Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The report by Schacter et al. (J Biol Chem 247: 3601, 1972) that an antibody to NADPH-cytochrome c oxidoreductase inhibited NADPH-cytochrome c reductase and heme oxygenase activities in rat and pig liver and spleen microsomes demonstrated the role of this flavoprotein in microsomal heme oxygenation. Recent studies from other laboratories (Yoshida et al., J Biochem 75, 1187: 1974 and Bissell et al., Fed Proc 33: 1246, 1974) have strongly suggested that cytochrome P-450 is not involved in heme oxygenation. The availability of a homogeneous preparation of NADPH-cytochrome c reductase prompted us to test heme oxygenase activity in a system devoid of hemoprotein contamination. NADPH-cytochrome c reductase catalyzed biliverdin formation at a rate of 8.26 +/- 0.5 SEM nmole min-1mg-1 in the absence of biliverdin reductase. The rate of bilirubin formation in the presence of biliverdin reductase was less than 10% of the rate of biliverdin formation, suggesting that mixture of biliverdin isomers may be produced. Biliverdin production was potently (70--80%) inhibited by catalase, but was unaffected by superoxide dismutase. Epinephrine also inhibited heme oxygenation, presumably by utilizing O2. required for the formation of H2O2 by the reductase. By extrapolation, the NADPH oxidase activity due to NADPH-cytochrome c reductase can account for heme degradation occurring in microsomes. However, the specificity of ring scission at the IXalpha position must be due to another microsomal protein, perhaps the heme oxygenase of Yoshida et al., and not cytochrome P-450.
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PMID:The catalysis of heme degradation by purified NADPH-cytochrome C reductase in the absence of other microsomal proteins. 82 31

Tritiated misonidazole (MISO) was injected intravenously (iv) into mice bearing five different tumors. At 24 hr the tumors were removed for analysis of bound MISO, and at the same time three normal tissues were removed (liver, labial gland, and esophagus). The labial gland and esophagus were selected as representatives of sebaceous and stratified squamous tissues, respectively, tissues that in many parts of the body retain high levels of MISO. The tumors used were early transplant generations of spontaneous mouse tumors of mammary gland, lung, and liver. The levels (mean +/- SEM) of MISO at 24 hr for the five tumors and three normal tissues, expressed as percentage of the injected dose per gram of tissue were: A110 (0.03 +/- 0.007), A114 (0.103 +/- 0.04), A150 (0.09 +/- 0.005), A167 (0.037 +/- 0.012), A168 (0.122 +/- 0.0016), esophagus (0.507 +/- 0.09), labial gland (0.125 +/- 0.013), liver (0.11 +/- 0.004). Histochemical examination of the normal tissues showed reductase activity in all three. In the esophagus and labial gland, inhibition of the reaction by dicumarol indicated the likely presence of the reductase DT-diaphorase which, by 2-electron transfer, can be expected to reduce MISO to a reactive, locally-binding metabolite, even in the presence of oxygen.
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PMID:Retention of misonidazole in normal and malignant tissues: interplay of hypoxia and reductases. 154 33

Bone is a target organ of androgens. The mechanism by which these steroids exert their action within bone cells is still poorly understood. The metabolism of androstenedione, the major circulating androgen in women, was, therefore, assessed in osteoblast-like bone cells cultured from bone of 16 postmenopausal women (mean age, 69 yr; range, 56-80) and 3 elderly men (mean age, 71 yr; range, 69-73) undergoing total hip replacement. Each cell strain was incubated under standardized conditions with varying concentrations of [1,2,6,7-3H]androstenedione (0.05-5 microM). In every instance 5 alpha-reduced metabolites and 17 beta-hydroxysteroids were formed. There was no correlation between the volumetric density of the resected bone and androstenedione metabolism of the corresponding cultured bone cell strains. The apparent Km for the 5 alpha-reductase activity (sum of androstanedione and dihydrotestosterone) of all 19 cell strains was 0.7 +/- 0.1 microM (mean +/- SEM), and the apparent Km for 17 beta-hydroxysteroid dehydrogenase (sum of testosterone and dihydrotestosterone) was 2.3 +/- 0.8 microM (mean +/- SEM), values similar to those reported for other androgen target organs. Our results demonstrate that human osteoblast-like cells have the capacity to transform androstenedione into the more potent biological androgens testosterone and dihydrotestosterone. Since the Km values of both 5 alpha-reductase and 17 beta-hydroxysteroid dehydrogenase exceed the serum androstenedione concentration, the formation of testosterone and dihydrotestosterone appears to be mainly a function of substrate availability.
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PMID:Androstenedione metabolism in cultured human osteoblast-like cells. 161 95

The accumulation of 5 alpha-dihydrotestosterone (DHT), particularly in stroma, is a possible etiological factor in regard of the age-dependent development of benign prostatic hyperplasia (BPH). In this context, we have recently demonstrated age-dependent alterations of 5 alpha-reductase, which is responsible for the irreversible conversion of testosterone to DHT. Therefore, it was also of interest to study possible age-dependent alterations of those enzymes mainly involved in the reversible metabolism of DHT to 5 alpha-androstanediols. Thus, we determined, in the presence of NADPH/NADP+, kinetic parameters [Km and maximum velocity (Vmax)] of 3-hydroxysteroid oxidoreductases (3 alpha-HSORred, 3 beta-HSORred, and 3 alpha-HSORox) in separated epithelium and stroma of 10 normal (NPR) and 20 hyperplastic prostates (BPH) and correlated the data with the age of the donors (15-86 yr). The mean Km (nanomolar concentrations +/- SEM) of 3 alpha-HSORred was significantly (P less than 0.01) higher in epithelium (NPR, 1391 +/- 181; BPH, 2150 +/- 157) than in stroma (NPR, 778 +/- 22; BPH, 749 +/- 62), indicating the presence of epithelial and stromal enzymes. The mean Km values of 3 beta-HSORred and 3 alpha-HSORox were similar. Concerning 3 alpha-HSORred, the mean potential capacity, i.e. the quotient of Vmax/Km (+/- SEM), was significantly (P less than 0.01) higher in epithelium (0.56 +/- 0.08) than in stroma (0.19 +/- 0.02) of NPR, while in BPH nearly identical mean potential capacities were found in epithelium (0.33 +/- 0.04) and stroma (0.26 +/- 0.02). The respective Vmax/Km of 3 beta-HSORred and 3 alpha-HSORox were significantly (P less than 0.05) lower. In addition, the potential capacity of all three enzymes was distinctly lower than the potential DHT-forming capacity of 5 alpha-reductase. With advancing age, the Vmax/Km decreased significantly (P less than 0.001; 3 alpha-HSORred and 3 beta-HSORred) or tendentiously (3 alpha-HSORox) in epithelium, while in stroma a significant (P less than 0.001; 3 alpha-HSORred and 3 alpha-HSORox) or tendentious (3 beta-HSORred) increase with age was found. Our results indicate that aging has a significant impact on DHT-removing enzymes. However, these enzymes counterbalance only in part the strong potential capacity of 5 alpha-reductase.
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PMID:Effect of aging on kinetic parameters of 3 alpha(beta)-hydroxysteroid oxidoreductases in epithelium and stroma of human normal and hyperplastic prostate. 169 99

There is increasing evidence that hypercholesterolaemia is an important contributor to the development of accelerated coronary arterial disease in the cardiac allograft. The optimal drug therapy of hypercholesterolaemia in recipients after cardiac transplantation, however, has not been defined. Simvastatin (an inhibitor of hydroxy-methyl glutaryl-coenzyme A reductase), at a dose of 10 mg/day, was administered to 12 recipients with serum total cholesterol greater than or equal to 7.8 mmol/l and serum triglyceride less than or equal to 4.5 mmol/l refractory to dietary measures during a follow-up period of 1-5 years after cardiac transplantation. All patients received maintenance doses of cyclosporin A and, in some instances, azathioprine and prednisolone. After 2 months treatment with simvastatin, serum total cholesterol was significantly reduced from 8.8 +/- 0.3 mmol/l (mean +/- SEM) to 5.5 +/- 0.5 mmol/l, P less than 0.001, low density cholesterol from 6.6 +/- 0.4 to 3.8 +/- 0.3 mmol/l, P less than 0.001 and triglycerides from 2.4 +/- 0.2 mmol/l to 1.8 +/- 0.2 mmol/l, P less than 0.005. These changes were maintained after a period of treatment of 8 months. Serum high density cholesterol, hepatic transaminase levels, serum creatinine, creatine kinase and cyclosporin A blood levels were not altered by treatment with simvastatin. It is concluded that, in this study group, low-dose simvastatin appears to be well tolerated and has favourable lipid modifying properties.
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PMID:Low-dose simvastatin for the treatment of hypercholesterolaemia in recipients of cardiac transplantation. 174 84

The effects of aging on the hepatic metabolism of cholesterol were studied in 1-, 6- and 24-month-old male Sprague-Dawley rats. Microsomal 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity, which regulates cholesterol biosynthesis, decreased from 835 +/- 144 (SEM) pmol/min/mg protein in the youngest group to 219 +/- 34 and 205 +/- 53 pmol/min/mg protein (p less than 0.001) in the 6- and 24-month-old groups, respectively. Cholesterol 7 alpha-hydroxylase activity, which governs bile acid synthesis, was gradually reduced from 70 +/- 14 pmol/min/mg protein in the 1-month-old group to 32 +/- 7 and 16 +/- 3 pmol/min/mg protein (p less than 0.05) in the 6- and 24-month-old groups, respectively. Acyl coenzyme A:cholesterol acyltransferase activity, which catalyzes the esterification of cholesterol, averaged 431 +/- 47 and 452 +/- 48 pmol/min/mg protein in the 1- and 6-month-old groups, respectively, and was increased to 585 +/- 55 pmol/min/mg protein (p less than 0.05) in the 24-month-old group. The level of total cholesterol showed an age-related increase from 1.56 +/- 0.16 mg/g liver in the 1-month-old group to 1.70 +/- 0.15 and 2.20 +/- 0.19 mg/g liver (p less than 0.05) in the 6- and 24-month-old groups, respectively. The increase was mainly caused by an accumulation of esterified cholesterol. We conclude that a marked decrease in HMG-CoA reductase occurs between 1 and 6 months of age; thereafter the enzyme activity stays unchanged. The activity of cholesterol 7 alpha-hydroxylase decreases progressively and drastically with age, whereas the capacity for esterifying cholesterol increases slightly.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Age-related changes in the metabolism of cholesterol in rat liver microsomes. 189 80

Androgen metabolism was investigated in normal human apocrine glands and in those isolated from age-matched patients with hidradenitis suppurativa. Axillary glands were isolated by shearing and androgen interconverting enzyme activities were measured in cell-free homogenates by incubation with [3H] dehydroepiandrosterone, [3H] androstenedione and [3H] testosterone. The activities (pmol/mg protein/min: mean + SEM) of 3 beta-hydroxysteroid dehydrogenase delta 4-5-isomerase (10.0 +/- 1.2 vs. 5.3 +/- 0.5: n = 5) and 17 beta-hydroxysteroid dehydrogenase (58.1 +/- 4.5 vs. 35.7 +/- 5.2: n = 5) were significantly lower (P less than 0.005) in hidradenitis suppurativa, whereas 5 alpha-reductase activity (12.5 +/- 2.3 vs. 12.5 +/- 2.0: n = 5) was similar. This report suggests that hidradenitis suppurativa cannot be attributed to exaggerated activities of end-organ androgen interconverting enzymes.
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PMID:Androgen metabolism by isolated human axillary apocrine glands in hidradenitis suppurativa. 195 17

The treatment of hypercholesterolemia in renal transplant recipients has been problematic. In the present double-blind study, 11 patients were treated with diet for at least 4 weeks. They were then randomized to placebo or the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, lovastatin (20 mg/day) for 6 weeks, followed by crossover to an additional 6 weeks of lovastatin or placebo. All patients had stable allograft function 8.4 +/- 1.2 years (mean +/- SEM) after transplantation, and received low-dose prednisone and azathioprine immunosuppression. Compared with diet alone, lovastatin caused a 21% reduction in total cholesterol from 307 +/- 14 mg/dL to 244 +/- 13 mg/dL (P less than 0.05). Lovastatin reduced LDL cholesterol 28% from 214 +/- 12 mg/dL to 155 +/- 11 mg/dL (P less than 0.05). Trends toward favorable changes in HDL cholesterol, serum triglycerides, and apolipoproteins were not statistically significant. Liver enzymes, creatine phosphokinase, and renal function remained stable. With lovastatin there was a 27% increase in the WBC (from 6220 +/- 530 cells/mm3 to 7780 +/- 510 cells/mm3, P less than 0.05) that was attributable to a 45% increase in neutrophils (P less than 0.05). This effect of lovastatin, possibly the result of reduced azathioprine bone marrow suppression, could have important implications for immunosuppressive therapy in this patient population. Altogether, these results suggest that lovastatin may be a safe and effective treatment for hypercholesterolemia in renal transplant recipients receiving conventional immunosuppression.
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PMID:Lovastatin treatment of hypercholesterolemia in renal transplant recipients. 210 48

NAD(P)H:quinone oxidoreductase (EC 1.6.99.2; DT-diaphorase) was present in the liver of 18- and 19-day-old chick embryos as assayed both by reduction of resorufin and by the more traditional assay, reduction of 2,6-dichlorophenolindophenol (DCPIP). Both reductions had the classic characteristics of DT-diaphorase: they were equally supported by NADPH and NADH and almost entirely inhibited by dicumarol. Chick embryo liver DT-diaphorase was entirely cytosolic. It was undetectable in the microsomal and mitochondrial fractions. Chick embryo liver cytosol and mitochondrial fractions contained an enzyme oxidizer of resorufin but not of DCPIP. The Km for NADPH for resorufin reductase was an order of magnitude higher in chick embryo than in rat or guinea pig cytosol (1 mM vs 0.1 mM). Resorufin reductase activity was higher for chick embryo than for rat or guinea pig cytosols: Vmax (nmol resorufin reduced per mg cytosolic protein per min +/- SEM) 355 +/- 28 for chick embryo, 159 +/- 10 for guinea pig and 68 +/- 28 for rat. The Vmax for DCPIP reduction was also twice as high in chick embryo as rat liver cytosol. In the chick embryo, 7 days after treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at 6.4 micrograms/kg egg (1 nmol/egg) mortality was increased 2.4-fold, hepatic DT-diaphorase 1.3-fold, and 7-ethoxyresorufin deethylase (7-EROD) 72-fold over control levels. At 32 micrograms/kg, mortality was increased 4.2-fold, DT-diaphorase 2.3-fold and 7-EROD 100-fold. In the guinea pig, 5 days after treatment with TCDD at 10 micrograms/kg, TCDD toxicity was also evident (loss of body weight and thymus weight); there was no change in DT-diaphorase as measured by resorufin reduction, confirming by a different assay the observation of Beatty and Neal (Biochem Pharmacol 27: 505-510, 1978) that TCDD does not induce DT-diaphorase in guinea pig liver, and 7-EROD was increased 8-fold. In contrast, in the rat, 7 days after exposure to TCDD at 10 micrograms/kg, there was no evidence of toxicity, DT-diaphorase was increased close to 7-fold and 7-EROD, 100-fold. The results demonstrate that avian liver contains DT-diaphorase and show that the extent to which DT-diaphorase is part of the pleiotypic response of the liver to an Ah (aryl hydrocarbon) receptor ligand is species dependent. They also suggest that DT-diaphorase induction and TCDD toxicity may be inversely related. The possibility that DT-diaphorase protects against TCDD toxicity and participates in species differences in sensitivity to TCDD toxicity warrants further investigation.
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PMID:NAD(P)H: quinone oxidoreductase (DT-diaphorase) in chick embryo liver. Comparison to activity in rat and guinea pig liver and differences in co-induction with 7-ethoxyresorufin deethylase by 2,3,7,8-tetrachlorodibenzo-p-dioxin. 210 32

Oxygen free radicals generated by xanthine oxidase have been implicated in cardiac damage. The activity of xanthine oxidase/reductase in adult rat heart is considerable. Its assay gives controversial results for other species, for example, rabbits and humans. Therefore, we perfused isolated hearts of various species, including explanted human hearts, to measure the conversion of exogenous hypoxanthine to xanthine and urate. We assayed these purines with high-performance liquid chromatography. The apparent xanthine oxidoreductase activities, calculated as release of xanthine plus 2x urate, were (milliunits per gram wet weight, mean +/- SEM) mice 33 +/- 3 (n = 5), rats 28.5 +/- 1.4 (n = 9), guinea pigs 14.4 +/- 1.0 (n = 5), rabbits 0.59 +/- 0.09 (n = 5), pigs less than 0.1 (n = 6), humans 0.31 +/- 0.04 (n = 7), and cows 3.7 +/- 0.8 (n = 4). In rabbit heart the conversion of hypoxanthine to xanthine was slow, and that of xanthine to urate was even slower. On the other hand, guinea pig and human heart released little xanthine, indicating that xanthine breakdown exceeds its formation. We conclude that isolated perfused mouse, rat, guinea pig, and also bovine hearts show considerable xanthine oxidoreductase activity, contrasting rabbit, porcine, and diseased human hearts.
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PMID:Xanthine oxidoreductase activity in perfused hearts of various species, including humans. 239 79


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