies. When expressed in terms of nmoles of total cytochrome P450, ethoxyresorufin O-deethylase activity was increased by treatment with streptozotocin, the extent of induction being the same in the two sexes. In contrast, lauric acid hydroxylase and ethylmorphine N-demethylase activities were induced only in the male rat. Finally, p-nitrophenol hydroxylase and pentoxyresorufin O-dealkylase were enhanced by the same treatment in both sexes, the effect being more pronounced in the male. These findings indicate that sex-specific changes in certain cytochrome P450 proteins exist in response to insulin-dependent diabetes but these cannot, however, be ascribed to sex differences in the severity of diabetes induced by streptozotocin since the degrees of hyperketonaemia and hyperglycaemia were the same in the two sexes. These are likely to reflect sex-specific differences in growth hormone and triglyceride levels in the diabetic animals.
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PMID:Sex differences in the diabetes-induced modulation of rat hepatic cytochrome P450 proteins. 843 90

The endothelial response to kinin stimulation is the result of a series of complex intracellular reactions involving changes in the intracellular concentration of free calcium ([Ca2+]i) and intracellular pH, enhanced phosphorylation of several proteins via the activation of at least four distinct families of protein kinases, and activation of membrane ion transport systems. Some of the more recent developments in this field suggest that endothelial tyrosine kinases and tyrosine phosphatases as well as serine/threonine phosphatases are also activated in response to bradykinin. In addition, the finding that the mitogen-activated protein kinase (MAP kinase) pathway was tyrosine phosphorylated, and presumably activated, in endothelial cells after an increase in [Ca2+]i has wideranging implications for these cells. Indeed, MAP kinase recognizes many different substrates in the cell, including growth factor receptors, microtubule-associated proteins, specific serine-threonine protein kinases, phospholipase A2, and transcription factors. Further recent studies of interest have underscored the role of endothelium-derived hyperpolarizing factor in addition to nitric oxide and prostacyclin in the coronary vasculature. Indeed, this mediator, which seems to be an endothelium-derived, cytochrome P450-derived metabolite of arachidonic acid, would now appear to represent a substantial constitutive component of the vasodilator response to bradykinin.
Diabetes 1996 Jan
PMID:Molecular responses of endothelial tissue to kinins. 852 5

The acute and chronic effects of streptozotocin diabetes on kidney and liver microsomal monooxygenases were studied using hamsters 2 days and 6 weeks following treatment with the diabetogen, respectively. Acute diabetes increased aniline hydroxylation and N-nitrosodimethylamine demethylation, decreased pentoxyresorufin O-dealkylation, without affecting benzo(a)pyrene hydroxylation and 7-ethoxycoumarin O-deethylation in kidney and liver microsomes. The effects of chronic diabetes on the microsomal monooxygenases were similar to the effects of acute diabetes, except that the chronic diabetic condition markedly decreased benzo(a)pyrene and 7-ethoxycoumarin oxidations in kidney microsomes. Total cytochrome P450 content and NADPH-cytochrome P450 reductase activity in kidney and liver microsomes of the diabetic hamsters were similar to the controls. Gel electrophoresis of microsomes from control and streptozoptocin treated hamster tissues revealed that diabetes enhanced the intensity of protein band(s) in the P450 molecular weight region. Immunoblotting of microsomal proteins showed that acute and chronic streptozotocin diabetes induced proteins immunorelated to P450s 2E1 and 1A in kidney and liver. In marked contrast, the acute and chronic diabetic conditions decreased the level of a P450 2B-immunorelated protein(s) in kidney and liver. The present study demonstrates that acute and chronic streptozotocin diabetes has the ability to induce P450 2E1 and 1A and suppress P450 2B in hamster kidney and liver and that the hamster monooxygenase responds to diabetes differently from the rat enzyme.
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PMID:Induction and suppression of renal and hepatic cytochrome P450-dependent monooxygenases by acute and chronic streptozotocin diabetes in hamsters. 882 78

Pretreatment of porcine aortic endothelial cells with high D-glucose results in enhanced endothelium-derived relaxing factor (EDRF) formation (39%) due to increased endothelial Ca2+ release (57%) and Ca2+ entry (97%) to bradykinin. This study was designed to investigate the intracellular mechanisms by which high D-glucose affects endothelial Ca2+/EDRF response. The aldose-reductase inhibitors, sorbinil and zopolrestat, failed to diminish high D-glucose-mediated alterations in Ca2+/EDRF response, suggesting that aldose-reductase does not contribute to high D-glucose-initiated changes in Ca2+/EDRF signaling. Pretreatment of cells with the nonmetabolizing D-glucose analog, 3-O-methylglucopyranose (3-OMG), mimicked the effect of high D-glucose on Ca2+ release (41%) and Ca2+ entry (114%) to bradykinin, associated with elevated EDRF formation (26%). High D-glucose and 3-OMG increased superoxide anion (O2-) formation (133 and 293%, respectively), which was insensitive to inhibitors of cyclooxygenase (5,8,11,14-eicosatetraynoic acid [ETYA], indomethacin), lipoxygenase (ETYA, gossypol, nordihydroguaiaretic acid [NDGA]), cytochrome P450 (NDGA, econazole, miconazole), and nitric oxide (NO) synthase (L-omega N-nitroarginine), while it was diminished by desferal, a metal chelator. The gamma-glutamyl-cysteine-synthase inhibitor, buthioninesulfoximine (BSO), also increased formation of O2- by 365% and mimicked the effect of high D-glucose on Ca2+/EDRF signaling. The effects of high D-glucose, 3-OMG, and BSO were abolished by co-incubation with superoxide dismutase. Like high D-glucose, pretreatment with the O2(-)-generating system, xanthine oxidase/hypoxanthine, elevated bradykinin-stimulated Ca2+ release (+10%), Ca2+ entry (+75%), and EDRF (+73%). We suggest that prolonged exposure to pathologically high D-glucose concentration results in enhanced formation of O2-, possibly due to metal-mediated oxidation of D-glucose within the cells. This overshoot of O2- enhances agonist-stimulated Ca2+/EDRF signaling via a yet unknown mechanism.
Diabetes 1996 Oct
PMID:High D-glucose-induced changes in endothelial Ca2+/EDRF signaling are due to generation of superoxide anions. 882 76

Bitter melon (Momordica charantia), commonly known as karela, has been reported to have hypoglycemic, antiviral, antidiabetic, and antitumor activities. In the present study, we have investigated the effects of oral feeding of karela fruit juice on the hepatic cytochrome P450 (CYP) and glutathione S-transferase (GST) drug-metabolizing enzymes in the streptozotocin (STZ)-induced diabetic rat. Hepatic CYP contents, ethoxycoumarin-O-deethylase (ECOD), ethoxyresorufin-O-deethylase (EROD), aniline hydroxylase (AH), and aminopyrene N-demethylase (APD) activities were measured in control, diabetic, and karela juice fed animals. Diabetic rats exhibited a 50-100% increase in AH and EROD activities that was reversed by karela juice feeding. In addition, a decrease (17-20%) in the activities of APD and ECOD was observed in diabetic rat liver. Feeding of karela juice to the diabetic animals brought the level of APD close to that of control animals, while ECOD was further reduced to 60% of the control value. The cytosolic glutathione concentration was decreased in diabetic rats, and karela juice feeding normalized the effect. However, an increase (of 20-30%) in the GST activity was observed in both diabetic and karela juice fed rats. Western immunoblot analysis of CYP and GST isozymes exhibited a differential response during diabetes. The expression of CYP1A1, 2B1, 2E1, 3A4, and 4A2 in diabetes, while a decrease in GST mu was observed. Our results suggest that the changes in hepatic phase I and phase II drug-metabolizing enzyme activities in the STZ-induced diabetic animals may be associated with the altered expression of different CYP and GST isozymes. In addition, we have also observed that karela does not always reverse the effects on drug-metabolizing enzymes in STZ-induced diabetes.
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PMID:Effect of bitter melon (Momordica charantia) fruit juice on the hepatic cytochrome P450-dependent monooxygenases and glutathione S-transferases in streptozotocin-induced diabetic rats. 893 80

The effect of vitamin C supplementation on hepatic cytochrome P450 expression was investigated in streptozotocin (STZ) diabetic male Wistar Albino rats. STZ-treated rats displayed the usual characteristics of diabetes including; hyperphagia, polydipsia, decreased body weight gain and also the increased expression and activity of hepatic CYP1A, 2B, 2E and 4A proteins. Vitamin C administration in drinking water (2% w/v) was associated with significant decreases in the levels of hyperglycaemia (P < 0.05), glycosylated haemoglobin (P < 0.05), hyperlipidaemia (P < 0.001), and hyperketonaemia (P < 0.001) associated with STZ-diabetes. Vitamin C-treatment selectively reduced the activity and expression of CYP2E proteins (P < 0.001). These effects on CYP2E expression may be mediated by the reduced levels of circulating ketone bodies, however, a direct effect on CYP2E expression in diabetes cannot be discounted.
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PMID:Effect of vitamin C supplementation on hepatic cytochrome P450 mixed-function oxidase activity in streptozotocin-diabetic rats. 900 94

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.
Diabetes 1997 Jul
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


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