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)

Gene differences may alter an individual's response to foreign compounds by affecting their absorption, binding, distribution, excretion, biotransformation, or drug-drug interactions. Genetic differences in the metabolism of xenobiotics among inbred strains of various laboratory animals and model systems are reviewed. The inbred mouse has been studied most extensively. Genetic differences in toxicity are shown to be caused by various environmental pollutants in several inbred strains of mice and in siblings of the (C57BL/6N)(DBA/2N)F1 X DBA/2N backcross, in which the phenotypes "aromatic hydrocarbon responsiveness" or "nonresponsiveness" had been predetermined. This trait of "responsiveness"--which refers to the capacity for induction of cytochrome P1450 and numerous monooxygenase activities by certain aromatic compounds--segregates almost exclusively as a single gene among offspring of this backcross. All nonresponsive mice ingesting benzo/a/pyrene (about 125 mg/kg per day) die within 4 weeks, whereas the survival of responsive mice receiving the chemical orally is not significantly different from that of control mice; the apparent cause of early death in these experiments in toxic depression of the bone marrow. The life span of animals exposed to certain environmental pollutants can therefore be markedly influenced by a single gene or a very small number of genes. The same genetic trait can be either beneficial or detrimental to the animal, depending on whether detoxification or metabolic potentiation occurs. There also may exist genetic differences in man's susceptibility to toxicity or cancer caused by the numerous foreign compounds in his environment.
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PMID:Importance of genetic factors influencing the metabolism of foreign compounds. 81 76

Effects of cyclopentenone inhalation were examined in a 78-week study with 420 hamsters evenly distributed over two inhalation chambers, one for exposure to air and the other for exposure to the test substance. Cyclopentenone was dosed at a level of 18 ppm (seven hr/day, five days/week) during the first 52 weeks, and at a level of 27 ppm during the last 26 weeks of the study. During the first 52 weeks, part of the animals in both chambers fortnightly received an intratracheal instillation of benzo(a)pyrene (BP) or diethylnitrosamine (DENA) in saline or saline alone. Exposure to cyclopentenone caused slight growth depression in both sexes, and slightly increased relative liver weights and enhanced development of renal amyloidosis in females only. There was no evidence of cyclopentenonne possessing carcinogenic activity or being a co-factor in respiratory tract carcinogenesis.
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PMID:Repeated exposure to cyclopentenone vapour: long-term study in Syrian golden hamsters. 102 May 35

Acute toxicity, inductive effects of liver enzymes and liver persistency of 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PenCDD) were compared with those of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) using male Wistar rats. 1,2,3,7,8-PenCDD treatment at a dose of 0.1 mumol/kg resulted in significant depression of growth of rats from a day to 28 days after treatment. However, the effect was relatively less than that of 2,3,7,8-TCDD. On 5 days, similarly to 2,3,7,8-TCDD-treated group, liver hypertrophy and thymic atrophy were observed in 1,2,3,7,8-PenCDD-treated groups. In addition, 1,2,3,7,8-PenCDD showed potent 3-methylcholanthrene-type inducing ability. For example, the activities of benzo(a)pyrene 3-hydroxylase and DT-diaphorase were 25-fold and 10-fold of control, respectively. On 30 days, about 50% of the inductive effects on 5 days were maintained in both 1,2,3,7,8-PenCDD- and 2,3,7,8-TCDD-treated groups. Amount of 1,2,3,7,8-PenCDD distributed to the liver on 5 days was about 80-90% of dose and was about 1.5 times greater than that of 2,3,7,8-TCDD. About 50% of dose of 1,2,3,7,8-PenCDD remained even on 30 days after treatment. From these results, it is suggested that 1,2,3,7,8-PenCDD possessing the potent acute toxicity comparable to 2,3,7,8-TCDD and higher persistency in the liver might be more important than 2,3,7,8-TCDD in terms of the chronic toxicity.
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PMID:[Acute toxicity, inductive effects of liver enzymes and distribution in the liver of 1,2,3,7,8-pentachlorodibenzo-p-dioxin in rats]. 191 88

The toxic side-effects of the immunosuppressive drug cyclosporin (CsA) include testicular dysfunction and a decline in circulating testosterone. However, mechanisms for the consistently observed CsA-mediated depression of serum testosterone levels are unclear because of conflicting reports concerning circulating gonadotropin levels and incomplete studies of intratesticular steroidogenesis. To elucidate these mechanisms, endocrine-regulated testicular steroidogenesis and heme metabolic parameters were studied in male rats given sc injections of either 25 or 40 mg/kg.day CsA for 6 days and then killed on the seventh day. Consistent with earlier reports, CsA treatment dramatically suppressed serum testosterone levels (less than 20% of control at both CsA doses). Additionally, the intratesticular testosterone content declined with the higher CsA dose. Serum LH and FSH levels were elevated up to 2- to 4-fold after the higher CsA treatment regimen. Measurement of decreases in testicular receptors for LH revealed for the first time that CsA treatment significantly reduced the ability of the testes to respond to normal or elevated circulating levels of LH. In animals receiving higher dose of the drug, cytochrome P-450-dependent mitochondrial cholesterol side-chain cleavage activity, which is the rate-limiting step in steroidogenesis, was markedly reduced to a mere 30% of the control value. Additionally, the activity of the microsomal cytochrome P-450-dependent 17 alpha-hydroxylase was decreased to less than half of the control value. Biotransformation of the prototype drug, benzo(a)pyrene, as well as microsomal cytochrome P450 levels declined significantly after the higher CsA dose, suggesting that CsA has an adverse affect on testicular cytochromes P-450 in general. In addition, CsA treatment altered heme metabolic parameters; significant increases in the activity of uroporphyrinogen-I synthetase and total porphyrin content were noted. Conversely, the activity of ferrochelatase, the enzyme that incorporates iron into porphyrin to form heme molecule, decreased significantly, as did the total heme levels. The latter was reduced to only 61% of control values. The findings suggest the likelihood that the observed inhibition of heme formation may contribute substantially to the reduced levels of microsomal cytochromes P-450 and steroidogenic activities that depend on them. Taken collectively, these data suggest a plausible mechanism by which CsA may induce testicular dysfunction; as the result of a combination of reduction in the number of LH receptors and a suppression of heme formation, the hemoprotein-dependent steroidogenic enzymes activities are compromised, leading to an impairment of normal testicular function.
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PMID:Cyclosporin-mediated depression of luteinizing hormone receptors and heme biosynthesis in rat testes: a possible mechanism for decrease in serum testosterone. 193 94

In the course of a larger project aimed at studying possible combination effects between common air pollutants and carcinogens, previous studies of our laboratory had shown that the genotoxic activity of benzo(a)pyrene (B(a)p) in fetal lung cells of the Syrian hamster is decreased by NOx and SO2. This particular study was performed to assess whether the gases may cause this depression by affecting the net yield of active B(a)p metabolites. Using the S. typhimurium assay as a model-system the gaseous exposure of subcellular activation systems to SO2 and NOx did not affect the yield of B(a)p induced mutants of S. typhimurium. Also the pretreatment of animals with SO2 or NOx in vitro did not result in a measurable induction or inhibition of B(a)p metabolizing enzymes, as was assessed also with S. typhimurium. Accordingly, neither direct enzymic interactions nor complex systemic pathways reflected possible mechanisms of combination effects between B(a)p and the air pollutants.
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PMID:In vitro and ex vivo effects of the air pollutants SO2 and NOx on benzo(a)pyrene activating enzymes of the rat liver. 225 26

Five polycyclic aromatic hydrocarbons (PAHs) of different carcinogenic activities were evaluated for their effects on DNA synthesis (3HTdR labeling index (L.I.] of rat and human mammary epithelial cells (MEC) and for their effects on chromosomes in MEC-mediated sister chromatid exchange (SCE) assays. When compared with DMSO-treated cells, exposures of rat MEC to the two most potent carcinogens (5 micrograms/ml for 24 hr), i.e., 7,12-dimethylbenz(a)anthracene (DMBA) and benzo(a)pyrene (B[a]P), resulted in a 45-62% reduction in the L.I. of rat MEC. Another carcinogen, 20-methylcholanthrene (MCA), produced a 35-48% reduction in L.I., while the noncarcinogenic PAHs, 1,2-benzanthracene (BA) and benzo(e)pyrene (B[e]P), showed no effect. Similarly, exposures of human MEC to DMBA and B[a]P resulted in a 50-90% depression in L.I. while BA was significantly less effective (30% reduction). When co-cultivated with Chinese hamster V-79 cells in the presence of PAH, both rat and human MEC can activate and release the active metabolites to induce SCE in V-79 cells. In the rat MEC-mediated assay for all 5 PAHs, the frequencies of SCE per chromosome in DMBA-, B[a]P-, MCA-, BA-, B[e]P-, and DMSO (solvent control)-treated groups were 6, 3, 1.4, 0.7, 0.4, and 0.3, respectively. DMBA was most effective in increasing SCE, while B[e]P was ineffective. In the human MEC-mediated assay, B[a]P was more effective than DMBA in inducing SCE, and the frequencies of SCE per chromosome were 4.5 and 3.6 in B[a]P- and DMBA-treated groups, respectively. Comparing depression of L.I., SCE, and in vivo carcinogenicity for the 5 PAHs, SCE mediated by rat MEC is better correlated with carcinogenicity in rat than L.I. depression.
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PMID:Genotoxic effects of five polycyclic aromatic hydrocarbons in human and rat mammary epithelial cells. 230 52

To investigate whether alteration in interferon (IFN) production might serve as a biomarker for certain toxic chemical exposures, an in vivo mouse model system was studied. Female C3H mice were injected intraperitoneally with varying doses of benzo[a]pyrene (BP), and at various times subsequent to this treatment, serum IFN levels, following Sendai virus induction, were determined by a cytopathic effect inhibition assay. Doses of 4.6 mg/mouse (180 mg/kg body weight) caused a significant depression in IFN production at 12, 48, and 120 h after BP administration. Doses of 0.46 mg also produced significant decreases at 48 h following exposure. At 48 h post-BP treatment, the reduction in serum IFN titers in treated animals relative to controls was: 62% for the 0.46-mg dose, and 94% for the 4.6-mg dose. These results indicate that systemic administration of BP can significantly depress the whole-animal IFN response to viral stimulation, and that such depression can persist for a rather extended period at certain dose levels.
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PMID:Inhibition of murine interferon production following in vivo administration of benzo[a]pyrene. 242 12

The level of cytochrome P-450 and the oxidation of aminopyrine and benzo(a)pyrene hydroxylase were depressed in hepatic microsomes prepared from mice infected with the gram positive bacteria Listeria monocytogenes. Maximum depression of mixed function oxidase occurred on the 2nd day of infection. This loss in drug biotransformation capacity in the liver was correlated directly with the number of organisms found in that organ. The ability of mice to metabolize drugs in vivo also was impaired during Listeria monocytogenes infection. During the infective period the half-life of theophylline was significantly prolonged and the N-demethylation of aminopyrine as measured by the expiration of 14CO2 from radiolabeled aminopyrine was diminished. The loss of drug metabolism was not due to interferon production, fever or morphological damage to the liver. These results indicate that certain bacterial infections can depress drug biotransformation and elimination in a similar manner to that already reported in viral and parasitic infections. This finding may be of significance to patients receiving drugs which are metabolized by the mixed function oxidase system during episodes of infection with some bacteria.
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PMID:Depression of murine hepatic mixed function oxidase during infection with Listeria monocytogenes. 244 64

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 effect of benzo(a)pyrene (BaP) at different molar (M) concentrations on the in vitro anti-sheep red blood cell (SRBC) plaque (antibody) forming cell (PFC) response and the one-way mixed lymphocyte response (MLR) was tested. Inhibition of the PFC response and the MLR occurred when spleen cells were exposed to a wide range of BaP concentrations from 10(-4) M to 10(-8) M. Maximum depression of the responses occurred at 10(-5) M for PFC production (47% of controls) and for the MLR (19% of controls) as measured by a stimulation index. No significant loss in cell viability was observed at this or lower molar concentrations of BaP. The non-carcinogenic analog of BaP, benzo(e)pyrene, did not suppress PFC responses at comparable concentrations. This in vitro system will facilitate manipulations of T and B lymphocytes and macrophages (adherent cells) in a controlled culture environment for precisely characterizing the sensitivity of these cells and their subpopulations on exposure to BaP.
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PMID:Suppression of humoral and cell-mediated immune responses in vitro by benzo(a)pyrene. 294 86


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