摘要:

AbstractThe adrenal cortex contains high amounts of detoxifying enzymes, as well as generators and protectors of reactive oxygen species. The high content of cytochrome P‐450 enzymes in the adrenal cortex together with its remarkable tendency to accumulate hydrophobic substances probably contributes to the extraordinary vulnerability of the gland to a number of xenobiotics. The best studied adreno‐corticolytic compounds are the potent carcinogen 7, 12‐dimethylbenz(a)anthracene (DMBA) and its liver metabolite 7‐hydroxymethyl‐12‐methylbenz (a)anthracene (7‐OHM‐12‐MBA). Adrenocorticolysis generated by these agents in vivo as well as in vitro demonstrates high regioselective requirements and is strongly influenced by the presence of ACTH, steroids, cytochrome P‐450 inhibitors and antioxi‐dants. Furthermore, 7‐OHM‐12‐MBA has been demonstrated to uniquely generate selective and massive oxidation of mitochondrial glutathione in cultured rat adrenal cells.The DMBA‐induced adrenocorticolysis is thoroughly discussed in this review with particular emphasis on the metabolism of DMBA and the influence of various effectors. A working hypothesis involving a possible peroxidativ

ISSN:0887-2082    

DOI:10.1002/jbt.2570050202

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractMicrosomal preparations from hamster kidney, a target tissue for the carcinogenic action of stilbene‐type and steroidal estrogens, catalyze the oxidative metabolism of diethylstilbestrol (DES). The formation of the major metabolite Z,Z‐dienestrol and of reactive intermediates capable of protein binding were mediated by enzyme activities requiring nicotinamide‐adenine dinucleotide phosphate (reduced form‐NADPH), cumene hydroperoxide, or arachidonic acid (ARA). In addition, hydroxylated DES metabolites were detected in NADPH‐supplemented incubations. The NADPH‐dependent oxidation of DES was inhibited by SKF 525A and metyrapone. Monooxygenase‐catalyzed metabolism was apparently responsible for the majority of DES oxidation in microsomes from whole hamster kidneys in vitro and this activity is preferentially localized in the kidney cortex. However, ARA‐dependent, i.e., prostaglandin H synthase (PHS) mediated oxidation of DES and of the catechol estrogen 2‐hydroxyestrone was demonstrated as well in the medulla of both rabbit and hamster kidney. It is proposed that monooxygenase and PHS activities act in concert in the metabolic activation of carcinogenic estrogens. This appears to apply in particular to steroidal estrogens, since catechol estrogens formed by monooxygenases are further oxidized to reactive intermediates by PHS and other pe

ISSN:0887-2082    

DOI:10.1002/jbt.2570050203

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractThe effects of Aroclor 1254 on cytochrome P‐450‐mediated steroidogenic activities were investigated in adrenal and testis microsomes of male guinea pigs. A significant decrease was recorded in the tissue content of adrenal microsomal cytochrome P‐450 as well as a significant reduction in the overall conversion of progesterone to steroid products., The effects of exposure to Aroclor 1254 on activities of cytochrome P450 21‐hydroxylase and cytochrome P450 17α‐hydroxylase /C17,20‐lyase were selective. Cytochrome P‐450 21‐Hydroxylase activity was inhibited, as reflected by a decrease in production of 11‐deoxycortisol and 11‐deoxycorticosterone, whereas the cytochrome P‐450 17α‐hydroxylase / C17,20‐lyase activities, represented by the production of 17α‐hydroxyprogesterone and androstenedione were elevated. The same and even more pronounced pattern of altered progesterone metabolism elicited by Aroclor 1254 was observed in vitro, when Aroclor 1254 was introduced into incubation mixtures prepared with adrenal microsomes from untreated animals. Under such experimental conditions, a decrease in the overall metabolism of progesterone was observed as well as a decrease in cytochrome P‐450 21‐hydroxylase activity, while there was significant elevation in the 17α‐hydroxylase /C17,20‐lyase activities.The effect of Aroclor 1254 on the testes differed largely from its effect on the adrenal cortex. In testis microsomes, pretreatment with Aroclor 1254 resulted in no changes in the cytochrome P‐450 content, contrary to the decrease observed in adrenal microsomes. In contrast to its inductive effect on the normally suppressed androgen producing pathway in adrenal microsomes, Aroclor 1254 had no effect on the 17‐hydroxylase /C17,20‐lyase activities in testis microsomes, both in the pretreated animals as well as when it was present in the incubation mixtures containing microsomes of untreated animals. The results of this study indicate a difference in the response of steroidogenic tissues to Aroclor 1254. In adrenal microsomes Aroclor 1254 may have modulated the steroidogenic activities at a posttranscriptional level, possibly by interfering with membrane regulation of these metabolic activities. At the same time, the results obtained do not exclude the possibility that Aroclor 1254 alters the composition of cytoch

ISSN:0887-2082    

DOI:10.1002/jbt.2570050204

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractIn liver fractions from male Sprague‐Dawley rats, the metabolism of methacrylonitrile (MeAN) to cyanide (CN−) was localized in microsomal fraction and required reduced nicotinamide adenine dinucleotide phosphate (NADPH) and oxygen for maximal activity. The biotransfomation of MeAN to CN−was characterized with respect to time, microsomal protein concentration, pH, and temperature. Metabolism of MeAN was increased in microsomes obtained from phenobarbital‐treated rats (310% of control) and decreased with CoCl2and SKF 525 A treatments (55% and 61%, respectively). Addition of the epoxide hydratase inhibitor, 1,1,1‐trichloropropane 2,3‐oxide, decreased the formation of CN−from MeAN. Addition of glutathione, cysteine, D‐penicillamine, and 2‐mercaptoethanol enhanced the released of CN−from MeAN. These findings indicate that MeAN is metabolized to CN−via a cytochrome P‐450‐dependent mixe

ISSN:0887-2082    

DOI:10.1002/jbt.2570050205

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractThe purpose of this study was to determine if the hypolipidemic peroxisome proliferator ciprofibrate, which induces peroxisomes in the liver, can induce peroxisomes in cultured porcine pulmonary endothelial cells. Ciprofibrate was added at three concentrations to cell cultures for a 6‐day period. The induction of peroxisomes in the cells was detected by determining total peroxisomal β‐oxidation and peroxisomal catalase activity. The addition of ciprofibrate was found to increase peroxisomal enzyme activities in a dose‐dependent manner, with the highest activity being reached at 1000 μM ciprofibrate. Ciprofibrate also caused an increased transfer of albumin across endothelial cells cultured on micropore filters. This study shows that peroxisomal enzyme activities can be induced by ciprofibrate in endothelial cells, which may have implications in diseases mediated by vascular

ISSN:0887-2082    

DOI:10.1002/jbt.2570050206

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractOrnithine decarboxylase, the rate‐limiting enzyme in polyamine synthesis, was significantly induced in female rat liver following oral administration of the pesticide mirex. After dual oral exposure (120 mg /kg of mirex; 21 and 4 hr prior to sacrifice), ornithine decarboxylae activity in rat liver cytosol was 70‐fold higher than control values. A single oral dose of mirex (180 mg /kg) induced hepatic ornithine decarboxylase activity 55‐fold over controls. After a single oral dose of mirex the maximal induction of ODC activity occurred at 36 hr. Mirex is an unusually potent and long‐lasting inducer of rat hepatic ornithine decarboxylase a

ISSN:0887-2082    

DOI:10.1002/jbt.2570050207

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractThe aralkyl‐CoA:glycineN‐acyltransferase and the arylacetyl‐CoA:amino acid ofN‐acyltransferase were purified from bovine liver mitochondria and their response to a variety of ions investigated. The activity of the aralkyl transferase was inhibited by divalent cations and high concentrations of monovalent cations with all substrates investigated. For benzoyl‐coenzyme A (CoA), K+was a competitive inhibitor, competing for binding at the benzoyl‐CoA binding site. With salicylyl‐CoA, K+did increase the dissociation constant (KD) for acyl‐CoA but it was not a competitive inhibitor and in addition, K+increased the Michaelis constant for glycine (Kglym) tenfold. The data suggest that the increase in Kglymis due to bound K+forcing reorientation of salicylyl‐CoA at the active site so that it impinges on the glycine binding site. Inorganic anions and cations did not affect the extent of product inhibition by hippuric acid with either acyl‐CoA and this was because they affected the binding of acyl‐CoA and hippuric acid to the same extent. Ions did, however, greatly reduce the extent of product inhibition by CoA. This is critical because under approximate in vivo conditions (2.5 mM CoA), the salt‐free enzyme would be almost completely inhibited by CoA. The arylacetyl transferase was activated by inorganic ions when assayed at saturating substrate concentrations. However, at physiologic concentrations of glycine certain salts were modestly inhibitory. The inhibitory effect of KCl was characterized by a large decrease in the affinity of the enzyme for phenylacetyl‐CoA, suggesting that the arylacetyl‐CoA region of the active site contained an inhibitory ion binding site. At low (physiologic) concentrations of substrate, the arylacetyl transferase was extensively inhibited by CoA and this inhibition was greatly reduced by ions. The 3′‐phosphate group on CoA was found to be important for binding to the salt‐free enzyme but in the presence of ions its importance was diminished. In the absence of inorganic ions the affinity of the enzyme for phenylacetyl‐CoA and naphthylacetyl‐CoA was so high that it could not be measured. In the presence of KCl the KDvalues for phenylacetyl‐CoA and naphthylacetyl‐CoA were similar, but the Kmfor glycine was extremely high for 1‐naphthylacetyl‐CoA conjugation, which accounts for its slow rate of metabolism. Conjugation with glutamine had a high Michaelis constant for glutamine (KGlum) and a low maximum velocity (Vmax) which accounts for

ISSN:0887-2082    

DOI:10.1002/jbt.2570050208

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

ISSN:0887-2082    

DOI:10.1002/jbt.2570050210

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

ISSN:0887-2082    

DOI:10.1002/jbt.2570050201

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY