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)

Measurement of the effect of drugs on the in vivo rates of synthesis of rabbit liver organelle bound proteins were measured following individual treatments with the inducers phenobarbital, 3-methylcholanthrene and PCB (a mixture of polychlorinated biphenyls) and the inhibitors, cycloheximide, aflatoxin B1, chloramphenicol and actinomycin D. Following their isolation from a homogenate containing the combined livers of 14C-leucine injected experimental animals and 3H-leucine injected control animals, purified fractions of the following proteins were prepared: microsomal cytochrome b5, cytochrome P-450, NADH-cytochrome b5 reductase, NADPH-cytochrome P-450 reductase and proteolipids, outer mitochondrial membrane cytochrome b5, NADH-cytochrome b5 reductase and proteolipids, inner mitochondrial membrane cytochrome c, NADH dehydrogenase and proteolipids, intermitochondrial membrane cytochrome b5 and circulating serum albumin. The effect of a drug was examined by measuring the 14C/3H ratio of leucine incorporation of each fraction; ratios which differed markedly from a control value of 1 represented actual changes in the relative rates of protein synthesis. Increased rates of synthesis of cytochrome P-450 and its reductase, intermitochondrial membrane cytochrome b5 and all three proteolipid fractions resulted from each inducer treatment. Treatments with 3-methylcholanthrene and PCB also increased the rate of synthesis of cytochrome b5 and its reductase in both the microsome and outer mitochondrial membrane. In addition, the PCB treatment increased the rates of synthesis of cytochrome c and NADH-dehydrogenase. The rates of synthesis of cytochromes, reductases and of circulating serum albumin were inhibited following treatments with cycloheximide, aflatoxin B1 and actinomycin D. Actinomycin D appeared to inhibit the release of newly synthesized albumin into the bloodstream while chloramphenicol treatment appeared to inhibit the incorporation of cytochrome c into the mitochondria. After 20 hours of treatment with inhibitors, the inhibitory effect of actinomycin D and cycloheximide were still apparent while the rates of protein synt;esis in chloramphenicol and aflatoxin B1 treated animals increased to levels above the controls. The incorporation of radioactively labeled leucine into the proteolipids of the microsomal, and the outer and inner mitochondrial membranes were inhibited following the treatment with actinomycin D and stimulated following the treatment with cycloheximide.
Mol Cell Biochem 1979 Dec 14
PMID:Effect of a single dose of inducers and inhibitors on the rate of synthesis of cytochromes and reductases in liver organelles. 11 59

Pregnenolone and progesterone concentrated in the microsomal fraction of cryptorchid mouse testis compared with mitochondria and cytosol. While the concentrating mechanisms had high capacity and low association constants the effect did not seem to be due to nonspecific solubility in the lipid components since 17-hydroxyprogesterone, dehydroepiandrosterone, androstenedione and testosterone did not show differential concentration. Also digestion with phospholipases A2 and C to the point where most of the phospholipids were specifically split, only lowered the differential binding of pregnenolone and progesterone by less than half. Trypsin had a greater effect, short digestion at 0 degrees C lowering the specific binding to 35-40% and decreasing the steroid dehydrogenases to a similar extent. The members of the mixed function oxidase system in the testis microsomes were particularly sensitive to trypsin, cytochrome P-450 and, as a consequence, 17alpha-hydroxylase and 17, 20-lyase activity being eliminated under tha same conditions while liver microsomal cytochrome P-450 was hardly affected. Bonds split by trypsin seem to play a more important role in the hydroxylase activity of testis microsomes than in the hepatic system.
Mol Cell Endocrinol 1976 Dec
PMID:Effects of trypsin and phospholipases A2 and C on enzyme organization in testis microsomes. 18 6

Addition of cholesterol to rat adrenal mitochondria resulted in a stimulation of pregnenolone synthesis. The slow step of the mitochondrial cholesterol side-chain cleavage reaction could be the interaction of the sterol with cytochrome P-450. The rate of cholesterol binding to this enzyme as observed spectroscopically correlated with the equilibration period (20 min) of the mitochondria and exogenous cholesterol required for maximal rates of pregnenolone synthesis. It is suggested that translocation of cholesterol between different sterol pools occurs within the mitochondria. Potential intracellular effectors that could be of importance in the movement or regulation of mitochondrial cholesterol include bivalent metallic ions, prostaglandins, cyclic nucleotides, polyamines and polylysine. Of the effectors studied, only calcium ions and polylysine markedly stimulated pregnenolone synthesis. These effectors might stimulate steroidogenesis by lateral displacement of cholesterol in the mitochondrial membrane into a compartment easily accessible to the cholesterol side-chain cleavage enzyme complex.
Mol Cell Endocrinol 1978 Apr
PMID:Regulation of cholesterol metabolism in rat adrenal mitochondria. 20 6

All organisms possess a number of genetically regulated mechanisms in order to cope with rapid adverse changes in the environment. The two systems which appear to respond to a seemingly endless array of chemical specificities are the immune response and the induction of drug-metabolizing enzymes. Similarities and differences between the immunoglobulin and the cytochrome P-450-mediated monooxygenase systems are described. DNA insertion sequences, plasmid "transposons," maize "controlling elements," gene duplication, intervening sequences, and high-frequency intergenic recombination are all discussed as possible methods by which organisms can "adapt" quickly to a new selective pressure. If the regulation of P-450 induction resembles in any way the other methods by which pro- and eukaryotes cope genetically with numerous forms of environmental adversity, therefore, it is very likely that mammalian tissues contain hundreds, if not thousands, of inducible forms of P-450.
Mol Cell Biochem 1979 Sep 28
PMID:Multiple forms of inducible drug-metabolizing enzymes: a reasonable mechanism by which any organism can cope with adversity. 22 4

Rat kidney microsomes have been found to catalyze the hydroxylation of medium-chained fatty acids to the omega- and (omego-1)-hydroxy derivatives. This reaction, which requires NADPH and molecular oxygen, is a function of monooxygenase system present in the kidney microsomes, containing NADPH-cytochrome c reductase and cytochrome P-450K. NADH is about half as effective as an electron donor as NADPH and there is an additive effect in the presence of both nucleotides. Cytochrome P-450K absorbs light maximally at 452-3 nm, when it is reduced and bound to carbon monoxide. The extinction coefficient of this complex is 91 mM(-1) cm(-1). Electrons from NADPH are transferred to cytochrome P-450K via the NADPH-cytochrome c reductase. The reduction rate of cytochrome P-450K is stimulated by added fatty acids and the reduction kinetics reveal the presence of endogenous substrates bound to cytochrome P-450K. Both cytochrome P-450K concentration and fatty acid hydroxylation activity in kidney microsomes are increased by starvation. On the other hand, phenobarbital treatment of the rats has no effect on either the hemoprotein or the overall hydroxylation reaction and 3,4-benzpyrene administration induces a new species of cytochrome P-450K not involved in fatty acid hydroxylation. Cytochrome P-450K shows, in contrast to liver P-450, high substrate specificity. The only substances forming enzyme-substrate complexes with cytochrome P-450K are the medium-chained fatty acids and certain derivatives of these acids. The chemical requirements for substrate binding include a carbon chain of medium length and at the end of the chain a carbonyl group and a free electron pair on a neighbouring atom. The distance between the binding site for the carbonyl group and the active oxygen is suggested to be in the order of 16 A. This distance fixes the ratio of omega- and (omega-1)-hydroxylated products formed from a certain fatty acid by the single species of cytochrome P-450K involved. The membrane microenvironment seems also to be of importance for the substrate specificity of cytochrome P-450K, since removal of the cytochrome from the membrane lowers its binding specificity to some extent. A comparison between the liver and kidney cytochrome P-450 systems suggests that the kidney cytochrome P-450K system is specialized for fatty acid hydroxylation.
Mol Cell Biochem 1975 Aug 30
PMID:Fatty acid hydroxylation in rat kidney cortex microsomes. 24 Oct 11

Ecdysone 20-monooxygenase, the enzyme system that hydroxylates ecdysone at C-20 of the side-chain to form ecdysterone, has been characterized in the fat body of early last instar larvae of the tobacco hornworm, Manduca sexta, using a radioenzymological assay. Ecdysterone was demonstrated to be the product of the enzyme system by high-pressure liquid chromatography, gas-liquid chromatography and mass spectrometry. Differential centrifugation, sucrose-gradient centrifugation, electron microscopy and organelle-marker enzyme analysis revealed that ecdysone 20-monooxygenase activity is associated with the mitochondria. The enzymatic properties of ecdysone 20-monooxygenase are that it is most active in a 0.05 M phosphate buffer, is inhibited by Mg2+ and exhibits pH and temperature optima at 7.5 and 30 degrees C, respectively. The enzyme complex has an apparent Km for ecdysone of 1.60 x 10(-7) M and is competitively inhibited by its product, ecdysterone, with an apparent Ki of 2.72 x 10(-5) M. The cytochrome P-450 nature of this insect steroid hydroxylase was initially suggested by its obligate requirement for NADPH and its inhibition by carbon monoxide, p-chloromercuribenzoate, metyrapone and p-aminoglutethimide but not by cyanide. Difference spectroscopy revealed the presence of cytochrome P-450 in the fat-body mitochondrial fraction. A photochemical action spectrum of ecdysone 20-monooxygenase activity confirmed the involvement of cytochrome P-450 in this monooxygenase system.
Mol Cell Endocrinol 1979 Sep
PMID:Ecdysone 20-monooxygenase: characterization of an insect cytochrome p-450 dependent steroid hydroxylase. 48 26

1. The effect of feeding with a diet containing 0.2% (w/w) hexachlorobenzene on hepatic and urinary porphyrins and hepatic cytochrome P-450 was studied at various time intervals in female Wistar rats. 2. Hexachlorobenzene administration for 45 days resulted in the development of porphyria in rats, which biochemically closely resembles symptomatic porphyria in humans, with elevation of urinary uroporphyrin excretion, hepatic uroporphyrin content, and hepatic cytochrome P-450 content, in addition to appearance of porphyrins of the isocoproporphyrin (P1) series in the faeces. 3. Spectral studies of the induced hepatic cytochrone P-450 at 45 days with carbon monoxide and ethyl isocyanide as ligands indicated the presence of a greater admixture of a haemoprotein distinct from cytochrome P-450. 4. Study in vitro of the kinetics of two reactions, namely aminopyrine N-demethylation and 3,4-benzpyrene hydroxylation, catalysed by the hepatic microsomal cytochrom P-450-dependent enzyme system, suggested that hexachlorobenzene induced a form of cytochrome P-450-dependent enzyme system, suggested that hexachlorobenzene induced a form of cytochrome P-450 with different catalytic properties from those of forms induced by either phenobarbital or 3-methylcholanthrene.
Clin Sci Mol Med 1978 Nov
PMID:The nature of hepatic cytochrone P-450 induced in hexachlorobenzene-fed rats. 71 99

Transplantable rat liver tumors 5123 t.c., 7288 ct.c., 5123 t.c.(H) and the Novikoff hepatoma have active mixed function oxidase systems capable of metabolizing a variety of drug and polycyclic hydrocarbon substrates. The tumor drug metabolism systems are at best 20% as active as rat liver. The tumor drug metabolism activities are induced by pretreatment with phenobarbital or beta-naphthoflavone and can be inhibited with specific inhibitors such as carbon monoxide or 7,8-benzoflavone. Tumor drug metabolism systems appear to consist of cytochrome P-450 and cytochrome P-450 reductase. The properties of the two protein components from tumors are highly similar to the corresponding components of the liver drug metabolism system. Cytochrome P-450 reductase has been at least partially purified from the Novikoff hepatoma and hepatoma 5123 t.c.(H). The kinetic and physical properties of the tumor reductases are similar to those of the liver reductase except that the Km of hepatoma 5123 t.c.(H) reductase, but not of the Novikoff hepatoma reductase for NADPH, is elevated an order of magnitude over the Km of the liver reductase. The mechanism for the interaction of electron donor and electron acceptor with liver or tumor reductases seems to be a sequential reaction mechanism. Experiments on the NADP-inhibition of the interaction of NADPH and cytochrome c with liver reductase indicate that NADP is competitive with NADPH and noncompetitive with cytochrome c. This result is consistent with the postulate of a sequential reaction for NADPH-cytochrome P-450 reductases of liver and tumors. These data support the conclusions that an active drug metabolism system is present in liver tumors and that the tumor systems are constituted like the liver system.
Mol Cell Biochem 1978 Dec 22
PMID:The drug metabolism systems of liver and liver tumors: a comparison of activities and characteristics. 74 99

1. Mitochondria and microsomal fractions have been isolated from liver biopsies from patients with alcoholic cirrhosis, cryptogenic cirrhosis or chronic aggressive hepatitis. 2. Cirrhotic livers yieled fewer mitochondria than normal liver. 3. The most significant change was a decrease in mitochondrial respiratory control. Cirrhotic microsomal fractions had a 50% diminution in cytochrome b5 and cytochrome P-450 content. 4. The two patients with chronic aggressive hepatitis showed similar mitochondrial and microsomal changes.
Clin Sci Mol Med 1977 Jun
PMID:Mitochondrial functions and content of microsomal and mitochondrial cytochromes in human cirrhosis. 88 31

Two approaches may be used to study the function of cytochrome P-450 in insects: (a) an evaluation of the spectral and catalytic properties of the hemoprotein while associated with microsomal membranes; (b) the solubilization, resolution and purification of the microsomal mixed-function oxidase system. The first approach has provided some understanding of the biochemical factors involved in the metabolism of a variety of compounds, including pesticides, drugs, hormones and many other xenobiotics. However, solubilization of the monooxygenase system allows the study of each of its components individually, providing a better insight on the sequence of events leading to the hydroxylation of a substrate, the type of intermediates formed, and the rate-limiting step(s). This report discusses studies carried out with the monooxygenase system associated with microsomal membranes, as well as procedures to solubilize and partially purify its components from housefly microsomes. The latter involves solubilization with either Triton X-100 or sodium cholate, followed by either ammonium sulfate fractionation, Sephadex G-200, DEAE-Sephadex A-50 column chromatography or by omega-amino-n-octyl-Sepharose 4B affinity chromatography. These procedures have shown that two cytochrome P-450 species (P-450 and P-450I) are present in microsomes isolated from a resistant housefly strain. Induction with either naphthalene or phenobarbital appears to increase cytochrome P-450I preferentially.
Mol Cell Biochem 1976 Jul 30
PMID:Insect cytochrome P-450. 96 61


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