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)

1 Pretreatment of rats with intraperitoneal injections of lead was shown to result in a depression of the microsomal mixed function oxidase system, as assessed by a decrease in hepatic microsomal P-450 and b5 content and by a decrease in the activity of the enzymes aniline hydroxylase and aminopyrine demethylase. Lead had a more marked effect on cytochrome P-450 than b5. 2 The activity of the rate-limiting enzyme of haem biosynthesis, delta-aminolaevulinic acid synthase, was inversely correlated with the microsomal cytochrome P-450 content. 3 The activity of the haem biosynthetic enzymes delta-aminolaevulinic acid dehydratase, coproporphyrinogen oxidase and ferrochelatase were decreased by increasing lead pretreatment. 4 The activity of the haem catabolic enzyme, haem oxygenase, was increased by lead pretreatment.
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PMID:Hepatic drug metabolism and haem biosynthesis in lead-poisoned rats. 65 97

The acute toxic effects of thiabendazole [2-(4'-thiazolyl)benzimidazole; TBZ] on the kidneys of ICR mice were investigated. The mice were given 0, 250, 500 or 1000 mg TBZ/kg body weight by gavage (using olive oil as a vehicle), and the kidneys were subjected to pathological examination at 1, 3, 5 or 24 hr after dosing. Gross findings were slight enlargement and the presence of whitish areas (white maculae) in kidneys of treated mice at 3, 5 or 24 hr after dosing. Histological findings were desquamation of degenerated cells in proximal tubules of treated mice at 1 hr. Dilation of proximal, distal and collecting tubules was apparent in treated mice at 3, 5 and 24 hr. TBZ-induced renal injury was reduced by pretreatment with inducers of the microsomal monooxygenase system (sodium phenobarbital, beta-naphthoflavone and 3-methylcholanthrene) and were enhanced by pretreatment with inhibitors of that system (2-diethylaminoethyl-2,2-diphenylvalerate hydrochloride and piperonyl butoxide). The concentration of TBZ in blood at 1 or 5 hr after dosing was lower in mice pretreated with microsomal monooxygenase system inducers and was higher in those pretreated with the inhibitors, than in those given TBZ alone. These results suggest that TBZ-induced renal injury may be attributable to the parent compound rather than its metabolites. Measurement of organic ion uptake into renal slices revealed significant depression of [1-14C]tetraethylammonium bromide (TEA) uptake in treated mice at 1 or 5 hr, whereas uptake of p-[glycyl-2-3H]aminohippurate (PAH) was not depressed at 1 or 5 hr after dosing. The reduction in uptake of TEA is interpreted as the result of competitive suppression of the tubular transport of TEA by TBZ. TBZ-induced renal injury was reduced by organic cation transport inhibitors [N'-methylnicotinamide (NMN) or thiamine] but not by organic anion transport inhibitor [p-(dipropylsulphamyl)benzoic acid probenecid], suggesting that the reduction of TBZ-induced renal injury is the result of competitive suppression of the tubular transport of TBZ by NMN or thiamine.
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PMID:Acute renal toxicity of thiabendazole (TBZ) in ICR mice. 147 96

N-Acetylcysteine (NAC) is protective against acetaminophen-induced hepatotoxicity primarily by providing precursor for the glutathione synthetase pathway, while cysteamine has been demonstrated to alter the cytochrome P-450 dependent formation of toxic acetaminophen metabolite. Mice administered acetaminophen (500 mg/kg) had elevations of serum alanine aminotransferase (ALT) to 273.0 +/- 37.5 and 555.8 +/- 193.4 U/mL at 12 and 24 h, respectively, after injection. Administration of cysteamine (100 mg/kg) or NAC (500 mg/kg) significantly reduced serum ALT activity (p less than 0.001). Reducing the dose of NAC or cysteamine by 50% greatly reduced their hepatoprotective effect while the co-administration of the reduced doses of NAC (250 mg/kg) and cysteamine (50 mg/kg) following acetaminophen overdose prevented elevation of serum ALT activity (39.2 +/- 1.17 and 32.5 +/- 5.63 U/mL at 12 and 24 h post-injection, p less than 0.001) and preserved normal mouse hepatic histology. Neither NAC (500 mg/kg), cysteamine (100 mg/kg), or the lower doses in combination of both agents were found to alter the half-life or peak levels of acetaminophen. Liver microsomal aryl hydrocarbon hydroxylase activity measured 24 h after drug administration was not significantly different between treatment groups and controls receiving only saline. These results indicate a possible role for the concomitant use of NAC and cysteamine in the prevention of hepatic necrosis following toxic doses of acetaminophen. Neither decrease in plasma acetaminophen levels nor depression of cytochrome P-450 enzyme activity appears to be the mechanism of protection when these doses of NAC, cysteamine, or both drugs together are administered with a toxic dose of acetaminophen in mice.
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PMID:Cysteamine in combination with N-acetylcysteine prevents acetaminophen-induced hepatotoxicity. 158 51

The effect of a single dose of bacterial endotoxin (lipopolysaccharide, LPS) was compared with that of tumor implantation in mice on the activity of several hepatic cytochrome P-450-dependent monooxygenases. These included ethoxycoumarin O-deethylase, p-nitrophenol hydroxylase, aminopyrine N-demethylase, pentoxyresorufin O-depentylase, ethoxyresorufin O-deethylase and testosterone hydroxylase. For this purpose, mice were treated i.p. with 5 micrograms of LPS or implanted in the right paw with S 180 sarcoma. A comparable depression (30-50%) of total microsomal P-450 content as well as of the different P-450 monooxygenase activities tested was observed in LPS-treated mice (24 h after LPS) and in tumor bearing mice (12 days after implantation). The lack of differences in the pattern of depression of microsomal enzymes between LPS-treated and tumor-bearing mice suggests that a common mechanisms might be involved in the depression of P-450 by LPS or S-180 implantation.
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PMID:Depression of hepatic drug metabolism in endotoxin-treated and sarcoma-bearing mice. 160 46

We have previously reported that monocyte aryl hydrocarbon hydroxylase (AHH) activity is depressed in patients with liver disease and is decreased more in cirrhosis than in early stage liver disease. To determine if monocyte AHH activity reflects liver AHH activity, we studied an animal model of cirrhosis, i.e., yellow phosphorus induced cirrhosis in the pig. AHH activity was detectable in monocytes isolated from peripheral blood of normal pigs (0.32 +/- 0.13 nmol.mg-1 P.h-1, n = 11) and was comparable to the level of AHH activity in hepatic Kupffer cells isolated from wedge or needle biopsies of livers of normal pigs (0.38 +/- 0.21, n = 7). The AHH level in pig Kupffer cells was approximately 10% of the AHH level in hepatocytes and microsomes. To induce liver disease, pigs were administered yellow phosphorus (0.6 mg/kg) 5 days per week for 16 weeks. At 4 weeks of treatment, monocyte AHH activity was not different from control and liver histology was normal. Depression of monocyte AHH activity was evident at 8 weeks of treatment when liver fibrosis was seen histologically. At 12 weeks of treatment when histology revealed extensive liver fibrosis and collagen levels were elevated, the level of monocyte AHH activity was decreased 67% compared with controls. Similar changes were observed at 12 weeks in Kupffer cell AHH activity (86% decrease) and hepatocyte AHH activity (70% decrease) compared with controls. These results suggest that monocyte AHH activity reflects liver AHH activity and may be a good indicator of change in liver enzyme function in liver disease in the pig model of cirrhosis.
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PMID:Monocyte aryl hydrocarbon hydroxylase (AHH) activity mimics Kupffer cell and hepatocyte AHH activity in an animal model of liver disease. 180 52

C3H/10T1/2 clone 8 (10T1/2) cells possess aryl hydrocarbon hydroxylase (AHH) activity capable of metabolizing polycyclic aromatic hydrocarbons to ultimate carcinogenic forms. AHH activity in 10T1/2 cells was measured before and after culturing in the presence of benzo[a]pyrene (B[a]P), and compared to the AHH activity found in carcinogen-transformed 10T1/2 cell lines treated similarly. The cell lines were also examined for B[a]P-DNA adduct formation, using the 32P-postlabelling technique. Treatment of parental 10T1/2 cells with B[a]P was found to significantly increase AHH activity and produce substantial numbers of DNA adducts. In addition to a major B[a]P-DNA adduct, 5-6 minor DNA adducts were also detected. Relative to parental 10T1/2 cells, an aflatoxin B1-transformed 10T1/2 cell line (7SA) was found to have significantly depressed AHH activity. In addition, after treatment with B[a]P, 7SA cells had only 8% of the B[a]P-DNA adduct levels found in 10T1/2 cells. This system may provide an in vitro model for investigating mechanisms responsible for the depression of cytochrome P-450 activities by chemical carcinogens.
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PMID:Induction of aryl hydrocarbon hydroxylase and DNA adduct formation in parental and carcinogen transformed C3H/10T1/2 clone 8 cells by benzo[a]pyrene. 250 24

The relative influence of Ah vs H-2 genotype on the outcome of Trichinella spiralis (Tsp) infections of mice was examined following methylcholanthrene (MC) treatment. Female mice of four inbred strains were treated with MC and infected 24 h later with Tsp muscle larvae. The strains, with their respective major histocompatibility complex (MHC) haplotype, aryl hydrocarbon hydroxylase responsiveness (Ah phenotype) and level of susceptibility to Tsp infection, were: C3HeB/FeJ (C3), H-2k, Ahb, Tsp susceptible; C57BL/10.BR (B10.BR), H-2k, Ahb, Tsp susceptible; C57BL/10.Q (B10.Q), H-2q, Ahb, Tsp resistant; and AKR/J (AK), H-2k, Ahd, Tsp resistant. The proliferative response of splenic lymphocytes to crude Tsp L1 stage antigen was significantly depressed in all MC-treated groups, with the exception of the B10.BR strain. MC administered at 40 mg/kg impaired the ability of C3 and B10.Q mice to eliminate adult worms. At 80 mg/kg, C3 strain mice were also impaired, as well as AK strain mice. The fecundity of female worms recovered from B10 or AK strain mice was not significantly altered by MC treatment, although female worms from treated C3 mice exhibited increased fecundity on day 9 post infection. Muscle larvae burdens of MC-treated B10 and C3 mice were elevated, while those of AK strain mice were unaffected. These data suggest that with acute exposures to MC, the immunogenetic resistance or susceptibility of a given mouse strain may have a more pronounced effect on immune depression and the severity of Tsp infection than does the Ah phenotype.
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PMID:The relative importance of Ah versus H-2 genotype on Trichinella resistance following exposure to 3-methylcholanthrene. 253 39

Administration of cysteamine to rats depressed hepatic aryl hydrocarbon hydroxylase (AHH) activity, cytochrome P-450, and total heme at 24 hr. Total heme remained decreased at 48 hr when all other parameters returned to control values. A significant 5-fold increase in heme oxygenase activity occurred in rat liver 5 hr after treatment, when AHH activity and total heme were unchanged. Histological examination of liver biopsies from rats treated with cysteamine revealed normal hepatic architecture. The observed effects of cysteamine on hepatic drug-metabolizing enzymes in vivo were not due to cysteamine-induced hepatotoxicity. Our results indicate that cysteamine increases heme oxygenase activity in rat liver, with a subsequent decrease in total heme, AHH activity, and cytochrome P-450 content. The depression of P-450 by cysteamine is likely to be an important mechanism for its protection in acetaminophen overdose. The protection studies illustrate this mechanism. Centrilobular hepatic necrosis and elevation in transaminase activity following a toxic dose of acetaminophen were prevented by treatment with cysteamine. The hepatoprotective effect of cysteamine was evident when acetaminophen was administered 24 hr after cysteamine but did not occur when acetaminophen was administered 5 hr after cysteamine or simultaneously. All groups of rats receiving cysteamine showed decreased mortality compared to the group receiving acetaminophen alone.
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PMID:The role of heme oxygenase and aryl hydrocarbon hydroxylase in the protection by cysteamine from acetaminophen hepatotoxicity. 260 41

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) (233 nmol/kg) causes a significant increase of hepatic uroporphyrin, heptacarboxyporphyrin, and total porphyrins in female C57BL/6 mice, ovariectomized C57BL/6 mice, male C57BL/10 mice, and male C57BL/6 mice 3 weeks after treatment. In contrast, 6-methyl-1,3,8-trichlorodibenzofuran (MCDF) was inactive at a dose of 750 mumol/kg. Cotreatment of the mice with TCDD (233 mol/kg) plus MCDF (750 mumol/kg) resulted in partial antagonism of TCDD-induced hepatic porphyrin accumulation only in the female mice. Parallel studies in female C57BL/6 mice showed that the TCDD-induced porphyria was accompanied by the induction of hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) activities and the depression of uroporphyrinogen decarboxylase (UROD). MCDF (750 mumol/kg) did not significantly affect these enzymes. In the cotreatment studies (MCDF plus TCDD), MCDF partially antagonized TCDD-induced hepatic porphyrin accumulation but did not affect the levels of hepatic AHH, EROD, or UROD. These results indicate that other factors, in addition to the induction of cytochrome P450-dependent monooxygenases and depressed UROD activity, are important in TCDD-induced porphyria in C57BL/6 female mice.
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PMID:2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced porphyria in genetically inbred mice: partial antagonism and mechanistic studies. 278 54

Idiopathic Parkinson's disease has been postulated to result from exposure to environmental toxins similar to the parkinsonism-causing neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). This study examines the interactions of MPTP with the cytochrome P-450 system--an enzyme system which is known to be involved in the detoxication of MPTP. In vitro studies, using control hepatic microsomes, studied changes in cytochrome P-450 content and enzyme activity with varying concentrations of MPTP and substrates. In vivo liver and brain studies were conducted using groups of 4 animals treated intraperitoneally with varying doses of MPTP and sacrificed at varying time intervals after treatment. Changes in cytochrome P-450 enzyme contents and activities were determined using standard analytical procedures. MPTP was found from in vitro studies to cause a mixed non-competitive inhibition of cytochrome P-450 dependent ethoxyresorufin O-dealkylase activity with an inhibition constant (Ki) of 0.06 mM. Two binding sites of MPTP to hepatic cytochrome P-450 were found by spectral perturbation studies--the higher affinity site binding about a hundred times more avidly to MPTP than the other. In vivo studies showed a depression of cytochrome P-450 content and activity in a dose-dependent manner. Cytochrome P-450 levels were lowest 3 to 6 hours after treatment with MPTP. MPTP was also found to cause a dose-dependent decrease in the cytochrome P-450 enzyme activities bufuralol hydroxylase (buf) and aryl hydrocarbon hydroxylase (AHH) in the brain. Bufuralol hydroxylase activity was found to be about 2000 times more sensitive than aryl hydrocarbon hydroxylase to the effects of MPTP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Studies on the interactions of MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) with the cytochrome P-450 enzyme system--clues to a possible aetiological factor in Parkinson's disease. 278 64


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