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)

We measured placental diffusing capacity for carbon monoxide (DpCO) in 10 unanesthetized sheep with catheters chronically implanted in maternal and fetal vessels. Serially measured DpCO during the last third of gestation averaged 0.55 +/- 0.02 (SEM) ml.(min.Torr.kg fetal wt)-1, essentially the same value as that previously reported in anesthetized, acutely operated animals. While placental CO diffusing capacity increased as a function of gestational age when expressed as ml.(min.Torr)(-1), it remained constant when calculated per kg fetal wt. In eight experiments, DpCO showed no change following the administration of several drugs which combine with cytochrome P450. We interpret this as evidence against the carrier hypothesis for placental CO exchange. We calculated the placental diffusing capacity for oxygen to be 0.68 ml.(min.Torr.kg)-1 and the mean maternal-to-fetal capillary Po2 difference to be 10 Torr. Caculations predict that maternal and fetal oxygen partial pressures equilibrate in end-capillary blood during the course of a single transit in placental exchange vessels; thus placental oxygen exchange is not limited by diffusion.
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PMID:Placental diffusing capacity for carbon monoxide and oxygen in unanesthetized sheep. 59 80

Dietary indoles in cruciferous vegetables induce cytochrome P450 enzymes and have prevented tumors in various animal models. Because estradiol metabolism is also cytochrome P450 mediated and linked to breast cancer risk, indoles may similarly reduce estrogen-responsive tumors in humans. We examined several indoles in female Sprague-Dawley rats for induction of hepatic estradiol 2-hydroxylation. The most potent inducer, indole-3-carbinol, was administered to humans (500 mg daily for 1 wk). It significantly increased the extent (mean +/- SEM) of estradiol 2-hydroxylation from 29.3% +/- 2.1% to 45.6% +/- 2.1% (P less than .001). These results indicate that indole-3-carbinol strongly influences estradiol metabolism in humans and may provide a new chemopreventive approach to estrogen-dependent diseases.
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PMID:Induction of estradiol metabolism by dietary indole-3-carbinol in humans. 163 91

Cimetidine, a histamine H2 antagonist, is known to interfere with the metabolism of exogenous drugs by binding to cytochrome P450. We examined the possibility that cimetidine might also inhibit the cytochrome P450-dependent biotransformation of endogenous compounds such as steroid hormones. Utilizing a radiometric assay and normal male volunteers, the acute effect of intravenous cimetidine (300 mg loading dose followed by 50 mg/hr) was determined. The extent of 2-hydroxylation of estradiol was reduced by 25% from 29.6 +/- 4.4% (mean +/- SEM) before, to 22.9 +/- 4.0% during cimetidine infusion (n = 8; p less than 0.0005). Following oral cimetidine (800 mg b.i.d.) for 2 wk, estradiol 2-hydroxylation was decreased by 40% from 31.7 +/- 2.3% to 19.7 +/- 2.4% (n = 9; p less than 0.0001) but 16 alpha-hydroxylation of estradiol was unaffected. Concomitantly, the urinary excretion of 2-hydroxyestrone was decreased by 25% (p less than 0.002) and the serum estradiol concentration was increased by 20% (p less than 0.04). In contrast, ranitidine, a second generation H2 receptor antagonist, had no effect on estradiol hydroxylation following 150 mg b.i.d. for 2 wk. The inhibition of estradiol 2-hydroxylation and the increase in serum estradiol concentrations caused by cimetidine administration may help to account for the symptoms of hyperestrogenization reported in long-term cimetidine therapy.
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PMID:The oxidative metabolism of estradiol: inhibition by cimetidine. 263 29

We determined whether alterations in hepatic microsomal function occur in association with iron-induced lipid peroxidation in vivo in rats with chronic dietary iron overload. In rats fed a 2.0% carbonyl iron diet for a period of 20 wk, there was no significant microsomal conjugated diene formation (evidence of microsomal lipid peroxidation) or difference in cytochrome P450 concentration found at mean (+/- SEM) hepatic iron concentrations of 1210 +/- 92 micrograms/g liver (wet wt) or 2730 +/- 100 micrograms/g. At a hepatic iron concentration of 4090 +/- 245 micrograms/g, however, there was significant conjugated diene formation (p less than 0.001) and a 56% decrease in the cytochrome P450 concentration (p less than 0.001). In rats fed a 2.5% carbonyl iron diet for 10 wk, achieving a liver iron concentration of 4820 +/- 420 micrograms/g, there was significant microsomal conjugated diene formation (p less than 0.001), a 35% reduction in cytochrome P450 (p less than 0.005), and a 16% reduction in aminopyrine demethylase activity (p less than 0.025), but only an 8% reduction in glucose-6-phosphatase activity (p = not significant). Finally, in rats fed a 3.0% iron-supplemented diet for 7 wk, achieving a liver iron concentration of 2730 +/- 205 micrograms/g, there was a 23% reduction in cytochrome P450 (p less than 0.025), a 28% reduction in cytochrome b5 (p less than 0.001), and a 47% increase in heme oxygenase activity (p less than 0.025) (heme oxygenase activity measured in this group only). We conclude that oral iron loading can produce microsomal lipid peroxidation in vivo that is associated with selective decreases in microsomal hemoprotein concentrations and cytochrome P450-dependent enzymes.
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PMID:Hepatic microsomal function in rats with chronic dietary iron overload. 300 59

The antimycotic agent ketoconazole is known to inhibit several cytochrome P450-dependent enzymes involved in the biosynthesis of steroid hormones from cholesterol. Since 1,25-dihydroxyvitamin D is also a sterol synthesized by cytochrome P450-dependent enzymes, we assessed whether ketoconazole would lower serum 1,25-dihydroxyvitamin D levels. In nine normal men, administration of ketoconazole for 1 week in doses of 300-1200 mg/day led to a dose-dependent reduction in serum 1,25-dihydroxyvitamin D levels (r = -0.64; P less than 0.001). At the highest dose taken by each man (1200 mg/day in six, 900 mg/day in one, and 600 mg/day in two), serum levels of 1,25-dihydroxyvitamin D fell significantly compared to baseline [14 +/- 1 (+/- SEM) vs. 39 +/- 3 pg/ml; P less than 0.001), but there was no change in serum levels of 25-hydroxyvitamin D, PTH, calcium, phosphate, or alkaline phosphatase. Ketoconazole may be potentially useful in exploring the pathogenetic role of 1,25-dihydroxyvitamin D in disorders of calcium metabolism and in treatment of patients with hypercalcemic disorders or renal stone disease.
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PMID:Ketoconazole-induced reduction in serum 1,25-dihydroxyvitamin D. 375 45

Omeprazole, a proton pump inhibitor, is used in the treatment of gastrointestinal diseases associated with hyperacidity. It binds to, and inhibits, some of the activities of hepatic cytochrome P450 resulting in increased half-lives of certain pharmacologic and endogenous compounds. It may also increase the activity of cytochrome P450 under certain conditions. Oxidative metabolism of endogenous estrogens, particularly the 2-hydroxylation pathway, is P450-dependent, and is highly sensitive to a variety of dietary and pharmacologic agents. We therefore studied the extent of estradiol 2-hydroxylation in 7 normal male volunteers before and during oral treatment with omeprazole 20 mg twice daily. Using a specific in vivo radiometric assay, the mean extent (+/- SEM) of estradiol 2-hydroxylation was found to be unchanged before and after omeprazole treatment (27.3 +/- 3.0 vs. 27.5 +/- 3.4%, respectively). The excretion of the endogenous urinary estrogen metabolites, 2-hydroxyestrone, estriol, and estrone was also unaltered by omeprazole. These results show that omeprazole, in contradistinction to other medications used in the treatment of peptic ulcer disease, is without effect on estradiol metabolism in men.
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PMID:Omeprazole fails to alter the cytochrome P450-dependent 2-hydroxylation of estradiol in male volunteers. 833 35

Hypercalcemia in human granuloma-forming diseases like sarcoidosis results from the endogenous overproduction of 1,25-dihydroxyvitamin D [1,25-(OH)2D] by disease-activated tissue macrophages. The recent identification of an immortalized chick myelomonocytic cell line, HD-11, that constitutively expresses a 25-hydroxyvitamin D (25-OHD) 1-hydroxylation reaction has alleviated dependence on studying primary macrophage cultures with no replicative potential in vitro. In these experiments we established conditions for the maximal expression of the HD-11 cell 25-OHD3-1-hydroxylation reaction and localized this activity to the mitochondrial fraction. On a per cell basis, the activity of HD-11 cell 25-OHD3 1-hydroxylation reaction was comparable to that in primary cultures of chick renal tubular epithelial cells, which express the authentic renal 25-OHD3 1-hydroxylase. Maximal product yield was achieved after incubation of HD-11 cells with 200 nM 25-OHD3 for 3 h. Although adherent monolayers possessed 3- to 4-fold more capacity for hormone production than cells in suspension, suspended cells exhibited easily detectable 25-OHD3 catalytic activity (0.58 +/- 0.08 pmol per 10(6) cells per h; +/- SEM), 50% of which remained solubilized in a sonicate of suspended cells cleared of nuclei and plasma membrane. Subcellular localization disclosed 91% of the residual activity to be concentrated in the mitochondrial subfraction. A detergent-solubilized extract of this mitochondrial subfraction contained 1.9 +/- 0.3 pmol 1,25-(OH)2D3 synthetic capacity per mg protein. The catalytic activity (1-hydroxylase activity) was concentrated 20.2-fold after chromatography on octyl-amino agarose and was associated with 0.054 nmol cytochrome P450 per mg protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Subcellular localization and partial purification of the 25-hydroxyvitamin D3 1-hydroxylation reaction in the chick myelomonocytic cell line HD-11. 838 98

The concentration of nitric oxide (NO) is increased in the exhaled air of patients with inflammatory lung diseases, including asthma, possibly reflecting cytokine-mediated chronic airway inflammation. Endogenous NO is generated from L-arginine by the action of several types of NO synthase (NOS). NOS have structural similarities with cytochrome P450 reductases. Alcohol decreases exhaled NO in animals, but this has not previously been investigated in man. We studied the effect of alcohol ingestion in nine asthmatic and 12 normal subjects, measuring the peak concentration of exhaled NO using a modified chemiluminescence analyser. A significant decrement in NO occurred in asthmatic patients (mean +/- SEM before ethanol 204 +/- 58 to 158 +/- 59 parts per billion (ppb) after ethanol; p < 0.02), without significant change in the normal subjects (122 +/- 14 to 114 +/- 15 ppb). Thus, in our study, alcohol decreased exhaled nitric oxide in asthmatic subjects but not in normal individuals. This may reflect preferential action on inducible nitric oxide synthase which is expressed in asthmatic airways. An inhibitory effect of ethanol on inducible nitric oxide synthase may contribute towards the effect of alcohol in asthma.
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PMID:The effect of alcohol ingestion on exhaled nitric oxide. 880 27

The objective of this study was to investigate changes in expression of mRNAs encoding FSH receptor (FSHr), LH receptor (LHr), cytochrome P450 side-chain cleavage (P450(scc)), cytochrome P450 17alpha-hydroxylase (P450(c17)), and cytochrome P450 aromatase (P450(arom)) during recruitment and selection of bovine ovarian follicles. Dairy heifers (4-5 per group) were ovariectomized at 12, 24, 36, 48, 60, 72, 84, or 96 h after initiation of the first follicular wave following estrus as determined by ultrasonography (Time 0 = initiation of follicular wave; mean +/- SEM = 42.0 +/- 2.6 h after estrus). Expression of mRNAs encoding FSHr, LHr, P450(scc), P450(c17), and P450(arom) was detected by in situ hybridization and quantified by image analysis. Antral follicles were classified as healthy or atretic. Healthy follicles expressed higher (p < 0.01) amounts of mRNAs for gonadotropin receptors and steroidogenic enzymes than did atretic follicles, and expression of LHr, FSHr, P450(scc), P450(c17), and P450(arom) increased (p < 0.01) with follicular size and stage of the follicular wave. Expression of mRNAs for P450(scc), P450(arom), and LHr was time- and size-dependent during recruitment and selection. During recruitment, expression of mRNAs for P450(scc) and P450(arom) was first detected in granulosa cells of 16 of 21 of the follicles 4-6 mm in diameter at 12 h. At 24 and 36 h, almost all follicles 6-9 mm in diameter, but not those 4-5 mm in diameter, expressed both P450(scc) and P450(arom) mRNA in the granulosa cells. At 48 h and thereafter, P450(scc) and P450(arom) mRNA were expressed predominantly in one healthy large follicle per cow with a few exceptions. Expression of LHr mRNA was first detected in granulosa cells at 36 h and was always found in granulosa cells of one follicle > or = 8 mm per cow with exception of one cow at 36 h (no expression) and another two cows, one each at 36 and at 84 h (expression in 2 follicles). In addition, LHr mRNA expression in the granulosa cell layer was limited to follicles that also expressed mRNAs for P450(scc) and P450(arom) in the granulosa cells. In summary, follicular recruitment in cattle was associated with expression of P450(scc) and P450(arom) mRNA within granulosa cells, and the process of follicular selection was associated with initiation of LHr mRNA expression in granulosa cells.
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PMID:Changes in messenger ribonucleic acid encoding luteinizing hormone receptor, cytochrome P450-side chain cleavage, and aromatase are associated with recruitment and selection of bovine ovarian follicles. 916 Jul 14

P-Glycoprotein (P-gp) and cytochrome P450 3A (CYP3A) share common substrates and expression properties, but the relationship of mdrl deficiency to CYP3A-mediated metabolism and protein expression is not established. The in vitro kinetic parameters of CYP3A-mediated metabolism of midazolam (MDZ), triazolam (TRZ), and dexamethasone (DEX) were studied in liver microsomes from three mrdrla(-/-) mice, one mdrla/b(-/-) mouse, and mdrla/b(+/+) controls. The kinetic profiles of CYP3A-mediated MDZ 4-hydroxylation were not significantly different between mdrl-deficient animals and controls. Overall mean (+/- SEM, N = 8) values were: Vmax, 0.74+/-0.05 nmol/min/mg protein; Km, 28.2+/-2.7 microM; and estimated intrinsic clearance, 0.026+/-0.003 mL/min/mg protein. Likewise, rates of formation of alpha-OH- and 4-OH-TRZ (from 500 microM TRZ), and of DEX metabolites sensitive to ketoconazole inhibition, M1 and M5 (from 20 microM DEX), did not differ between mdrl-deficient and control animals. Immunoquantified microsomal CYP3A protein levels in mdrla(-/-), mdrla/b(-/-), and mdrla/b(+/+) mice were not different, with overall mean immunoreactive protein levels of 2.68+/-0.09 pmol/microg protein. Although CYP3A and P-gp share aspects of activity and expression, disruption of the mdrl genes does not affect CYP3A-mediated metabolism or protein expression in the mouse.
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PMID:Unchanged cytochrome P450 3A (CYP3A) expression and metabolism of midazolam, triazolam, and dexamethasone in mdr(-/-) mouse liver microsomes. 1023 Jul 66


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