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1.
Treatment of uninduced, phenobarbital and 3-methylcholanthrene induced rats with fluroxene and allyl-iso-propylacetamide decreased hepatic microsomal cytochrome P-450 and equivalently decreased microsomal heme, aniline binding and p-nitroanisole demethylase. In contrast, ethylmorpnine demethylase, benzpyrene-3-hydroxylase and ethoxyresofurin deethylase were not in all cases decreased in proportion to the loss of cytochrome P-450. After phenobarbital induction fluroxene and allyl-iso-propylacetamide degrade multiple forms of cytochrome P-450, but degrade in the greatest amounts the form(s) of cytochrome P-450 inducible by phenobarbital. After 3-methylcholanthrene induction fluroxene preferentially degrades cytochrome P-448, while allyl-iso-propylacetamide is relatively specific for the form(s) of cytochrome P-450 inducible by phenobarbital.  相似文献   

2.
The degradation of cytochrome P-450 heme in the liver has been studied by a new approach. In rats, hepatic heme was labeled by administration of a tracer pulse of [5-14C]δ-aminolevulinic acid (ALA), and its degradation was analyzed in terms of labeled carbon monoxide (14CO) excretion, which is a specific degradation product of the labeled heme. Within minutes after administration of [5-14C]ALA, 14CO was detectable and increased after 2 h to an “early peak,” reflecting the elimination of labeled heme from a rapidly turning over pool in the liver. Beyond the early peak, the rate of 14CO production decreased in a log-linear manner, consistent with the degradation of heme in stable hepatic hemoproteins. From the rate at which 14CO production declined during this phase, from the predominant labeling of cytochrome P-450 heme by the administered [5-14C]ALA and from the known turnover characteristics of this hemoprotein in the liver, it could be inferred that production of 14CO—between 16 and 30 h after administration of labeled ALA—largely reflected degradation of cytochrome P-450 heme. This approach, which permits serial measurements in a single animal, was used to study the effect on cytochrome P-450 heme of administered heme or endotoxin, both of which are potent stimulators of hepatic heme oxygenase activity. Both of these substances caused marked acceleration of the degradation of cytochrome P-450 heme, the effect occurring over the same dose range as that for stimulation of hepatic heme oxygenase. The findings suggest that stimulation of this enzyme activity in the liver is closely related to the rate of degradation of cytochrome P-450 heme.  相似文献   

3.
Hepatic heme oxygenase activity was significantly altered in vitamin C-deficient guinea pigs. It was increased two-fold after 14 days and was decreased by 20% after 21 days of deprivation of the vitamin (always in comparison with the control value). The apparent Km of the enzyme was also altered in the course of ascorbic acid deficiency. The data of hepatic heme oxygenase activity correspond to previous results on the metabolism of hepatic cytochrome P-450 in different stages of ascorbic acid deprivation. Splenic heme oxygenase activity decreased progressively arriving at 50% of the control value after 21 days of vitamin C omission, its apparent Km remained unaltered.  相似文献   

4.
Studies were carried out to compare the effects of several physiological variables on adrenal microsomal drug (ethylmorphine demethylation) and steroid (21-hydroxylation) metabolism in guinea pigs. The rate of adrenal ethylmorphine (EM) metabolism increased with maturation in males but not females, resulting in a sex difference (M > F) in adrenal enzyme activity in adult guinea pigs. Twenty-one hydroxylase activity, in contrast, was similar in adrenals from males and females. The concentration of adrenal microsomal cytochrome P-450 was unaffected by age or sex. ACTH administration decreased adrenal EM demethylase activity but did not affect 21-hydroxylation. Testosterone, when given to female guinea pigs, increased the rate of EM metabolism and decreased 21-hydroxylase activity. Various compounds known to interact with adrenal microsomal cytochrome P-450 had divergent effects on EM metabolism and 21-hydroxylation invitro. Prostaglandins E1 and F, spironolactone, and canrenone inhibited EM demethylation but not 21-hydroxylation. Simple aromatic hydrocarbons (benzene, toluene), in contrast, inhibited 21-hydroxylation but did not affect EM metabolism. The results indicate that adrenal drug and steroid metabolism are independently regulated and that different terminal oxidases (cytochrome P-450) are probably involved in adrenal 21-hydroxylation and EM demethylation.  相似文献   

5.
The effect of pretreatment with phenobarbitone, rifampicin, β-naphthoflavone, antipyrine and spironolactone on the irreversible binding of ethynyloestradiol to guinea pig liver microsomes has been examined and the corresponding changes in microsomal P-450 content and cytochrome c reductase activity measured. Rifampicin produced the greatest increase (220%) in irreversible binding while phenobarbitone produced the greatest increase in both microsomal P-450 content (172%) and cytochrome c reductase activity (210%). There was no correlation of irreversible binding with either microsomal P-450 content or with cytochrome c reductase activity.  相似文献   

6.
Administration of allylisopropylacetamide (AIA) produces a dose-related destruction of the heme moiety of the phenobarbital-induced subspecies of hepatic cytochrome P-450. This results in delayed plasma disappearance of the inactivating agent as determined after injection of [14C]AIA. In phenobarbital-pretreated rats, infusion of heme reversed this AIA-mediated impairment of the plasma disappearance of [14C]AIA. In the absence of phenobarbital pretreatment, cytochrome P-450 destruction by AIA was minimal and heme infusion failed to enhance plasma disappearance of [14C]AIA. Since exogenously administered heme is incorporated into hepatic cytochrome P-450 in vivo, these observations suggest that the infused heme restored the functional capacity of the phenobarbital-induced mixed function oxidase system by substituting for the prosthetic heme moiety destroyed by AIA. Heme infusion is a potentially useful therapeutic modality for enhancing drug biotransformation after intoxication with compounds that inactivate cytochrome P-450.  相似文献   

7.
In the presence of hepatic microsomes, vinyl chloride produces a ‘type I’ difference spectrum and stimulates carbon monoxide inhibitable NADPH consumption. A comparison of the binding and Michaelis parameters for the interaction of vinyl chloride with uninduced, phenobarbital and 3-methylcholanthrene induced microsomes indicates that the binding and metabolism of vinyl chloride is catalyzed by more than one type P-450 cytochrome, but predominantly by cytochrome P-450. Metabolites of vinyl chloride from this enzyme system decrease the levels of cytochrome P-450 and microsomal heme, but not cytochrome b5 or NADPH-cytochrome c reductase in vitro.  相似文献   

8.
Cytochrome P-450 was purified from phenobarbital-treated guinea pigs to a specific content of 19.8 nmoles per mg of protein, and was free of cytochrome b5 and NADPH-cytochrome c reductase. The purified cytochrome P-450 gave a single protein band on sodium dodecylsulfate-polyacrylamide gel electrophoresis, and an apparent molecular weight of about 49,000 was estimated. Benzphetamine N-demethylation activity could be reconstituted by mixing the purified cytochrome, NADPH-cytochrome c reductase and phosphatidylcholine.  相似文献   

9.
Treatment of guinea pigs on adequate ascorbic acid (AA) with 20-methylcholanthrene (MCA) and phenobarbital (PB) significantly increased hepatic arylhydrocarbon hydroxylase (AHH), cytochrome P-450 and cytochrome-b5 activities. In lungs, only MCA treatment significantly enhanced the activities of AHH, cytochrome P-450 and cytochrome b5. In animals on excessive doses of AA, there was inhibition of hepatic AHH, cytochrome P-450 and cytochrome b5 levels by treatment with these xenobiotics. Also, inhibition was observed in pulmonary AHH and cytochrome P-450 levels. The relevance of these observations in excessive AA-fed guinea pigs to carcinogenesis requires further extensive investigations.  相似文献   

10.
J T Stevens 《Life sciences》1974,14(11):2215-2229
Parathion, malathion and their oxygenated analogs bind to the reduced form of cytochrome P-450 from rats and mice producing spectra with a maximum at 421 nm and a minimum at 450 nm. Determinations of microsomal heme suggest that the Soret at 421 nm is not associated with conversion of cytochrome P-450 to cytochrome P-420. In vivo pretreatment with C14-parathion indicates that this insecticide covalently binds to mouse hepatic microsomal protein. These findings suggest that the mechanism by which these insecticides and their analogs inhibit hepatic microsomal metabolism is identical to their mode of inhibiting esterases, that is, covalent binding to catalytic site.  相似文献   

11.
Treatment with fluroxene or allyl-iso-propylacetamide of rats induced for elevated levels of cytochromes P-450 results in markedly decreased levels of hepatic microsomal cytochromes P-450 and heme as determined by spectral assay but in unchanged levels of cytochromes P-450 as determined by SDS gel electrophoresis. Since SDS gel electrophoresis does not detect changes in the heme of cytochromes P-450, it is concluded that fluroxene and AIA do not chemically degrade the apoproteins of cytochromes P-450.  相似文献   

12.
Human exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can result in hirsutism and chloracne, symptoms that suggest an alteration in endocrine regulation. Consequently, the effect of TCDD on guinea pig testicular cytochrome P-450 has been investigated. Twelve hours after a single, oral dose of TCDD (1 μg/kg), testicular microsomal cytochrome P-450 content was depressed by approximately 36%. Microsomal cytochrome P-450 content reached a maximal depression at approximately 1 day (52% of control) and remained at this level for 9 days. No appreciable alterations of testicular microsomal heme levels or activity of testicular δ-aminolevulinic acid (ALA) synthetase were observed.  相似文献   

13.
D Kupfer  J Navarro 《Life sciences》1976,18(5):507-513
This study demonstrates the metabolic transformation of prostaglandin A1 (PGA1) by guinea pig and rat liver microsomes. The transformation, which required NADPH and oxygen, yielded polar (presumably hydroxylated) products. Incubations with guinea pig liver microsomes yielded one zone of product on tlc, whereas rat liver microsomes produced two discernable metabolic zones. It was demonstrated that PGA1 metabolism in the guinea pig and the rat was inhibited by the addition of SKF-525A, metyrapone, carbon monoxide and cytochrome C; nicotinamide (10 mM) inhibited only the guinea pig system. These findings indicate that the enzymatic activity responsible for PGA1 metabolism is composed of a typical cytochrome P-450 monooxygenase system.  相似文献   

14.
Cytochrome P-450 LM2 was reconstituted by the cholate-dialysis method into vesicles containing a mixture of either phosphatidylcholine or phosphatidylethanolamine with up to 50 mol% of phosphatidic acid. Phase transition curves in the presence or absence of cytochrome P-450 were obtained from electron paramagnetic resonance experiments by measuring the partitioning of 2,2,6,6-tetramethylpiperidine-1-oxyl. Protein-free phospholipid vesicles exhibit a phase separation into domains of gel phase enriched in phosphatidic acid in a surrounding fluid matrix containing mainly phosphatidylcholine. The phase transition of the phosphatidic acid domains disappeared following incorporation of cytochrome P-450 into the bilayers. In contrast, in vesicles containing mixtures of egg-phosphatidic acid and dimyristoyl phosphatidylcholine, the phase transition of the domains enriched in dimyristoyl phosphatidylcholine was less sharp than in the corresponding vesicles containing cytochrome P-450. The results of both of these experiments could be explained by a redistribution of the mol fraction of the two phospholipids in the gel phase due to preferential binding of the egg-phosphatidic acid to the cytochrome P-450. For comparison, incorporation of cytochrome P-450 into uncharged vesicles of dimyristoyl phosphatidylcholine and egg-phosphatidylethanolamine did not alter the  相似文献   

15.
Cytochrome P-450-dependent monooxygenase activities and cytochrome P-450 levels were depressed in hepatic microsomes from rats treated with 12 interferon inducing agents of various types: small molecules (e.g. tilorone), an RNA virus (Mengo), a fungal mycophage (statolon), liver RNA, a synthetic double-stranded polynucleotide (poly rI · poly rC), a bacterial lipopolysaccharide (E.coli endotoxin) and an attenuated bacteria (B.pertussis vaccine). The results suggest that the depression of hepatic cytochrome P-450-dependent monooxygenase systems may be a general property of interferon inducing agents.  相似文献   

16.
Limitations on the determination of the concentration of the major phenobarbital inducible form of cytochrome P-450 (P-450b) in hepatic microsomes by the metyrapone assay of Luu-The et al. (1) are reported. Compounds which bind to the Type I, II and IR binding sites, or convert cytochrome P-450 to P-420, decrease the apparent concentration of cytochrome P-450b by 20 to 100% in hepatic microsomes from untreated and pregnenolone-16α-carbonitrile or phenobarbital treated rats. It is calculated that errors of greater ca. 40% in the concentration of cytochrome P-450b can arise in the presence of appreciable quantities of the major pregnenolone-16α-carbonitrile or polycyclic hydrocarbon inducible forms of cytochrome P-450.  相似文献   

17.
When Cd (3.58 mg CdCl2·H2O/kg, ip) was administered to male guinea pigs 72 h prior to sacrifice, the metal significantly inhibited the aniline 4-hydroxylase (AH) (16%), ethylmorphoneN-demethylase (EMND) (26%), and aminopyrineN-demethylase (AMND) (18%) activities and cytochrome P-450 (12%) and cytochrome b5 (10%) levels. Cd did not alter the hepatic microsomal heme level. Cd, however, significantly increased the hepatic microsomalp-nitroanisoleO-demethylase (p-NAOD) (53%) activity. When Ni (59.5 mg NiCl2·6H2O/kg, sc) was administered to the guinea pigs 16 h prior to sacrifice, the metal significantly depressed AH (49%),p-NAOD (66%), EMND (47%), and AMND (37%) activities, and cytochrome P-450 (15%), cytochrome b5 (24%), and microsomal heme (28%) levels. For the combined treatment, animals received the single dose of Ni 56 h after the single dose of Cd and then were killed 16 h later. In these animals, significant inhibitions were noted in AH (51%), EMND (47%), and AMND (30%) activities, and cytochrome P-450 (15%), cytochrome b5 (26%), and microsomal heme (30%) compared to those of controls. In the case ofp-NAOD activity, the influence was in favor of Ni, i.e, the inhibition was about 61% by the combined treatment. These results reveal that:
1.  The response of all substrates of hepatic monooxygenases to Cd are not the same, possibly indicating differential regulation of cytochrome P-450 isozymes by Cd;
2.  The inhibitory effect of Ni on hepatic monooxygenases is more profound than that of Cd; and
3.  The combination of Cd and Ni does not have a synergistic effect of hepatic monooxygenases of the guinea pig.
  相似文献   

18.
Rhizobium hemeproteins P-450a, b, and c cross react with antibodies to P-450CAM and P-450LM-2. Anti P-450CAM IgG and phenobarbital, each bound to Sepharose 4B, were effective in purification of Rhizobium P-450c; the latter was more convenient. The amino acid composition of highly purified Rhizobium P-450c resembles the compositions of P-450CAM and P-450LM-2. These results suggest that P-450 heme proteins of unrelated substrate specificities may nevertheless contain similar structural features.  相似文献   

19.
J T Stevens  F E Greene 《Life sciences》1973,13(12):1677-1691
Invitro inhibition of ethylmorphine metabolism in rat hepatic microsomes by parathion, malathion, malaoxon and paraoxon was not well correlated with their effects on NADPH oxidation, cytochrome C reduction or the reduction of cytochrome P-450. A parallel relationship was observed between inhibition of ethylmorphine metabolism by parathion, malathion and malaoxon and the binding affinity of these agents to microsomal cytochrome P-450 obtained from rats pretreated with an anticholinesterase agent, Bis-[?-nitrophenol] phosphate.  相似文献   

20.
Studies were carried out to investigate the effects of prostaglandins (PG) in vitro on adrenal microsomal steroid and drug metabolism in the guinea pig. The addition of PGE1, PGE2, PGA1, PGF or PGF to isolated adrenal microsomes produced typical type I difference spectra. The sizes of the spectra (ΔA385–420) produced by prostaglandins were smaller than those produced by various steroids including progesterone, 17-hydroxyprogesterone and 11β-hydroxyprogesterone. However, the affinities of prostaglandins and steroids for adrenal microsomal cytochrome P-450, as estimated by the spectral dissociation constants, were similar. Prior addition of prostaglandins to isolated adrenal microsomes did not affect steroid binding to cytochrome P-450 or the rate of steroid 21-hydroxylation. In contrast, prostaglandins inhibited adrenal metabolism of ethylmorphine and diminished the magnitude of the ethylmorphine-induced spectral change in adrenal microsomes. The results indicate that prostaglandins inhibit adrenal drug metabolism by interfering with substrate binding to cytochrome P-450. Since 21-hydroxylation was unaffected by PG, different cytochrome P-450 moieties are probably involved in adrenal drug and steroid metabolism.  相似文献   

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