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

Although hyperketonemia and/or altered growth hormone secretion caused by diabetes have been implicated in enhanced CYP2E1, 2B, 3A and 4A expression, the effect of insulin on hepatic P450 expression, in the absence of associated metabolic/hormonal alterations, remains unknown. Primary cultured rat hepatocytes have been shown (Zangar et al., Drug Metab. Dispos., 23:681, 1995) to express stable and inducible CYP2E1 mRNA and protein levels, and provide an excellent system for mechanistic examination of the effect of insulin on CYP2E1, 2B, 3A and 4A expression. Maintaining primary rat hepatocytes in culture in the absence of insulin for 48, 72, or 96 h increased CYP2E1 mRNA levels 5-, 11-, and 4-fold, respectively, relative to cells maintained in the presence of the standard concentration of 1 microM insulin. In contrast, CYP2B mRNA levels increased only approximately 2-fold in the absence of insulin, when compared with the presence of 1 microM insulin. CYP2E1 and 2B protein levels were increased 6.7- and 3.8-fold, respectively, in cells cultured for 96 h in the absence of insulin as compared with those cultured in medium containing 1 microM insulin. Concentration-response studies revealed that decreasing the concentration of insulin below 10 nM (i.e. 1 nM, 0.1 nM, no insulin) increased CYP2E1 mRNA levels 4-, 7-, and 11-fold, respectively. In contrast, no such concentration-dependence was observed for CYP2B mRNA expression. As CYP3A and 4A expression is also elevated in diabetic rats, the effects of insulin on these P450s was also examined. CYP3A mRNA levels were unaltered and CYP4A mRNA levels were decreased marginally (approximately 50%) by the absence of insulin relative to levels in cells cultured in the presence of 1 microM insulin over 96 h in culture. The results of this study provide evidence that insulin itself, in the absence of other diabetes-induced metabolic or hormonal alterations, affects CYP2E1 and 2B, but not CYP3A or 4A, expression in primary cultured rat hepatocytes. Furthermore, CYP2E1 expression is differentially regulated by insulin relative to CYP2B, 3A or 4A. This study also demonstrates that decreasing the concentration of insulin in the culture medium provides a method by which CYP2E1 levels can be increased in primary cultured hepatocytes to facilitate mechanistic studies on the regulation of CYP2E1 expression.
 ...
PMID:Insulin effects on CYP2E1, 2B, 3A, and 4A expression in primary cultured rat hepatocytes. 940 51

Tacrolimus (FK 506) is a new macrocyclic lactone immunosuppressant which possesses similar but more potent immunosuppressive properties compared with cyclosporin. It is able to inhibit T cell proliferation and the production of interleukine 2 (and other growth promoting cytokines). A major interest of tacrolimus is that it can be used as a rescue therapy since clinical trials have demonstrated its ability to be effective in some patients who develop rejection episodes refractory to current regimens, including corticosteroids. Tacrolimus is highly bound to erythrocytes and is largely metabolized, primarily in the liver, by Cyt P450 3A4. Its excretion pathway concerns the bile almost exclusively. Like cyclosporin, the drug is associated with a range of adverse effects including nephrotoxicity, neurotoxicity and diabetes. Tacrolimus also exhibits a large inter- and intra-individual variability of its pharmacokinetics. Because of this variability and the narrow therapeutic index of tacrolimus, monitoring of tacrolimus blood concentrations would be useful for optimization of therapy. However, even if we know that by maintaining the residual blood concentration under 15 micrograms/l it is possible to reduce dramatically the occurrence of adverse effects, we still have not determined the threshold value of clinical efficacy. This will be important for current and future clinical pharmacology investigations with tacrolimus.
 ...
PMID:[Clinical pharmacokinetics and therapeutic monitoring of tacrolimus]. 943 90

Diabetes complicates 2-3% of all pregnancies and is associated with an increase in both perinatal morbidity and mortality, though reasons for these adverse outcomes are unknown. Estrogen biosynthesis is a critical factor during pregnancy and is carried out in the placenta via aromatase (cytochrome P450 19A1), which catalyzes the conversion of C-19 androgens to C-18 estrogens. Previous studies have shown that hormones such as insulin-like growth factors and insulin regulate aromatase activity when studied in vitro. Interestingly, levels of these hormones are altered in patients with diabetes. Thus, we hypothesized that the presence of maternal diabetes may alter placental aromatase activity and thus estrogen biosynthesis, possibly serving as one factor in the adverse outcomes of babies born to mothers with diabetes. To this end, we measured the production of 19-hydroxyandrostenedione, 19-oxoadrostenedione and estrone in 30 placental tissues from diabetic patients, using [7-3H]androst-4-ene-3,17-dione as a model substrate for aromatase (P450 19A1). A statistical difference was detected in the percentage of 19-oxoandrostenedione formed between the overt and control groups (P < 0.05). Additionally, NADPH P450-reductase levels were measured in these same tissues to determine whether alterations in this enzyme necessary for aromatase activity could be affected by diabetes. No differences in reductase levels were detected among the patient groups. However, a statistical correlation was found between NADPH P450-reductase activity and the formation velocities of all three estrogen products (P < 0.05). Thus, it appears that the presence of diabetes does not affect placental aromatase activity.
 ...
PMID:The effects of diabetes on placental aromatase activity. 944 16

Adrenal P450 enzymes 21-hydroxylase (21OH), 17alpha-hydroxylase (17OH) and side chain cleavage enzyme (SCC) represent major target antigens in adrenal autoimmunity. To evaluate the diagnostic sensitivity of autoantibodies to recombinant adrenal antigens we established rapid and sensitive radioligand assays and compared the results with adrenocortical autoantibodies (ACA) as detected by the standard immunofluorescence test. A high prevalence of antibodies to 21OH (21OH-A) was observed in patients with isolated Addison's disease (IAD) and patients suffering from autoimmune polyendocrine syndrome type II (APS II). 21OH-A were found in 19 of 25 (76%) patients with IAD and in 34 of 40 (85%) patients with APS II. In contrast, antibodies to 17OH (17OH-A) as well as antibodies to SCC (SCC-A) were detected in 12 (30%) and 13 (33%) patients with APS II whereas only a few sera from patients with IAD had 17OH antibodies (n = 3) and SCC-A (n = 1), respectively (p < 0.0001). The majority of patients with 17OH-A (83.3%) or SCC-A (76.9%) were also found positive for 21OH-A and all three antibody specificities were positively correlated with the presence of ACA. Among 52 sera with ACA 49 (94.2%), 11 (21.2%), and 9 (17.3%) were positive for 21OH-A, 17OH-A and SCC-A, respectively. By combination of 21OH-A with 17OH-A all ACA positive individuals were identified. The availability of recombinant steroid P450 enzymes made it possible to develop radiobinding assays which allow simple, sensitive and quantitative detection of autoantibodies to defined adrenal autoantigens. We here demonstrate that autoantibodies to 21-hydroxylase are sensitive markers for autoimmune Addison's disease with and without polyglandular failure. The presence of 17OH-A or SCC-A may suggest the coexistence of or progression towards polyglandular autoimmunity.
Exp Clin Endocrinol Diabetes 1999
PMID:Autoantibodies to adrenal cytochrome P450 antigens in isolated Addison's disease and autoimmune polyendocrine syndrome type II. 1037 48

The rat CYP8B cDNA encoding sterol 12alpha-hydroxylase was cloned and sequenced. The amino acid sequence of the heme-binding region of CYP8B was close to those of CYP7A (cholesterol 7alpha-hydroxylase) and CYP7B (oxysterol 7alpha-hydroxylase). Molecular phylogenetic analysis suggests that CYP8B and the CYP7 family derive from a common ancestor. The P450s of the CYP7 and CYP8 families, except for CYP8A (prostacyclin synthase), catalyze the oxygenation of sterols from an alpha surface in the middle of the steroid skeleton. These facts suggest that CYP8B is a P450 closely linked to those of the CYP7 family. CYP8B was expressed specifically in liver. Hepatic CYP8B mRNA level and the 12alpha-hydroxylase activity were altered by cholestyramine feeding, starvation, streptozotocin-induced diabetes mellitus, and administration of clofibrate, dexamethasone or thyroxin, indicating the pretranslational regulation of CYP8B expression. The enhanced CYP8B mRNA expression in streptozotocin-induced diabetic rats was significantly decreased by insulin within 3 h of its administration. These facts demonstrate a regulatory role of insulin in CYP8B expression as a suppressor.
 ...
PMID:Structure, evolution, and liver-specific expression of sterol 12alpha-hydroxylase P450 (CYP8B). 1039 16

Unlike other selective serotonin reuptake inhibitors (SSRIs), sertraline has linear pharmacokinetics so that increases in dose lead to proportional increases in drug concentration. The half-life of sertraline is about 26 h so that it reaches a steady state in one week, according to the product monograph. Hypoglycemia associated with sertraline and coadministration of oral hypoglycemics belonging to the sulphonylurea derivatives has rarely been reported. A patient with schizoaffective disorder with non-insulin-dependent diabetes mellitus (NIDDM) treated with sertraline, risperidone and glyburide who developed hypoglycemia is presented. The article highlights that inhibition of P450 enzymes can be affected by several different factors. Interactions are possible whenever a patient concomitantly receives two drugs that bind to the same P450 system Greater inhibition was likely induced at doses higher than those recommended. This process was reversed within 10 days of discontinuing the sertraline. Good glycemic control followed discontinuation of psychotropic drugs and the oral hypoglycemic agent. Knowledge of the individual P450 enzymes is important in the metabolism of individual drugs, together with an understanding of the patient's drug metabolizing ability. These factors may lead to more appropriate prescribing and further research into specific P450 enzymes responsible for metabolism of particular drugs, which remains unclear.
 ...
PMID:Hypoglycemia associated with high doses of sertraline and sulphonylurea compound in a noninsulin-dependent diabetes mellitus patient. 1046 60

We studied the long-term effects of streptozotocin-induced diabetes on tissue-specific cytochrome P450 (CYP) and glutathione-dependent (GSH-dependent) xenobiotic metabolism in rats. In addition, we also studied the effect of antidiabetic Momordica charantia (karela) fruit-extract feeding on the modulation of xenobiotic metabolism and oxidative stress in rats with diabetes. Our results have indicated an increase (35-50%) in CYP4A-dependent lauric acid hydroxylation in liver, kidney, and brain of diabetic rats. About a two-fold increase in CYP2E-dependent hepatic aniline hydroxylation and a 90-100% increase in CYP1A-dependent ethoxycoumarin-O-deethylase activities in kidney and brain were also observed. A significant increase (80%) in aminopyrene N-demethylase activity was observed only in rat kidney, and a decrease was observed in the liver and brain of diabetic rats. A significant increase (77%) in NADPH-dependent lipid peroxidation (LPO) in kidney of diabetic rats was also observed. On the other hand, a decrease in hepatic LPO was seen during chronic diabetes. During diabetes an increased expression of CYP1A1, CYP2E1, and CYP4A1 isoenzymes was also seen by Western blot analysis. Karela-juice feeding modulates the enzyme expression and catalytic activities in a tissue- and isoenzyme-specific manner. A marked decrease (65%) in hepatic GSH content and glutathione S-transferase (GST) activity and an increase (about two-fold) in brain GSH and GST activity was observed in diabetic rats. On the other hand, renal GST was markedly reduced, and GSH content was moderately higher than that of control rats. Western blot analyses using specific antibodies have confirmed the tissue-specific alterations in the expression of GST isoenzymes. Karela-juice feeding, in general, reversed the effect of chronic diabetes on the modulation of both P450-dependent monooxygenase activities and GSH-dependent oxidative stress related LPO and GST activities. These results have suggested that the modulation of xenobiotic metabolism and oxidative stress in various tissues may be related to altered metabolism of endogenous substrates and hormonal status during diabetes. The findings may have significant implications in elucidating the therapeutic use of antidiabetic drugs and management of Type 1 diabetes in chronic diabetic patients.
 ...
PMID:Modulation of xenobiotic metabolism and oxidative stress in chronic streptozotocin-induced diabetic rats fed with Momordica charantia fruit extract. 1071 28

Sera from 300 Italian patients with Addison's disease were collected over a 30 year period. Among these patients, 82% had autoimmune disease, 13% had tuberculosis and 5% had another causal condition. In 59% of the cases, autoimmune disease was associated with the autoimmune manifestations contributing to the description of polyglandular autoimmune disease (PGAD). In PGAD type 1, the disease was associated with chronic candidiasis and/or chronic hypoparathyroidism. In PGAD type 2, the patients had autoimmune thyroid disease and/or diabetes mellitus type 1, and in PGAD type 4, they presented a combination with other autoimmune diseases excluding those previously mentioned. Finally, the autoimmune disease was apparently isolated in 41% of the cases. In addition, patients with these four forms of disease exhibited a different genetic pattern, sex distribution, and age at presentation in addition to minor frequency of autoimmune diseases. Adrenal cortex autoantibodies directed against 21-hydroxylase were common serological markers for these four main clinical forms, showing a very high frequency at clinical onset of adrenal insufficiency. In some patients, steroid-producing cell autoantibodies were also present and correlated with gonadal failure and they recognize of 17alpha-hydroxylase or P450 side chain cleavage enzymes as target antigens.
 ...
PMID:Autoimmunity in isolated Addison's disease and in polyglandular autoimmune diseases type 1, 2 and 4. 1135 94

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.
 ...
PMID:Hepatic cytochrome P450 regulation in disease states. 1146 24

Pioglitazone is a thiazolidinedione that increases insulin sensitivity in target tissues. It is well-absorbed, with a mean absolute bioavailability of 83% and reaching maximum concentrations in around 1.5 hours. It is metabolised by the hepatic cytochrome P450 enzyme system. However, unlike troglitazone, studies have provided no evidence to suggest that pioglitazone administration leads to inhibition or induction of any of the P450 isoenzymes involved in drug metabolism. Therefore pioglitazone may have lower potential for drug interaction. The half-life is about 9 hours but two active metabolites mainly contribute to the extended glucose-lowering effects. It is administered once daily without regard to meals. The pharmacokinetics are not significantly altered in Type 2 diabetes, renal or hepatic insufficiency or in the elderly. In placebo-controlled clinical studies, pioglitazone effectively improved glycaemic control in people with Type 2 diabetes as evidenced by significant reductions in HbA1c and fasting plasma glucose, whether used as monotherapy or in combination with sulphonylurea, metformin or insulin. Pioglitazone also had a beneficial effect on the abnormal lipid profile seen in Type 2 diabetes. Compared with placebo, pioglitazone significantly reduced serum triglycerides and increased high density lipoprotein cholesterol with no change in low density lipoprotein or total cholesterol.
 ...
PMID:Pharmacokinetics and clinical efficacy of pioglitazone. 1159 40


<< Previous 1 2 3 4 5 6 7 8 Next >>