Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The data and experimental results reviewed here allow the construction of the following hypothesis: alcohol-induced liver disease results from a combination of two phenomena. The first is the induction of the maximum activity of CYP 2E1 by several dietary factors, i.e. (1) low carbohydrate-high fat diet; and (2) the dietary fats composed of PUFA (Yang et al., 1992). The second is the production of lipid peroxidation induced by CYP 2E1 oxidation of ethanol maintained at high blood alcohol levels (> 200 mg %) with the availability of PUFA as substrate (Ekstrom and Ingelman-Sundberg, 1988; Koop, 1992). Thus, lipid peroxidation may be the final common pathway which supports the induction of ALD. Further, it may provide the common denominator which links ALD pathogenesis to non-alcoholic steato-hepatitis (NASH) (French et al., 1989b), where CYP 2E1 is induced by high fat diet and/or diabetes (Dong et al., 1988).
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PMID:Nutrition in the pathogenesis of alcoholic liver disease. 847 Oct 92

The placenta possesses the ability to metabolize a number of xenobiotics and endogenous compounds by processes similar to those seen in the liver. Animal and in vivo studies have observed that the presence of diabetes alters the expression of hepatic metabolizing enzymes (cytochrome P450 and glutathione S-transferase); however, it is unknown whether similar alterations occur in the human placenta. To evaluate whether diabetes has any effect of placental xenobiotic metabolizing activity, the catalytic activities of 7-ethoxyresorufin O-deethylation (EROD, CYP1A1), chlorzoxazone 6-hydroxylation (CYP2E1), dextromethorphan N-demethylation (CYP3A4), dextromethorphan O-demethylation (CYP2D6), and 1-chloro-2, 4-dinitrobenzene (CDNB) conjugation with glutathione (glutathione S-transferase, GST) from placentas of diet (class A1) and insulin-dependent (class A2) gestational diabetics and overt diabetics were compared with matched controls. EROD activity (CYP1A1) ranged from 0.29 to 2.67 pmol/min/mg protein. However, no differences were observed among overt or gestational diabetics and their respective matched controls. CDNB conjugation (GST) ranged from 0.275 to 1.65 units/min/mg protein. In contrast to that observed with CYP1A1, a small but statistically significant reduction in GST activity was noted in overt diabetics as compared with their matched controls and gestational diabetics. CYP2E1, 2D6, and 3A4 enzymatic activities were not detected in human placental tissue. GST protein was detectable in all tissues studied, but no CYP protein could be detected in any of the tissues. Thus, it seems that pregnant women with overt diabetes have reduced GST activity in the placenta, which could potentially result in the exposure of the fetus to harmful electrophiles. However, the full clinical significance of this finding remains to be elucidated.
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PMID:Effects of gestational and overt diabetes on human placental cytochromes P450 and glutathione S-transferase. 953 26

Benzene is a ubiquitous environmental pollutant primarily metabolized by a cytochrome P-450 (CYP-450) isoenzyme, CYP-450 IIE1. A consistent induction of CYP450 IIE1 has been observed in both rat and human affected by diabetes mellitus. The aim of this study was to evaluate whether streptozotocin (STZ)-induced diabetes determines modifications in the metabolic pathways of benzene in rat. Benzene (100 mg/kg per day, dissolved in corn oil) was administered i.p. once a day for 5 days. Urine samples were collected every day in STZ-treated and normoglycaemic animals, treated and untreated with benzene (n = 10). Urinary levels of trans,trans-muconic acid and of phenol, catechol and hydroquinone (free and conjugated with sulphuryl and glucuronic group) were measured by high-performance liquid chromatography (HPLC). In normoglycaemic rats during the 5 days of treatment with benzene we observed a progressive and significant decrement in the urinary excretion of phenol, phenyl sulphate and glucuronide, catechol, catechol glucuronide, hydroquinone, hydroquinone glucuronide and t,t-muconic acid (P < 0. 05). In the diabetic animals, conversely, the same metabolites showed progressively increasing urinary levels (P < 0.05). Catechol sulphate and hydroquinone sulphate levels were below the instrument's detection limit. In the comparison between diabetic and normoglycaemic benzene treated rats, the inter-group difference was significant (P < 0.05) from day 3 of treatment for t,t-muconic acid, and from day 1 for free and conjugated phenol, free and glucuronide catechol and free hydroquinone. In the normoglycaemic rat exposed to benzene the decreasing trend observed in urinary excretion of free and conjugated metabolites may be due to their capability to reduce cytochromial activity. Conversely, in the diabetic rat, urinary levels of benzene metabolites tended to increase progressively, probably due to the consistent induction of CYP-450 IIE1 observed in diabetes, which would overwhelm the inhibition of this isoenzyme caused by phenolic metabolites. Furthermore, the metabolic switch towards detoxification metabolites observed after administration of high doses of benzene is not allowed in the diabetic because of reduced glutathione-S-transferase activity. As a consequence, higher levels of hydroquinone, phenol and catechol, considered the actual metabolites responsible for benzene toxicity, will accumulate in the diabetic rat. Extrapolating these data to human, we may thus suggest that occupational exposure to benzene of a diabetic subject poses a higher risk level, as his metabolism tends to produce and accumulate higher levels of reactive benzene catabolites.
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PMID:Modifications in the metabolic pathways of benzene in streptozotocin-induced diabetic rat. 1044 56

Diabetes mellitus is associated with endothelial dysfunction that is believed to result in impaired release of vasoconstrictor and vasodilator substances from the endothelium and thereby diminished reactivity of many vascular beds. This study was designed to characterize bradykinin (BK)-induced coronary vasodilation in normal and diabetic rats. Bradykinin-stimulated vasodilation of the rat coronary vasculature is mediated by a cytochrome P450-1A (CYP-1A)- inhibitable metabolite that activates KCa, but not KATP, channels on the coronary vascular smooth muscle. Although BK stimulates the release of nitric oxide from the vascular endothelium, the released nitric oxide and its ability to stimulate guanylate cyclase only modulates the duration of, rather than the magnitude of, BK-induced coronary vasodilation. Twelve weeks of streptozotocin-induced diabetes did not affect the coronary vascular responses to BK or the components that mediate BK-induced vasodilation (ie, K-channel activation, nitric oxide-guanylate cyclase). The data support the conclusions that the coronary vasodilator response of the rat to BK is CYP-1A and KCa-channel mediated, that coreleased nitric oxide only modulates the duration of BK-induced vasodilation, and that these mechanisms are unaffected by moderate diabetes.
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PMID:Coronary vasodilator responses to bradykinin in euglycemic and diabetic rats. 1136 66

Superficial fungal infections or tinea infections (also known as the dermatophytoses) are commonly encountered conditions in clinical practice, affecting the skin, hair, and nails. The most commonly prescribed modality to treat these infections is topical antifungal therapy. However, this method of treating tinea infections may be less convenient and efficacious in the immunocompromised patient. In such patients, skin infections are more difficult to treat because the disease is often more extensive and severe. Tinea infections of the hair and nails usually require oral therapy. Further, topical treatment is not as efficacious as oral antifungal therapy and, with the exception of the topical antifungal agent ciclopirox, is not indicated for the treatment of tinea unguium (onychomycosis). The 2 most frequently prescribed oral antifungal agents to treat onychomycosis are itraconazole and terbinafine. In the general population, both agents are effective in treating fungal nail infections; however, differences in the agents' mechanism of action and metabolic pathways result in differences in efficacy and drug-drug interaction potential. However, limited data exist on the use of these agents in immunocompromised patients for the treatment of onychomycosis and superficial tinea infections. The available efficacy data we have are limited to case reports or small pilot studies; thus, data supporting the efficacy of these agents for the treatment of tinea infections in the immunocompromised patient must be extrapolated from the general population. For safety issues, however, some postmarketing data exist supporting the safety of these agents in the diabetic and human immunodeficiency virus (HIV) patients populations; indeed, both agents appear to be safe. However, one contrasting point between these 2 agents is drug interactions. Oral terbinafine, unlike itraconazole (a potent cytochrome P-450 [CYP] 3A4 inhibitor), has a relatively low potential for drug-drug interactions, making terbinafine a useful agent for the treatment of tinea infections in immunocompromised patients (e.g., those who are HIV positive and those with diabetes), who are likely to be receiving concomitant medications. Further, recently conducted studies of terbinafine for the treatment of tinea pedis, tinea cruris, and tinea corporis infections in these high-risk patient groups also support efficacy claims and reemphasize its relatively safe profile and low potential for drug interactions. Additional studies in other immunocompromised patient populations may be useful to confirm recent studies and expand the potential use for this agent.
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PMID:Role of oral antifungal agents for the treatment of superficial fungal infections in immunocompromised patients. 1149 33

Troglitazone, rosiglitazone and pioglitazone are members of the thiazolidinedione (TZD) class - antidiabetic agents that have proven efficacy in the treatment of patients with type 2 diabetes. All three agents are believed to mediate their effects via activation of the gamma isoform of the peroxisome proliferator-activated receptor (PPAR gamma). Despite this common mechanism of action, they all have unique chemical structures and receptor-binding affinities, and consequently, in addition to the class effects (probably mediated through PPAR gamma), each TZD has a unique safety profile. Side effects have been categorized as unique to individual TZDs, or common to the class of drug. Of the unique effects, the best characterized is hepatotoxicity, which has been associated specifically with troglitazone to date. Studies with rosiglitazone and pioglitazone indicate that hepatotoxicity is not a class effect. Further differences in the safety profiles of these agents arise because the oxidative metabolism for each agent occurs by distinct cytochrome pathways: troglitazone and pioglitazone involve CYP 3A4 and CYP 2C8 whereas rosiglitazone is principally metabolized by CYP 2C8. CYP 3A4 is involved in the metabolism of over 150 drugs, hence the potential for drug interactions with troglitazone and pioglitazone is much greater than with rosiglitazone. Class effects include edema, slight reductions in hemoglobin and hematocrit (due to hemodilution), weight gain and alterations in plasma lipid profiles. This article considers safety data obtained from both clinical trials and clinical practice as a means of differentiating among troglitazone, rosiglitazone and pioglitazone.
Diabetes Metab Res Rev
PMID:Differentiating members of the thiazolidinedione class: a focus on safety. 1192 35

The liver steatosis is a frequent human disease. The most frequent cause of the process is the alcohol consumption. But it also may arise without significant alcohol abuse. This pathogenetic process is called non-alcoholic steatohepatitis (NASH), that is characterized by the same conditions like the alcoholic steatohepatitis. In the pathogenesis of the NASH various factors participate i.e. obesity, diabetes mellitus type II, hyperlipidaemia, pregnancy, variable chemotoxins, parenteral nutrition, jejunoileal bypass, chronic inflammatory diseases, protein deficient nutrition and inborn metabolic diseases. Pathobiochemically the process consists of oxidative stress and lipid peroxidation. This condition comes from the progressive accumulation of the free fatty acids in mitochondria and from the induction of cytochrome P450, CYP 2E1 isoform in hepatocytes and Kupffer cells. The free fatty acids and ketons can cause the induction of CYP 2E1 system, that is why diabetes mellitus and obesity are the two most important factors in the NASH pathogenesis. This article is concerned mainly in the explanation of NASH pathomechanism.
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PMID:[Role of lipid peroxidation in non-alcoholic steatohepatitis]. 1511 15

Major depressive disorder (MDD) is a highly prevalent disease, frequently characterized by recurrent or chronic course, and by comorbidity with other medical illnesses. The lifetime prevalence of MDD ranges up to 17% in the general population, and it almost doubles in patients with diabetes (9-27%), stroke (22-50%), or cancer (18-39%). Moreover, MDD worsens the prognosis, quality of life, and treatment compliance of patients with comorbid medical illnesses. Similar to what is observed with other comorbid illnesses, MDD worsens the outcome of kidney disease patients by increasing both morbidity and mortality. Treatment of depressive symptoms in renal failure patients increases medication acceptability and therefore potentially improves the overall patient outcome. The issue of the safety of antidepressant treatment in subjects with renal failure is frequently counterbalanced by the risks associated with depression comorbidity, provided that antidepressants with a low volume of distribution and low protein binding are prescribed, and most important, at low initial doses. Screening for CYP isoenzyme interactions with current medications is also recommended before starting antidepressant treatment.
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PMID:Depression and renal disease. 1577 49

(1) Neuroleptics are the standard treatment for schizophrenia. The first drugs of this class, such as haloperidol, were marketed nearly 50 years ago, and neuroleptics released over the past 15 last years have provided no major advance. (2) Aripiprazole is a new neuroleptic licensed for the treatment of schizophrenia. (3) Five double-blind placebo-controlled trials lasting 4 to 6 weeks showed that aripiprazole was a little more effective than placebo at daily doses of 10 mg to 30 mg, without a clear dose-response relationship. Based on the least demanding definition of "treatment response" (a 30% reduction in the PANSS global score), less than 50% of patients responded to aripiprazole. (4) In a double-blind trial lasting 6 months, aripiprazole 15 mg/day was more effective than placebo in preventing acute relapses of schizophrenia (34% versus 57%), but the clinical relevance of the combined endpoint used to define relapse is unclear. (5) The only double-blind comparison versus another neuroleptic (haloperidol) involved two trials that were pooled for analysis. Haloperidol was provided at a moderate dose (10 mg/day). These trials were designed to demonstrate the superiority of high-dose aripiprazole (30 mg/day), but failed to do so. The proportion of patients who "responded" during an acute episode, based on the least stringent definition, was about 70% in both groups. In both groups, response persisted in approximately three-quarters of patients. (6) Aripiprazole exhibits the adverse effects classically seen with neuroleptics. In clinical trials, daily doses of aripiprazole, ranging from 15 mg to 30 mg, provoked fewer extrapyramidal disorders than haloperidol 10 mg/day. In contrast, there was no difference in the frequency of extrapyramidal disorders with aripiprazole 20 or 30 mg/day and risperidone (6 mg). Aripiprazole has no proven advantage over haloperidol in terms of the risk of tardive dyskinesia. One trial showed no difference between aripiprazole and olanzapine in the risk of diabetes. Weight gain appears to be comparable with aripiprazole and haloperidol. Aripiprazole provoked postural hypotension and neuroleptic malignant syndrome, but the precise risk relative to other neuroleptics has not been documented. Supra-therapeutic doses of aripiprazole cause dose-dependent QT prolongation. (7) Increased mortality was seen in elderly patients treated with aripiprazole. (8) Animal studies have shown retinal degeneration in rats and biliary lithiasis in monkeys. These adverse effects have not been observed in clinical trials, but they have not been specifically assessed in humans. (9) Animal studies raised the possibility of fetal toxicity and teratogenicity. (10) The aripiprazole dose must be either halved or doubled during co-administration with inhibitors or inducers of cytochrome P450 isoenzymes CYP 3A4 and CYP 2D6. (11) In practice, there are too many unanswered questions to recommend aripiprazole for patients with schizophrenia.
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PMID:Aripiprazole: new drug. Just another neuroleptic. 1628 69

Increasing evidence implicates dietary factors in the progression of diseases, including certain cancers, diabetes and obesity. Diet also regulates the expression and function of CYP genes, which impacts on drug elimination and may also significantly affect disease pathogenesis. Upregulation of CYPs 2E1 and 4A occurs after feeding of experimental diets that are high in fats or carbohydrates; these diets also promote hepatic lipid infiltration, which is a component of the metabolic syndrome that characterises obesity. Increased availability of lipid substrates for CYPs can enhance free radical production and exacerbate tissue injury. Similar processes may also occur in other models of experimental disease states that exhibit a component of altered nutrient utilization. Food-derived chemicals, including constituents of cruciferous vegetables and fruits, modulate CYP expression and the expression of genes that encode cytoprotective phase II enzymes. Certain dietary indoles and flavonoids activate CYP1A expression either by direct ligand interaction with the aryl hydrocarbon receptor (AhR) or by augmenting the interaction of the AhR with xenobiotic response elements in CYP1A1 and other target genes. Other dietary chemicals, including methylenedioxyphenyl (MDP) compounds and isothiocyanates also modulate CYP gene expression. Apart from altered CYP regulation, a number of dietary agents also inhibit CYP enzyme activity, leading to pharmacokinetic interactions with coadministered drugs. A well described example is that of grapefruit juice, which contains psoralens and possibly other chemicals, that inactivate intestinal CYP3A4. Decreased presystemic oxidation by this CYP increases the systemic bioavailability of drug substrates and the likelihood of drug toxicity. Dietary interactions may complicate drug therapy but inhibition of certain CYP reactions may also protect the individual against toxic metabolites and free radicals generated by CYPs. Chemicals in teas and cruciferous vegetables may also inhibit human CYP enzymes that have been implicated in the bioactivation of chemical carcinogens. Thus, food constituents modulate CYP expression and function by a range of mechanisms, with the potential for both deleterious and beneficial outcomes.
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PMID:Altered CYP expression and function in response to dietary factors: potential roles in disease pathogenesis. 1645 93


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