Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The isoform of cytochrome P450 that catalyzes the 12 alpha-hydroxylation of 7 alpha-hydroxy-4-cholesten-3-one, an intermediate in the conversion of cholesterol to cholic acid, was purified to homogeneity from rabbit liver microsomes. The extent of purification in the various steps was judged by an assay involving high performance liquid chromatography. The purified enzyme showed a single band on SDS-polyacrylamide gel electrophoresis (M(r) = 50,000). The NH2-terminal amino acid sequence is as follows: Val-Leu-Trp-Gly-Leu-Leu-Gly-Ala-Leu-Leu-Met-Val-Met-Val-Gly-, which is different from that of any other P450s so far reported. The specific content of the enzyme was 13.3 nmol of cytochrome P450/mg of protein. Upon reconstitution with NADPH-cytochrome P450 reductase and cytochrome b5, the P450 enzyme showed a high activity of 12 alpha-hydroxylation with a turnover number of 36.6 min-1 at 37 degrees C. The omission of either cytochrome P450 or NADPH-cytochrome P450 reductase resulted in complete loss of activity, and the omission of cytochrome b5 resulted in 40% loss of activity. Antibodies prepared from mouse inhibited the 12 alpha-hydroxylase activity of rabbit liver microsomes about 90% and that of the rat liver microsomes 50%. The enzyme activity was not inhibited by other antibodies raised against other forms of P450 that catalyze different monooxygenation reactions toward xenobiotics or endogenous substrates. Anti-cytochrome b5 antibody inhibited the activity 40%, suggesting the functional role of this protein, and anti-reductase inhibited the activity almost completely. The microsomal enzyme activity was markedly elevated by starvation or streptozotocin administration to the animals. However, an immunoblotting experiment showed no correlation between the enzyme activity and the amount of protein, suggesting that post-translational modification may occur.
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PMID:Purification and characterization of 7 alpha-hydroxy-4-cholesten-3-one 12 alpha-hydroxylase. 140 Apr 44

The possible roles of cytochrome P450 (P450) enzymes in the metabolic activation of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) by rat liver microsomes have been examined in a system containing the bacterial tester strain Salmonella typhimurium NM2009, a newly developed strain showing high O-acetyltransfer activities. The DNA-damaging activity could be determined by measuring expression of the umu gene in a plasmid containing the fused umuC-lacZ gene construct in the bacteria. The following lines of evidence support the view that both NDMA and NDEA are principally oxidized to reactive products by P450 2E1 in rat liver microsomes. First, NDMA and NDEA were activated by rat liver microsomes in a protein- and substrate-dependent manner and the former chemical was more active than the latter; both activities were induced in rats treated with P450 2E1 inducers such as ethanol, acetone and isoniazid and by starvation. Second, activation of NDMA and NDEA were both inhibited significantly by antibodies raised against rat P450 2E1 and by P450 2E1 inhibitors such as diethyldithiocarbamate and 4-methylpyrazole in rat liver microsomes. Finally, in reconstituted monooxygenase systems containing purified rat P450 enzymes, P450 2E1 gave the highest rates of the activation of both NDMA and NDEA; the addition of rabbit cytochrome b5 to the system caused about a 1.5-fold increase in both reactions. In separate experiments we also found that N-nitrosomethylacethoxymethylamine, a compound that reacts with DNA after ester cleavage, is more genotoxic in S.typhimurium NM2009 than in S.typhimurium NM2000, a strain that is defective in O-acetyltransferase activity. Part of the pathway involved in the activation of nitrosamines is suggested to be acetylation of alkyldiazohydroxides formed by P450 or acetylesterase, because the genotoxic activity of N-nitrosomethylacethoxymethylamine in S.typhimurium NM2009 could be inhibited by the O-acetyltransferase inhibitor pentachlorophenol. These results indicate that NDMA and NDEA are oxidized to gentoxoic products by rat liver microsomes and that a P450 2E1 enzyme plays a major role in the activation of these two potent carcinogens. The activation pathway of N-nitrosodialkylamines through acetylation by O-acetyltransferase has been proposed. This simple bacterial system for measuring genotoxicity should facilitate studies on the activation of N-nitroso alkylamines.
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PMID:Participation of rat liver cytochrome P450 2E1 in the activation of N-nitrosodimethylamine and N-nitrosodiethylamine to products genotoxic in an acetyltransferase-overexpressing Salmonella typhimurium strain (NM2009). 160 Jun 20

Hypertrehalosemic hormone (a carbohydrate-mobilizing neuroendocrine decapeptide) and starvation markedly increased levels of a cockroach (Blaberus discoidalis) fat body cytochrome P450 message. The gene represented by the cloned P450 cDNA has been named CYP4C1 (cytochrome P450 family 4, subfamily C, gene 1), a newly identified member of the ubiquitous cytochrome P450 monooxygenase gene superfamily. Blaberus CYP4C1 (511 amino acids, Mr = 58,485) has a hydrophobic NH2 terminus and a sequence near the COOH terminus that is homologous to the cysteine-containing heme-binding region definitive of cytochromes P450. The cockroach sequence is 32-36% identical to mammalian family 4A and 4B enzymes. It contains a 13-residue sequence characteristic of family 4 but not other P450s. This study suggests that CYP4C1 is hormonally regulated in association with energy substrate mobilization and supports the idea that family 4 is an old and widespread gene family.
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PMID:Cytochrome P450 family 4 in a cockroach: molecular cloning and regulation by regulation by hypertrehalosemic hormone. 203 94

The regulation of heme oxygenase activity in the developing neonate is essential to the control of bilirubin production as well as intracellular heme and hemoprotein metabolism. The coordinated activity of the microsomal enzymes, heme oxygenase and NADPH-cytochrome c (P450) reductase, and the cytosolic enzyme biliverdin reductase is responsible for the degradation of heme. The complete reaction sequence requires oxygen and NADPH, and produces bilirubin and carbon monoxide in equimolar amounts. Although heme oxygenase expresses a rather broad range of substrate affinities, the oxidative degradation of heme is exclusively alpha-specific. Heme oxygenase is found in several tissues, with significant activity levels in the liver, spleen, and erythropoeitic tissue. Heme oxygenase activity is inducible by heme and other metalloporphyrins, hormones, starvation, stress, toxins, and xenobiotics. Heme oxygenase induction is generally considered to be the result of an increased protein synthesis and gene transcription. This hypothesis is supported by recent studies of the heme oxygenase gene that identified inducer element binding sites responsive to metal administration, heat shock, and nutrient availability. In the developing fetus and neonate, hepatic heme oxygenase activity and mRNA levels are elevated above that of the adult. This suggests that the elevated heme catabolism observed in neonates may be associated with an increased transcription of the heme oxygenase gene. The apparent induction of hepatic heme oxygenase during the neonatal period is probably the result of tissue-specific and time-dependent transcriptional regulating factors including potentially hormones and heme. Several metalloporphyrins, such as the tin and zinc porphyrin complexes, inhibit heme oxygenase activity and thus have therapeutic potential for the treatment of neonatal jaundice. Recent studies suggest that the meso- and bis-glycol derivatives of these metalloporphyrins may be more potent inhibitors of heme oxygenase activity in vitro and in vivo than the protoporphyrin structures. As structural analogues of heme, however, these compounds may also have other less desirable effects on the regulation of heme and hemoprotein metabolism, particularly in the developing neonate.
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PMID:Developmental biology of heme oxygenase. 219 31

The effects of starvation on rat renal cytochrome P-450s were studied. The content of spectrally measured cytochrome P-450 in the renal microsomes of male rats increased 2-fold with 72 h starvation, but cytochrome b5 and NADPH-cytochrome P-450 reductase were not induced. 7-Ethoxycoumarin O-dealkylation and aniline hydroxylation activities of the renal microsomes of control male rats were very low but were induced 2.5-3-fold by 72 h starvation. Aminopyrine N-demethylation and lauric acid hydroxylation activities were induced 1.5-2-fold by 72 h starvation. The changes in catalytic activities suggested that the contents of individual cytochrome P-450s in the renal microsomes were altered by starvation. The contents of some cytochrome P-450s were measured by Western blotting. P450 DM (P450IIE1), a typical form of cytochrome P-450 induced by starvation in rat liver, was barely detected in rat kidney and was induced 2-fold by 72 h starvation. P450 K-5, a typical renal cytochrome P-450 and lauric acid hydroxylase, accounted for 81% of the spectrally measured cytochrome P-450 in the renal microsomes of control male rats and was induced 2-fold by 72 h starvation. P450 K-5 was not induced in rat kidney by treatment with chemicals such as acetone or clofibrate. The renal microsomes of male rats contained 6-times as much P450 K-5 as those of female rats. These results suggest that P450 K-5 is regulated by an endocrine factor.
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PMID:Induction and regulation of cytochrome P450 K-5 (lauric acid hydroxylase) in rat renal microsomes by starvation. 222 22

Previous data indicate that the CYP2E1 gene is transcriptionally activated after birth, but that the expression of ethanol-inducible CYP2E1 protein, hereafter, is regulated by post-transcriptional mechanisms. The constitutive expression of CYP2E1 protein is restricted to the perivenous region of the liver lobule. Here we present results from in situ hybridization and run off experiments indicating that this regioselectivity is caused by a higher rate of gene transcription in the perivenous hepatocytes. We also show that transcription of the CYP2E1 gene is activated by starvation, indicating that also this P450 gene is under transcriptional control under certain physiological conditions.
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PMID:Transcriptional control of CYP2E1 in the perivenous liver region and during starvation. 225 23

The effects of starvation on the composition of 12 different cytochrome P450s in rat hepatic microsomes were studied with a specific antibody. Changes in the metabolic activity of the microsomes were studied at the same time. P450 DM (P450j) was induced 2.5-fold by a 48-h starvation and its increase reflected the increase of metabolic activity of hepatic microsomes toward aniline, 7-ethoxycoumarin, and N-nitrosodimethylamine. P450 K-5, the major renal cytochrome P450 in untreated male rat, was also induced 2.5-fold by a 48-h starvation. P450 UT-2 (P450h) and P450 UT-5 (P450g), typical male-specific forms, decreased with starvation. P450 UT-2 had high testosterone 2 alpha- and 16 alpha-hydroxylation activities. These activities of hepatic microsomes were reduced with the decrease in P450 UT-2. P450 PB-1, testosterone 6 beta-hydroxylase, was increased time-dependently by starvation. P450 UT-4 (RLM2), a minor male-specific form, was not changed by starvation. P450 PB-2 (P450k), present in both sexes, was changed little by starvation. P450 PB-4 (P450b) and P450 PB-5 (P450e) are strongly induced in rat liver by phenobarbital in coordinate fashion. Starvation increased P450 PB-4 12-fold but reduced P450 PB-5 to 22% of the control level. P450 MC-1 (P450d) was decreased by starvation. P450 MC-5 (P450c) was barely detected in control rats and was not changed by starvation. P450 IF-3 (P450a), rich in immature rats, was increased by starvation, accompanied by an increase in testosterone 7 alpha-hydroxylation activity in the hepatic microsomes. We further investigated whether new cytochrome P450s appeared upon starvation by comparison of chromatographic profiles of cytochrome P450 from starved rats with those of cytochrome P450 from control rats using HPLC. Three new cytochrome P450s were detected in the starved rats. These cytochrome P450s were purified to homogeneity. One of them was P450 DM, judging from spectral properties, catalytic activity, and the NH2-terminal sequence. The two other forms were designated P450 3b and 4b. The minimum molecular weights of P450 3b and 4b were 53,000 and 52,000, respectively, and their CO-reduced absorption maxima were at 449 and 452 nm, respectively. P450 3b metabolized aminopyrine, N-nitrosodimethylamine, 7-ethoxycoumarin, and lauric acid, but with low activity. P450 4b was efficient in lauric acid omega- and (omega-1)-hydroxylation only. The spectral properties, catalytic activity, peptide map, and NH2-terminal sequence of P450 4b agreed with those of P450 K-5. P450 3b was a new cytochrome P450, judged by these criteria.
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PMID:Changes in the amount of cytochrome P450s in rat hepatic microsomes with starvation. 232 56

2,4,5,2',4',5'-hexachlorobiphenyl (HCB) induces hepatic microsomal cytochromes P450 with a similar selectivity for responsive genes to phenobarbital (PB). CYP2Bl, CYP2B2, CYP2C6, CYP3Al, and CYP2Al each showed large strain differences in induction by HCB Fisher F344 >> Wistar Furth (WF) that were much more evident in female rats, paralleling previous observations with PB. These five P450s and epoxide hydrolase were, however, induced more effectively by HCB than by PB and strain differences were even larger. With HCB, strain differences in male rats were much more apparent than with PB. This change was not due to the greater HCB induction since a 2-fold lower induction was maintained even with a 10-fold lower dose of HCB. The sex and strain differences were seen both by immunoblot analysis and by form-selective enzyme activity assays. induction of CYP2B1, CYP2B2, and CYP3A1 by HCB was decreased 3-fold when starvation during the final 24 hr was replaced by continuous feeding. This effect was similar in each strain and therefore independent of the regulatory processes associated with the differential suppression of induction in WF rats. This modulation of induction by feeding was also seen with PB which caused only a 30% lowering of induction in continuously fed F344 rats. A 52-kDa microsomal protein (p52) was prominently induced by both HCB and PB after starvation, while minor induction of a 50-kDa microsomal protein (p50) also occurred after the same treatment. Furthermore, a 100-kDa microsomal protein (p100) was induced by HCB but not by PB and only in rats that were continuously fed. These results suggest that the induction of multiple forms of P450 following HCB treatment functions through the same PB-stimulated pathway that shows a strain-dependent endocrine (GH/T3/testosterone)-sensitive suppression mechanism. The induction of p5O, p52, and plOO by HCB suggests the presence of at least two additional hepatic response mechanisms for HCB.
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PMID:The regulation by gender, strain, dose, and feeding status of the induction of multiple forms of cytochrome P450 isozymes in rat hepatic microsomes by 2,4,5,2',4',5'-hexachlorobiphenyl. 868 6

The function of ovarian interstitial cells has been largely addressed using rat theca-interstitial cell culture. However, this preparation is primarily enriched with theca and secondary interstitial cells, which make it difficult to address selectively the function of the primary interstitial cells. We have developed an in vitro culture of hamster ovarian primary interstitial cells. Cells were isolated from postnatal hamster ovaries by collagenase digestion and purified over a Percoll gradient. The preparation contained 90% viable, pure interstitial cells, which anchored to the plastic and glass culture surface in the presence of fetal bovine serum. Cell proliferation was noted in the presence of serum dosages higher than 0.2%; however, reduction of serum concentration to 0.1% or complete serum starvation did not affect cell viability but almost completely abolished cell proliferation as determined by [3H]thymidine incorporation, labeling index, and DNA content of the culture. All cells exhibited active 3beta-hydroxysteroid dehydrogenase and P450 side chain cleavage immunoreactivity, which corresponded to basal progesterone and androstenedione accumulation. Replacement of serum to starving cells resulted in the induction of the "S" phase and "M" phase specific cyclins, and resumption of cell proliferation. Our results indicate that hamster primary interstitial cells can be cultured in vitro as a monolayer, and the anchorage and proliferation of these cells depend on serum supplement; however, a viable monolayer can be maintained for several days without serum. This model will be useful for addressing the mechanisms of differentiation of ovarian interstitial cells.
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PMID:In vitro culture of hamster ovarian primary interstitial cells: effect of serum. 978 Mar 26

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.
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PMID:Structure, evolution, and liver-specific expression of sterol 12alpha-hydroxylase P450 (CYP8B). 1039 16


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