Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intraperitoneal administration of 150 mg dexamethasone (DEX) Kg-1 body wt for four days to rhesus monkeys resulted in statistically significant increases in the activities of hepatic tyrosine aminotransferase (3 fold), microsomal cytochrome P450 (2 fold) and erythromycin N-demethylase (4 fold), but no change in the activities of aminopyrine N-demethylase and NADPH cytochrome c reductase. Three peaks were obtained from control or DEX-treated monkey livers on fractionation of detergent solubilized microsomes by anion exchange chromatography on DE-52. Peak II obtained from DEX-treated monkey microsomes on DE-52 demonstrated the highest specific activity of cytochrome P450 (5.84 nmol mg-1 protein) as compared to other peaks from the same microsomes or any of the peaks obtained from the control microsomes. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of the microsomes from control and experimental animals and peak II obtained after anion exchange chromatography of DEX-treated microsomes demonstrated the intensification of two polypeptides of 52.5 and 50 kDa. The results indicate that DEX is an inducer of cytochrome P450 and dependent erythromycin N-demethylase in non-human primate, Macaca mulatta.
Biochem Mol Biol Int 1994 Aug
PMID:Induction of hepatic microsomal cytochrome P450 by dexamethasone in rhesus monkey (Macaca mulatta). 780 39

The tertiary structure of cytochrome P450 14 alpha demethylase--Candida albicans (P450 CA) is modeled on the basis of sequence alignment with two closely related proteins and the crystallographic structure of Pseudomonas putida P450cam. The secondary structure prediction system used combines the information from several algorithms and trains the data to offer an optimized prediction of the known P450cam. The trained algorithm was then used to predict the secondary structure of the other P450 sequences. The prediction of the surface coil regions was aided by an alignment between P450 CA and the homologous sequences P450 14 alpha demethylase--Saccharomyces cerevisiae (66 SD) and P450 14 alpha demethylase--Candida tropicalis (72 SD). The prediction and alignment information was combined to establish an alignment between P450 CA and P450cam, and to assign full secondary structure to the target protein. This secondary structure was folded from the template of P450cam and the predicted structure was relaxed by molecular dynamics. Model checking highlighted minor adjustments in the alignment, correctly orienting hydrophobic and hydrophilic side chains. The model offers explanations for several known experimental results and suggests further investigations that may prove fruitful in understanding the structure and mechanisms of the P450 family (Porter, T.D. and Coon, M.J. Minireview cytochrome P450. J. Biol. Chem. 1991, 266, 13469-13472. Waterman, M.R. Cytochrome P450 cellular distribution and structural considerations. Current Opinion in Structural Biology 1992, 2, 384-387. Aoyama, Y., Yoshida, Y., Sonohdo, Y. and Sato, Y. Structural analysis of the interaction between the side-chain of substrates and the active site of lanosterol 14 alpha demethylase (P450 14DM) of yeast. Biochim. Biophys. Acta 1992, 1122, 251-255.).
J Mol Graph 1994 Sep
PMID:Modeling cytochrome P450 14 alpha demethylase (Candida albicans) from P450cam. 781 60

Male Fischer rats were maintained for a period of 17 weeks on an iron-deficient diet along with suitable controls. The effect of long term deprivation of iron on xenobiotic metabolism was studied by the activities of various drug metabolising enzymes in both liver as well as extra-hepatic tissues like lungs, kidneys and intestinal mucosa (I.M.). The results show that among the Phase I (activating) enzymes, the hepatic activities of benzo(a)pyrene hydroxylase (AHH) and microsomal epoxide hydrolase (mEH) are significantly reduced in iron deficiency. The other parameters of the activating system, namely cytochrome P450, aminopyrene demethylase (ADM) and aniline hydroxylase (AH), are not altered. Of the two Phase II (conjugating) enzymes studied, only uridine diphospho glucuronyl transferase (UDPGT) is found to be depressed, but not glutathione S-transferase (GST) in liver in iron deficiency. Activities of Phase I enzymes are markedly lowered in extra-hepatic tissues compared to liver; such depression is not observed in conjugating enzymes. Iron deficiency does not seem to make much impact on the enzyme activities of extra-hepatic tissues. Overall, the hepatic results suggest a defect in detoxification mechanisms in iron deficiency. Such impairment may very well predispose an iron-deficient host to an increased risk of carcinogenesis.
Comp Biochem Physiol B Biochem Mol Biol 1995 Jan
PMID:Effect of long term iron deficiency on the activities of hepatic and extra-hepatic drug metabolising enzymes in Fischer rats. 785 40

Endothelium is a single-cell layer lining blood vessels and constituting capillaries and could be a primary site of chemical effects in the cardiovasculature and systemically. Cytochrome P4501A1 (CYP1A1) is strongly inducible in vertebrate endothelium in vivo by aryl hydrocarbon receptor (AhR) agonists [Mol. Pharmacol. 36:723-729 (1989); Mol. Pharmacol. 41:1039-1046 (1992)]. We investigated CYP1A expression and activity in porcine aorta endothelial cells (PAEC) exposed in culture to the AhR agonists 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3',4,4'-tetrachlorobiphenyl (TCB), benzo[a]pyrene (BP), or beta-naphthoflavone (BNF). Immunoblotting with monoclonal anti-CYP1A1 and polyclonal anti-CYP1A1 and anti-CYP1A2 antibodies showed that CYP1A1 was induced in cultures exposed to TCDD, TCB, BP, or BNF but was not detectable in untreated or dimethylsulfoxide-exposed cultures. CYP1A1 was strongly induced at intermediate concentrations (0.1 microM or 1.0 microM) of TCB, BP, or BNF, but induction was suppressed by higher concentrations, a response not due to general toxicity; cell viability (trypan blue exclusion) was > 97% with BNF or TCB at up to 10 microM. CYP1A1 induction by TCDD was maximal at 0.3-1.0 nM. ED50 values for induction of CYP1A1 by TCDD, TCB, and BP were 0.016 nM, 3-10 nM, and 180 nM, respectively. Immunohistochemical analysis confirmed CYP1A1 induction in PAEC but also showed that only some cells in the cultures were induced. Subcellular fractionation, marker enzyme analysis, and immunoblot analysis showed that PAEC had a typical complement of microsomal electron-transport components. NADPH-cytochrome P450 reductase showed comparable rates (approximately 40 nmol/min/mg) in induced and control cultures. Cultures maximally induced by 0.1 microM TCB had microsomal CYP1A1 [ethoxyresorufin-O-deethylase (EROD)] activity averaging 25 pmol/min/mg. Addition of purified rat reductase to PAEC microsomes increased the EROD rates 3-fold. EROD rates measured in intact cells maximally induced by BP, TCB, or TCDD ranged from 15 to 30 pmol/min/mg of whole-cell protein. Methoxyresorufin O-demethylase activity induced by TCDD was 2 pmol/min/mg, i.e., < 10% of the EROD activity. In cultures in which CYP1A1 was strongly induced, CYP1A2 was not detectably expressed. The CYP1A2 inducer acenaphthylene did not induce EROD or methoxyresorufin O-demethylase in intact cells. The results show that CYP1A1 but not CYP1A2 is strongly induced in mammalian endothelial cells in culture and that CYP1A1 is active in intact cells, although the catalytic rates are low.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1995 Feb
PMID:Induction of cytochrome P4501A1 by aryl hydrocarbon receptor agonists in porcine aorta endothelial cells in culture and cytochrome P4501A1 activity in intact cells. 787 38

The effects of subchronic mercuric acetate and of acute mercuric acetate and cadmium chloride administration to rat hepatic microsomal protein and total cytochrome P450, as well as on p-nitrophenol hydroxylase (CYP2E) and erythromycin N-demethylase (CYP3A) activities were examined. It was found that Hg2+ and Cd2+ intoxication resulted in a significant decrease of total cytochrome P450 content. Acute Hg2+ and Cd2+ exposure decreased microsomal protein level. These metals also reduced CYP2E1 activity, while they did not seem to alter CYP3A1-mediated drug metabolism. This effect on CYP2E1 may be connected to free radical generation during Hg2+ and Cd2+ intoxication. Investigation is in progress using more P450 markers for elucidation of the effect of Hg2+ and Cd2+ on P450 activities.
Res Commun Mol Pathol Pharmacol 1994 Jul
PMID:Influence of mercury and cadmium intoxication on hepatic microsomal CYP2E and CYP3A subfamilies. 795 96

Adult rats with two-thirds of the liver removed were administered diets supplemented with benzodiazepine drugs over a period of 10 days and the mass of organ regenerated or the liver increment ascertained. For a number of the drugs, liver regeneration was stimulated; the effect was more consistent and reproducible in the adult female. On the basis of the lower sensitivity of the male, such animals provided an approach toward rating the hepatotrophic efficacy of the agents and in relation to structure. According to the current classification, hepatotrophic activity was higher with lorazepam, loprazolam, oxazepam and chlordiazepoxide; intermediate with nitrazepam, temazepam, quazepam, halazepam and triazepam and lower with diazepam, clorazepate dipotassium, clobazam and alprazolam. More reproducible responses in terms of g wet and dry liver per 100 g body weight were obtained with sham-operated or intact males. The antagonist, flumazenil, fed at 0.080% was not effective as such nor modified the responses in admixture with several drugs in partially hepatectomized or intact males. In vivo hepatic microsomal changes in protein, cytochrome P-450 or the enzymes, aminopyrine demethylase and benzo[a]pyrene hydroxylase with the various series were not remarkable or sporadic. Among other factors, the liver incremental changes noted currently are dependent on the metabolic intermediate benzodiazepines of varying elimination half-lives which may be distinct from that of the parent drug coupled with the alterations induced by partial ablation of the organ in rats of either sex.
Res Commun Mol Pathol Pharmacol 1994 Jul
PMID:Hepatotrophic activity of benzodiazepine drugs in adult rats of either sex. 795 98

Isolates of Nectria haematococca (anamorph: Fusarium solani) are able to detoxify the pea phytoalexin pisatin through expression of pisatin demethylase (pda). This enzyme is a substrate-inducible cytochrome P450 monooxyenase that is encoded by the PDA gene family. In the current study, PDA1, a highly inducible PDA gene, was cloned and the 5' untranslated region was sequenced. The PDA mRNA levels were measured in pisatin-treated mycelium and found to increase by 20-fold over untreated control. Gel shift assays identified a 35-bp region, -514 to -480 bp relative to the first mRNA start site, that binds a factor found in extracts of pisatin-treated mycelium and absent in untreated mycelium. The function of the binding site in pisatin regulation of the PDA1 gene was tested in an in vivo competition assay by introduction of multiple ectopic copies of the binding site into N. haematococca through transformation. In such transformants, induction of pda activity by pisatin was delayed and reduced, consistent with the titration of a trans-acting factor which responds to pisatin. These results suggest the 35-bp region is functioning as a pisatin-responsive activator binding site for PDA1. Additional controls were characterized that act on PDA1 expression. Induction of pda by pisatin was suppressed by the addition of 0.8% Casamino Acids or 5% glucose to the suspended mycelium. A unique DNA binding factor was detected only in extracts from mycelia treated with the Casamino Acids that bind to the same 35-bp region of the PDA1 gene as the pisatin-responsive factor.
Mol Plant Microbe Interact
PMID:Characterization of the PDA1 promoter of Nectria haematococca and identification of a region that binds a pisatin-responsive DNA binding factor. 801 44

The effect of dietary n-3 deficiency on liver microsome enzymes activities and fatty acid composition was studied in adult (3 months old) and old rats (18 months old). At these two ages, deficient animals were refed with 18:3n-3 diet for 1 or 2 months and the recovery of these parameters was investigated. Cytochrome P 450 level was decreased by n-3 PUFA (Polyunsaturated fatty acid) deficiency. After refeeding, it returned to control values after 1 month. NADH-cytochrome b5 reductase activity was decreased, the activities of NADPH cytochrome c reductase, aminopyrine demethylase, aniline hydroxylase were also decreased, but in old rats they were increased by refeeding. N-3 PUFA deficiency caused a decrease of 18:2n-6 and 22:6n-3 and an increase in 20:4n-6, 22:5n-6 and 18:1n-9. After refeeding, in adult rats, the PUFA level remained lower; in old rats, the MUFA (Monounsaturated fatty acid) and PUFA levels returned to control values. Liver microsomal enzyme activities depend on the degree of unsaturation of fatty acids rather than the specific species of polyunsaturated fatty acids.
Biochem Mol Biol Int 1994 Apr
PMID:Comparison of liver microsome enzyme and fatty acid composition recovery in adult and old rats deficient in 18:3n-3 refed a diet containing 18:3n-3. 806 36

The influence of food restriction (FR) on the induction of liver microsomal cytochrome P-450 (P-450) was examined in rats, FR by 40% for 6 weeks caused increase in the levels of P-450, cytochrome b5 (b5), NADPH P-450 reductase, NADH b5 reductase, P-450 dependent testosterone 6 beta-, 16 alpha- and 16 beta-hydroxylases (P < 0.05). Treatment of 3-methylcholanthrene (MC) to food restricted rats (FR rats) induced more P-450, but phenobarbital (PB) induced it less. MC-inducible P-450 from FR rats did not increase its specific ethoxycoumarin O-deethylase activity but it increased testosterone 2 alpha-hydroxylase activity, and the maximum absorption of its CO complex was shifted from 448 nm to 450 nm. PB-inducible P-450 showed less increase in the activities of its specific benzphetamine N-demethylase and it rather significantly decreased testosterone 16 alpha-hydroxylase activity (P < 0.05). These results indicate that the drugs did not induce their unique types of P-450 in FR rats. Such alterations in P-450 induction in FR rats seem to be closely related to the level of P-450 and its related components enhanced by FR, and it could result in modulation of mixed function oxidase system.
Biochem Mol Biol Int 1994 Apr
PMID:Modulation of cytochrome P-450 induction by long-term food restriction in male rats. 806 38

The gene PDAT9 from the fungus Nectria haematococca encodes pisatin demethylase, an enzyme that detoxifies the phytoalexin pisatin, an antimicrobial compound produced by pea in response to infection by this plant pathogen. PDAT9 was found to contain an open reading frame (ORF) encoding 515 amino acids and four introns of 52-58 nucleotides each within its coding region. The amino acid sequence F-G-A-G-S-R-S-C-I-G, indicative of the "fifth ligand binding site" present in all cytochrome P450s, occurs as residues 446 to 455, confirming that PDAT9 is a cytochrome P450. The deduced amino acid sequence is distinct from all other reported cytochrome P-450s, and PDAT9 has been assigned to a new cytochrome P450 family, CYP57. A 1.3 kb SacI fragment of the PDAT9 ORF that lacked the fifth ligand binding site, hybridized to unique DNA fragments in N. haematococca isolates known to possess PDA genes that encode different whole cell phenotypes for pisatin demethylating activity. These genes were also tentatively identified as cytochrome P450s by the hybridization of the same fragments to separate subclones of PDAT9, one of which contained the fifth ligand sequence. That probe also hybridized to DNA other than that attributed to pisatin demethylase genes; these other DNAs are presumed to represent other cytochrome P450s.
Mol Gen Genet 1994 Jun 03
PMID:A gene from the fungal plant pathogen Nectria haematococca that encodes the phytoalexin-detoxifying enzyme pisatin demethylase defines a new cytochrome P450 family. 820 42


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