Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experiments were conducted to examine the role of zinc in the prevention of bromobenzene hepatoxicity in male rats. Bromobenzene (BB) (7.5 mmol/kg, ip) produced a marked hepatotoxicity as evidenced by increases in plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and a marked depression in hepatic glutathione (GSH) content 24 hr after administration. The administration of zinc (92 mumol Zn/kg, ip, at 48 and 24 hr prior to the bromobenzene) ameliorated the bromobenzene elevations in plasma AST (25%) and plasma ALT (50%) but did not alter the decreases in hepatic GSH. Following administration of [14C]BB, the radioactive label was distributed primarily in the cytosolic and lipid fractions derived from liver homogenates. Furthermore, the subcellular distribution of [14C]BB was not altered by zinc pretreatment. The extent of covalent binding of [14C]BB metabolites to hepatic tissue was significantly depressed in zinc-treated rats. Zinc induced the hepatic levels of metallothionein but [14C]BB did not bind to this sulfhydryl rich protein. Further experiments showed that zinc treatment depressed cytochrome P-450 content, the activity of NADPH cytochrome c reductase, and the metabolism of aniline, but not that of ethylmorphine. These studies suggest that the hepatoprotective effect of zinc against bromobenzene toxicity does not involve altered binding of the reactive toxic metabolite to glutathione or metallothionein, but it may be mediated by the inhibitory effect of zinc on the microsomal cytochrome P-450-dependent drug metabolizing system.
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PMID:Amelioration of bromobenzene hepatotoxicity in the male rat by zinc. 398

Recovery characteristics of dispositional and pharmacodynamic tolerances produced by chronic Na-pentobarbital treatment were studied. To study dispositional tolerance, the rate of disappearance of pentobarbital from blood was estimated by sequential blood sampling before and after chronic treatment and during 15 days of withdrawal after chronic treatment. Pentobarbital half-life values were compared with four representative cytochrome P-450-mediated hepatic microsomal mixed-function oxidase reactions: aminopyrine demethylase, benzo(a)pyrene hydroxylase, 7-ethoxycoumarin deethylase and 7-ethoxyresorufin deethylase and with the concentration of cytochrome P-450 in sequentially biopsied liver samples. Pharmacodynamic tolerance was evaluated by measuring the increase in pentobarbital blood concentration required to produce predetermined central nervous system functional depression ratings. The recovery from dispositional tolerance was more rapid than the recovery from pharmacodynamic tolerance. Thus, whereas cytochrome P-450 levels and pentobarbital elimination rates were increased to close to twice pretreatment values by chronic treatment, by about 2 week post-withdrawal the values had normalized. In contrast, pharmacodynamic tolerance persisted after no residual dispositional tolerance remained. The neuronal functions most sensitive to barbiturate (i.e., sedation and loss of fine motor coordination) exhibited a greater degree of pharmacodynamic tolerance than other functions; hence the recovery of these neuronal functions took a longer period of time for their recovery. However, the rates of recovery of pharmacodynamic tolerance at all levels of central nervous system function seemed relatively constant indicating that there are uniform readaptation mechanisms for all the central nervous systems functions.
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PMID:Recovery from dispositional and pharmacodynamic tolerance after chronic pentobarbital treatment. 404 24

In mice treated with ordinarily sublethal doses of parathion 2 to 5 days postinfection with murine cytomegalovirus (MCMV) 50 to 100% mortality was observed. These mortalities appeared to be due to a decrease in the ability of infected mice to detoxify parathion. Pentobarbital-induced sleeping time was also enhanced 3 and 6 days postinfection and cytochrome P-450 concentrations were markedly depressed in mice tested 3 days after infection. MCMV-induced effects on sensitivity to parathion and pentobarbital did not appear to be directly attributable to liver infection since concentrations of virus in the liver persisted at maximum concentrations well beyond the time when sensitivity to these compounds returned to normal. The time frame during which enhanced sensitivity to parathion and pentobarbital was observed suggests that this sensitivity may have been caused by viral-induced interferon-mediated depression of cytochrome P-450.
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PMID:Increased susceptibility to parathion poisoning following murine cytomegalovirus infection. 609 89

In contrast to what is well known to occur in rats, pigeons receiving CCl4 (1 ml/kg i.p.) were not susceptible to necrogenic effects of the hepatotoxin at 24 h. There were, however, other early biochemical alterations observable, such as depression of glucose 6 phosphatase activity, decrease in the cytochrome P-450 content and in aminopyrine-N-demethylase activity in pigeon liver microsomes at 3 and 6 h after CCl4 administration. Pigeon liver was able to activate CCl4 to reactive metabolites that bind covalently to lipids, but no CCl4-induced lipid peroxidation was proved by the diene hyperconjugation technique in pigeon liver microsomes at 1, 3 or 6 h after administration. Results suggest that covalent binding of CCl4-reactive metabolites are more relevant to early biochemical alterations induced by CCl4 than is lipid peroxidation. Absence of CCl4-induced necrosis in pigeon liver could be attributable to a smaller intensity of covalent binding interactions observed, when compared to susceptible species, and to absence of lipid peroxidation.
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PMID:Carbon tetrachloride-induced early biochemical alterations but not necrosis in pigeon's liver. 609 76

A previously validated small mammal trauma model, hind-limb ischemia secondary to infrarenal aortic ligation in the rat, was utilized to further investigate the effects of traumatic injury on the hepatic cytochromes P-450. In vitro drug metabolism studies with hexobarbital and zoxazolamine as substrates confirmed the post-traumatic depression of the cytochrome P-450-catalyzed oxidation of these drugs which was suggested by previous in vivo pharmacokinetic studies. Enzyme kinetic studies revealed diminished Vmax values with no change in Km, a finding which would seem to concur with the previously demonstrated decrease in hepatic cytochrome P-450 content after model trauma. Moreover, a battery of in vitro microsomal monooxygenase assays demonstrated that model trauma exerted a differential effect on various hepatic cytochrome P-450 isoenzymes. This phenomenon was confirmed by anion-exchange HPLC of solubilized hepatic microsomal hemoproteins. One of the most interesting aspects of this selective effect on cytochrome P-450 subtypes was the relative induction of cytochrome P-448 content and activity, in contrast to the variable decrease seen with cytochrome P-450 activities. The potential in vivo sequelae of this differential influence were suggested by changes observed in the urinary metabolic profile of antipyrine after model trauma.
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PMID:Effects of model traumatic injury on hepatic drug metabolism in the rat. III. Differential responses of cytochrome P-450 subpopulations. 614 9

Fischer 344 male rats were treated with N-nitrosodiethylamine, and two weeks later promotion was effected by treatment with N-2-acetylaminofluorene for 14 days. At midpoint of the promotion protocol, one group of rats was subjected to partial hepatectomy (model A); others were treated with either carbon tetrachloride (model B) or thioacetamide (model C). Alterations in the activities of marker enzymes (glucose-6-phosphatase, gamma-glutamyl transpeptidase, cytochrome P-450, N-demethylase) during hepatocarcinogenesis were followed biochemically. The highest incidences of liver foci and of hepatocellular carcinomas were observed in model A, and these showed a good correlation with long-lasting elevated gamma-glutamyl transpeptidase activity. Analysis of the marker alterations suggests that there are three stages in hepatocarcinogenesis: (1) depression resulting from the toxic action of the initiator; (2) recovery and adaptation to cellular injury; and (3) long-lasting adverse alterations in the activities of the marker enzymes after promotion. The loss of certain non-histone proteins soon after promotion was also observed. Comparative studies of the individual actions of initiators and promoters on marker enzymes indicated that both contribute to the marker changes during hepatocarcinogenesis.
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PMID:Alterations of markers during hepatocarcinogenesis in rats. 615 22

Induction of type II interferon by sensitization of mice with Mycobacterium tuberculosis strain BCG and challenge with tuberculin resulted in a depression of the cytochrome P-450 drug metabolism system of the liver. The degree of depression was significantly greater than in mice that were only sensitized to BCG. Cytochrome b5 levels were not affected. In addition, the level of the depression of the cytochrome P-450 system correlated with the levels of type II interferon induced. Passive transfer of exogenous type II interferon preparations also significantly depressed the cytochrome P-450 system. Passive transfer of mock interferon or of normal serum had no effect.
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PMID:Type II interferon induction and passive transfer depress the murine cytochrome P-450 drug metabolism system. 615 62

Following the administration of D-galactosamine the utilization of [2-14C] orotic acid for the synthesis of the cytidine components of the acid-soluble extract and liver RNA cytosine is markedly decreased. The depression of the specific activity of the cytidine components takes place after application of low doses of the drug which do not interfere with the specific activity of the uridine components of the acid-soluble extract or of liver RNA uracil. Simultaneously the administration of [U-14C]cytidine paralleled by its enhanced liver uptake. The total amount of uridine as well as cytidine components of the acid-soluble extract following the administration of D-galactosamine increases; however, the molar ratio of both pyrimidines does not change. The alterations of the cytidine metabolism after the administration of the drug are accompanied by the increased level of microsomal cytochrome P-450.
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PMID:Biosynthesis of cytidine nucleotides in rat liver after administration of D-galactosamine. 616 66

Induction of gamma (Type II) interferon results in depression of the cytochrome P-450 system of mice. The gamma interferon is induced by sensitization of mice with Mycobacterium bovis strain BCG followed by challenge with tuberculin. The degree of depression of the cytochrome P-450 system correlates with the levels of interferon induced. passive transfer of exogenous gamma interferon also results in depression of the murine cytochrome P-450 system. In the present study the metabolism of diphenylhydantoin, a drug metabolized by the cytochrome P-450 system, was examined in mice in which gamma interferon was induced. The metabolism of diphenylhydantoin was severely inhibited in mice in which interferon was induced, and the level of inhibition correlated with the liter of gamma interferon induced. Passive transfer of gamma interferon also depressed the metabolism of diphenylhydantoin by the murine cytochrome P-450 system.
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PMID:Effects of passive transfer and induction of gamma (type II immune) interferon preparations on the metabolism of diphenylhydantoin by murine cytochrome P-450. 618 Jan 5

The utilization of (2-14C)orotic acid for the synthesis of cytidine components of the acid-soluble extract and for the RNA cytosine is decreased in the liver of rats which fasted for 24 or 72 h. The depression of the specific activity of the cytidine components is greater in animals which received alpha-HCH during the 24-hour interval after removal of food than in the control group; by contrast, the specific activity of the cytidine components again increases in rats fasting for 72 h. Analogous changes also occurred in the specific activity of RNA cytosine. Both the (U-14C)cytidine uptake and its utilization for the synthesis of RNA cytosine are enhanced in fasting rats; the administration of alpha-HCH has a potentiating effect. The total content of cytidine components of the acidsoluble extract of 1 g of liver tissue is enhanced 24 h after the animals of the control and experimental group were deprived of food. There are no marked differences in the concentration of the uridine components. Fasting has an additive effect on the increase of cytochrome P-450 level in the alpha-HCH treated rats. Alpha-HCH = alpha-1,2,3,4,5,6-hexachlorocyclohexane.
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PMID:Effect of fasting on the metabolism of cytidine nucleotides in the liver of intact and alpha-hexachlorocyclohexane-treated rats. 620 37


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