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)

Male Fischer rats were maintained for a period of 17 weeks on an iron-deficient diet along with suitable controls. The effect of long term deprivation of iron on xenobiotic metabolism was studied by the activities of various drug metabolising enzymes in both liver as well as extra-hepatic tissues like lungs, kidneys and intestinal mucosa (I.M.). The results show that among the Phase I (activating) enzymes, the hepatic activities of benzo(a)pyrene hydroxylase (AHH) and microsomal epoxide hydrolase (mEH) are significantly reduced in iron deficiency. The other parameters of the activating system, namely cytochrome P450, aminopyrene demethylase (ADM) and aniline hydroxylase (AH), are not altered. Of the two Phase II (conjugating) enzymes studied, only uridine diphospho glucuronyl transferase (UDPGT) is found to be depressed, but not glutathione S-transferase (GST) in liver in iron deficiency. Activities of Phase I enzymes are markedly lowered in extra-hepatic tissues compared to liver; such depression is not observed in conjugating enzymes. Iron deficiency does not seem to make much impact on the enzyme activities of extra-hepatic tissues. Overall, the hepatic results suggest a defect in detoxification mechanisms in iron deficiency. Such impairment may very well predispose an iron-deficient host to an increased risk of carcinogenesis.
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PMID:Effect of long term iron deficiency on the activities of hepatic and extra-hepatic drug metabolising enzymes in Fischer rats. 785 40

We evaluated humoral immunity by measuring IgG, IgA, IgM, and IgE concentrations in 274 male workers in an iron foundry in Cracow, Poland. There were two groups: 199 coke oven workers and 76 cold-rolling mill workers. The groups were similar with respect to age, length of work (average 15 years), and smoking habits. Exposure to polycyclic aromatic hydrocarbons (PAHs), assessed by personal and area monitoring, ranged from 0.2 to 50 micrograms/m3 benzo[a]pyrene in coke plant workers and was of 3-5 magnitudes higher than in the cold-rolling mill employees. Comparison of the two groups revealed a marked depression of mean serum IgG and IgA in coke oven workers (p < 0.001, Student's unpaired t-test). In the same subjects, serum IgM had a tendency to decrease, whereas serum IgE showed a trend toward higher values. Thus, workers exposed chronically to complex mixtures of air pollutants, composed primarily of PAHs, develop immunosuppression. It remains to be established whether the immunosuppression described here is related to the frequent development of lung cancer reported in coke plant employees. Workers exposed chronically to PAHs should have serum immunoglobulins monitored regularly.
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PMID:Humoral immunosuppression in men exposed to polycyclic aromatic hydrocarbons and related carcinogens in polluted environments. 973 2

Acute intraperitoneal administration of benzo(a)pyrene (80 mg/kg b.wt.) resulted in time-dependent increases in chromosome aberrations, especially of break-type in the bone marrow of treated mice. Pretreatment with murine interferon-alpha/beta (5 x 10(4) IU daily for two days) caused a significative decrease in the cytogenetic response in vivo of benzo(a)pyrene (up to 51%) and a stabilization of aberrant cells up to 48 hr. The administration of murine interferon-alpha/beta gave rise to a marked depression of microsomal monooxygenase system after 24 hr, as exemplified by the significant reduction of cytochrome P450 content as well as deethylation of ethoxyresorufin. Interferon treatment delayed the obtainment of basal levels of oxidative metabolism to approximately 30 hr. After interferon plus benzo(a)pyrene treatment, ethoxyresorufin O-deethylase activity showed a reduction up to 60%; levels comparable to benzo(a)pyrene treated group were restored by 48 hr. Immunoblotting analysis confirmed reduced CYP1A1 level. Results suggest that the inhibition of benzo(a)pyrene hepatic metabolism by interferon was reflected by changes in its clastogenic activity. Persistence of low level of chromosome aberration at 48 hr may be reconducible to other interferon sensitive processes than effects on hepatic mixed-function oxidase system, such as DNA repair activity and cell proliferation.
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PMID:The modulating activity of interferon on benzo(a)pyrene bioactivation and clastogenesis in mice. 809 Jun 95

Few studies have investigated the chronic cytokinetic effects of carcinogen exposure in the mouse skin. We report two experiments involving the repeated application of benzo[a]pyrene (BaP) to the dorsal skin of female Ha/ICR mice. In the first experiment, the cytokinetic, inflammatory, and DNA adduct responses were studied daily over a 9-day period encompassing the fourth and fifth weekly applications of BaP at doses of 16, 32, and 64 micrograms. The second experiment involved the same cytokinetic measurements at 1, 3, 5, and 8 months, and the weekly BaP doses were 4, 8, and 16 micrograms. The first study showed that after each application of 32 or 64 micrograms BaP, there was a wave of slow DNA synthesis in the epidermis which peaked at 24 hr, in coincidence with a wave of BaP-DNA adducts, followed by the appearance of dead and damaged keratinocytes. For the first few days after BaP application there was a depression in the mitotic rate which recovered several days before the next BaP application. There was a predominantly monocytic dermal inflammation throughout the observation period. In the second experiment, at the lower BaP doses, there was proliferative depression at 1 month, without dermal inflammation. With continued exposure, the proliferative depression changed to a dose-dependent increase in the rate of proliferation and dermal inflammation. The level of BaP-DNA adducts was followed in the 4 micrograms/week dose group, which showed a threefold increase after 4 months with the appearance of inflammation and heightened cell proliferation. These results suggest that the delayed inflammatory reaction, possibly based on a cell-mediated immune reaction to BaP, might have been responsible for the late cytokinetic responses and the associated increase in the level of BaP-DNA adducts.
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PMID:Epidermal cytokinetics, DNA adducts, and dermal inflammation in the mouse skin in response to repeated benzo[a]pyrene exposures. 856 Apr 81

The rates and products of the reactions of (+/-)-7beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (1) and (+/-)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (2) in water and dioxane-water mixtures have been determined over a pH range wider than that of earlier studies. This study provides additional insight on the mechanisms of the pH-independent reactions of 1 and 2. The rate profile for reaction of 1 shows acid-catalyzed hydrolysis at pH <5, a rate plateau at pH 5-9.5, a negative inflection at pH 10-11.5, and a rate increase at pH >11.5. The rate decrease between pH 10 and pH 11.5 is accompanied by a decrease in the yield of tetrols from 60% (pH 8) to 29% (pH 11.2) and is interpreted to be the result of a partial change in mechanism brought about by attack of hydroxide ion acting as a base to deprotonate a carbocation intermediate and regenerate 1 at pH >10, thus reducing the contribution of the pathway for tetrol formation in which water attacks the carbocation. The rate profile for the reaction of 2 exhibits only a single rate plateau at intermediate pH, along with increases in rate at low and high pH because of second-order reactions of 2 with H+ and HO-, respectively. The lack of a rate depression at pH >10 and the product studies for the reaction of 2 in dilute sodium azide solutions suggest that the tetrol-forming reactions of the pH-independent reaction of 2 are concerted or near-concerted.
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PMID:New insights on the mechanisms of the pH-independent reactions of benzo[a]pyrenes 7,8-diol 9,10-epoxides. 1144 82

A highly efficient procedure for converting 7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (1) to its trans-9,10-chlorohydrin (5) with excellent yield and purity by the reaction of anhydrous HCl in THF has been developed. The rate of reaction of 5 has been determined as a function of sodium chloride concentration in 1:1 dioxane-water solutions. A large common ion rate depression for the reaction of the chlorohydrin was observed, and the rate data are fit to a mechanism in which all of the tetrol products are formed by the reaction of water with the C-10 carbocation intermediate. Yet, the cis/trans ratio of tetrols from the reaction of the carbocation intermediate from the hydrolysis of chlorohydrin 5 is different than the cis/trans tetrol ratio from the acid-catalyzed hydrolysis of diol epoxide 1, which hydrolyzes via a carbocation with the same connectivity as that formed in the hydrolysis of 5. To rationalize these results, it is proposed that the S(N)1 reaction of chlorohydrin 5 yields a different distribution of carbocation conformations than that formed from the reaction of 1 with H(+). The energy barrier for the inversion of these carbocation conformations must be large relative to the energy barriers for the reaction of each carbocation conformation with water. In solutions containing sufficient concentrations of chloride ion, however, a lower energy pathway via a halohydrin exists for the interconversion of the carbocation conformations. Thus, chloride ion catalyzes the interconversion of these two carbocation conformations.
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PMID:Chloride ion catalyzed conformational inversion of carbocation intermediates in the hydrolysis of a benzo[a]pyrene 7,8-diol 9,10-epoxide. 1245 12

The cytochrome P450 (CYP1A1) enzyme metabolically activates many polycyclic aromatic hydrocarbons, including benzo[a]pyrene (BaP), to DNA- and protein-binding intermediates that are associated with toxicity, mutagenesis, and carcinogenesis. As a result, it is widely accepted that CYP1A1 potentiates the toxicity of this class of chemicals. In distinct contrast, we show here that CYP1A1 inducibility is essential in the detoxication of oral BaP. We compared Cyp1a1(-/-) knockout mice, having the genetic absence of the CYP1A1 enzyme, with Cyp1a1(+/+) wild-type mice. At an oral BaP dose of 125 mg/kg/day, Cyp1a1(-/-) mice died within 30 days whereas Cyp1a1(+/+) mice displayed no outward signs of toxicity. The rate of BaP clearance was 4-fold slower in Cyp1a1(-/-) than Cyp1a1(+/+) mice. The cause of death in Cyp1a1(-/-) mice receiving oral BaP seemed to be immunotoxicity, including toxic chemical depression of the bone marrow; some toxic effects in Cyp1a1(-/-) mice were noted at a BaP dose as low as 1.25 mg/kg/day. DNA post-labeling studies demonstrated dramatically higher BaP-DNA adduct levels in all Cyp1a1(-/-) tissues assayed, with the exception of the small intestine, which is probably a major site of BaP metabolism in Cyp1a1(+/+) mice. Different BaP-DNA adduct patterns were also observed between the two genotypes receiving oral BaP. Despite previous studies in vitro and in cell culture that have shown a participatory role for CYP1A1 in BaP toxicity, the present data indicate that, in the intact animal, inducible CYP1A1 is extremely important in detoxication and protection against oral BaP toxicity.
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PMID:Oral exposure to benzo[a]pyrene in the mouse: detoxication by inducible cytochrome P450 is more important than metabolic activation. 1510 51

In recent years, population declines related to viral outbreaks in marine mammals have been associated with polluted coastal waters and high tissue concentrations of certain persistent, lipophilic contaminants. Such observations suggest a contributing role of contaminant-induced suppression of cell-mediated immunity leading to decreased host resistance. Here, we assessed the effects of the prototypic polycyclic aromatic hydrocarbon (PAH), benzo[a]pyrene (B[a]P), and two polychlorinated biphenyls (PCBs), CB-156 and CB-80, on the T-cell proliferative response to mitogen in harbor seal peripheral lymphocytes. Despite the variability associated with our samples from free-ranging harbor seals, we observed a clear suppressive effect of B[a]P (10 uM) exposure on T cell mitogenesis. Exposures to 10 uM CB-156 and CB-80, and 1.0 and 0.1 uM B[a]P, did not produce significant depression in lymphoproliferation. Exposure to the model PAH at 10 uM resulted in a 61% (range 34-97%) average reduction in lymphoproliferation. We were able to rule out a direct cytotoxic effect of B[a]P, indicating that observed effects were due to altered T cell function. Based on our in vitro results, we hypothesize that extensive accumulation of PAH by top-trophic-level marine mammals could alter T cell activation in vivo and impaired cell-mediated immunity against viral pathogens.
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PMID:Proliferative responses of harbor seal (Phoca vitulina) T lymphocytes to model marine pollutants. 1514 18

(+/-)-7beta,8alpha-Dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (DE-1) undergoes reaction with anhydrous HCl in dioxane to yield predominantly ( approximately 94%) a single chlorohydrin. This chlorohydrin was assigned structure 9, in which the chloro goup at C-10 is located cis to the C-9 hydroxyl group, on the basis of its (1)H NMR spectrum. This result is in contrast to the reaction of a diastereomeric benzo[a]pyrene 7,8-diol 9,10-epoxide (DE-2) with HCl, which yields only trans-chlorohydrin 8. The hydrolysis of cis-chlorohydrin 9 in 10:90 dioxane-water solutions yields the same ratio of tetrols ( approximately 89% cis/11% trans) as that formed by acid-catalyzed hydrolysis of DE-1. This result again contrasts with the hydrolysis of trans-chlorohydrin 8, which undergoes hydrolysis to give tetrols in a ratio different from that from acid-catalyzed hydrolysis of DE-2. A marked common ion rate depression in the hydrolysis of cis-chlorohydrin 9 is observed, which shows that hydrolysis proceeds via an intermediate carbocation that has a sufficient lifetime to be trapped by external chloride ion. The observation that DE-1 reacts with HCl to give mainly the cis-chlorohydrin is rationalized by quantum chemical calculations that suggest that the cis-chlorohydrin is more stable than the epimeric trans-chlorohydrin.
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PMID:Synthesis and hydrolysis of a cis-chlorohydrin derived from a benzo[a]pyrene 7,8-diol 9,10-epoxide. 1552 84

The complex formation between nonionic alkyldimethylamine oxide (CnDMAO, n=14, 16, and 18) and sodium palmitate (NaPa) in the solid phase of CnDMAO/NaPa mixtures and the dependence of the interaction parameter beta of the regular solution theory (RST) on the mixed micelle composition of C16DMAO/NaPa mixtures were investigated. The dissolution temperature showed a maximum at a NaPa mole fraction X(Pa)(*) of 0.3-0.4 for C16DMAO/NaPa and 0.2 for C18DMAO/NaPa. The compositions of the complexes suggested by X(Pa)(*) are C16DMAO: NaPa=3:2 or 2:1 and C18DMAO:NaPa=4:1. The composition X(Pa)(*) depended on the chain length of the amine oxides. The maximum was not observed in the case of the C14DMAO/NaPa/water system. In the range 0.7< or =X(Pa)< or =1.0, dissolution temperature depression was observed with decreasing X(Pa). The dissolution temperature depression was analyzed by taking into account the nonideal behavior in the mixed micelles and the counterion binding on the mixed micelle surface. The negative beta values were obtained for all three mixed systems. It was shown that the counterion activity remained practically constant in the range of 0.7< or =X(Pa)< or =1.0. The cmc values of C16DMAO/NaPa mixtures were determined by pyrene fluorescence measurement. For C16DMAO/NaPa mixtures, the dependence of the RST interaction parameter beta on the mixed micelle composition X(Pa) was determined for a wide range (0.2< or =X(Pa) < or =0.9). In the range 0.2< or =X(Pa)< or =0.5, the beta values were obtained from an analysis of cmc based on the RST. In the range 0.7< or=X(Pa)< or=0.9, the beta values were obtained from an analysis of the dissolution temperature depression. From the analysis of the micelle composition dependence of the beta values, a short-range attractive interaction between the headgroup of C16DMAO and palmitate anion is suggested.
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PMID:Complex formation in alkyldimethylamine oxide/sodium palmitate/water mixtures. 1569 44


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