Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have explored the effects of PCBs on Ca(2+)-homeostasis and inositol phosphates in an attempt to understand cellular mechanism(s) for neurotoxicity of PCBs. The selected prototypic congeners have non-dioxin-like (2,2'-dichlorobiphenyl; 2,2'-DCB; IUPAC # 4; ortho-substituted) and dioxin-like (3,3',4,4',5-pentachlorobiphenyl; 3,3',4,4',5-PeCB; IUPAC # 126; non-ortho substituted) properties. The hypothesis is that some PCBs in vitro alter Ca(2+)-homeostasis and interfere with intracellular second messengers. One of the consequences of this perturbation is protein kinase C (PKC) translocation, and these events could lead to cytotoxicity. Our results indicate that the non-dioxin like PCB (ortho-substituted one) is active in vitro and perturbed signal transduction mechanism including Ca(2+)-homeostasis and PKC translocation. The effects were seen at relatively low concentrations (5-50 microM), whereas higher concentrations (> 200 microM) were required to produce cytotoxicity. Results from SAR, in general, indicate that congeners with chlorine substitutions at ortho-position or low lateral substitutions (mostly meta-) are active in vitro where as non-ortho congeners are inactive. In summary, these results indicate that low lateral substitution (especially without para-substitution that favor coplanarity) or high lateral content in the presence of ortho-substitution (to hinder coplanarity) may be the most critical structural requirement underlying the activity of PCB congeners in vitro. Additional experiments with polychlorinated diphenyl ethers (PCDEs) and their analogs, where coplanarity is difficult regardless of degree and pattern of chlorination, provided important information supporting our hypothesis that coplanarity plays a key role in the activity of PCBs in vitro. For example, a PCB congener with 3,3',4,4'-chlorine substitutions is not active whereas a PCDE with the same chlorine substitutions is active. Similarity, 4,4'-DCB is not active whereas PCDE with 4,4'-substitutions is active. One major structural difference in PCDE when compared to the corresponding PCB is non-coplanarity. The PCBs compared here are coplanar and not active, whereas PCDEs are non-coplanar and active in vitro in neuronal preparations. Molecular mechanics calculations and conformational searches confirmed the extent of coplanarity among PCBs and PCDEs. Non-ortho PCBs are more coplanar in nature when compared to ortho-PCBs and PCDEs. These results demonstrate that the extent of coplanarity of certain chlorinated aromatic hydrocarbons can affect their potency in vitro, and ortho-substitutions on the biphenyl, which increase non-coplanarity, are characteristics of the most active PCB congeners.
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PMID:Structure-activity relationships of potentially neurotoxic PCB congeners in the rat. 929 92

PCBs have been shown to alter several neurochemical end-points and are implicated in the etiology of some neurological diseases. Recent in vivo studies from our laboratory indicated that developmental exposure to a commercial PCB mixture, Aroclor 1254, caused perturbations in calcium homeostasis and changes in protein kinase C (PKC) activities in rat brain. However, it is not known which molecular substances are targets for PCB-induced developmental neurotoxicity. Since the PKC signaling pathway has been implicated in the modulation of motor behavior as well as learning and memory, and the roles of PKC are subspecies specific, the present study attempted to analyze the effects on selected PKC isozymes in the cerebellum and the hippocampus following developmental exposure (gestational day 6 through postnatal day 21) to a PCB mixture, Aroclor 1254. The results indicated that the developmental exposure to PCBs caused significant hypothyroxinemia and age-dependent alterations in the translocation of PKC isozymes; the effects were greatly significant at postnatal day (PND) 14. Immunoblot analysis of PKC-alpha (alpha) from both cerebellum and hippocampus revealed that developmental exposure to Aroclor 1254 caused a significant decrease in cytosolic fraction and an increase in particulate fraction. There was no significant difference between these two brain regions on the level of fractional changes. However, the ratio between the fractions (particulate/cytosol) from cerebellum only was increased in a dose-dependent manner. Analysis of PKC-gamma (gamma) in cerebellum on PND14 showed a decrease in cytosolic fraction in both dose groups and an increase in particulate fraction at high dose (6 mg/kg) only. The ratio between the two fractions was increased in a dose-dependent manner. In the hippocampus, there was a significant decrease in PKC-gamma in cytosolic fraction of the high-dose group and a significant increase in particulate fraction of the low-dose group. But, the ratio between the fractions showed a significant increase (2.6-fold increase in high dose on PND14). Analysis of PKC-epsilon (epsilon) in cerebellum showed a significant decrease in cytosolic fraction at PND14, while particulate PKand an increase in ratio between fractions at 6 mg/kg on PND14. The results from this study indicate that the patterns of subcellular distributions of PKC isoforms following a developmental PCB exposure were PKC isozyme- and developmental stage-specific. Considering the significant role of PKC signaling in motor behavior, learning and memory, it is suggested that altered subcellular distribution of PKC isoforms at critical periods of brain development may be a possible mechanism of PCB-induced neurotoxic effects and that PKC-alpha, gamma, and epsilon may be among the target molecules implicated with PCB-induced neurological impairments during developmental exposure. It is believed that this is the first report successfully identifying PKC isoforms responding to PCBs during developmental exposure.
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PMID:Alterations in brain protein kinase C isoforms following developmental exposure to a polychlorinated biphenyl mixture. 1265 12

For most Canadians, food represents one of the major sources of environmental contaminants. Among them, organochlorine compounds (OCs) are known to affect calcium (Ca2+) homeostasis. They are neurotoxic by perturbation of Ca2+ channels and pumps, and they interfere with protein kinase C (PKC) and Ca2+ binding protein (CaBP). Ca2+ is an essential element to adequate fetal growth and development. The aim of the present study is to determine the relation between low environmental maternal exposure to OCs, such as polychlorinated biphenyls (PCB 153), Aroclor 1260, p,p'-dichlorodiphenyltrichloroethane (DDT) and p,p'-dichlorodiphenyl-dichloroethane (DDE), Ca2+ levels in serum and placenta, placental Ca2+ transfer, and newborn development. Total Ca2+ and OCs were measured in women's serum samples, as well as in umbilical cord's serum and placenta at term. Placentas were taken for trophoblast cells isolation and Ca2+ incorporation kinetic experiments. Our results were obtained from 30 pregnant women from the southwestern area of Quebec. Concentrations of Aroclor 1260, PCB 153, DDE, and DDT were respectively 6.1, 6.0, 3.1, and 2.9 times lower in the umbilical cord serum than in the mother's serum at term. In the placenta, DDE was accumulated at higher levels than other contaminants. A tendency towards an inverse relation was observed for in OCs found in three compartments and Ca2+ levels in maternal serum and in placental tissues. Maternal Ca2+ concentrations do not influence Ca2+ uptake by syncytiotrophoblast. Only DDE (>/=0.70 mug/l) in maternal serum significantly was associated with a small increase in Ca2+ uptake by syncytiotrophoblast. This study will help us determine if low OC contamination significantly modifies Ca2+ transfer in syncytiotrophoblast.
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PMID:Effects of low concentrations of organochlorine compounds in women on calcium transfer in human placental syncytiotrophoblast. 1297 May 76

17beta-Estradiol (E2) activates non-genomic pathways in MCF-7 cells, and this study investigates the effects of structurally-diverse estrogenic compounds on activation of mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI3-K), protein kinase C (PKC), PKA, and calcium calmodulin-dependent kinase IV (CaMKIV). Activation of kinases was determined by specific substrate phosphorylation and transactivation assays that were diagnostic for individual kinases. The compounds investigated in this study include E2, diethylstilbestrol (DES), the phytoestrogen resveratrol, and the following synthetic xenoestrogens, bisphenol-A (BPA), nonylphenol, octylphenol, endosulfan, kepone, 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), and 2',3',4',5'-tetrachloro-4-biphenylol (HO-PCB-Cl(4)). With the exception of resveratrol, all the compounds activated PI3-K and MAPK. Activation of PKC by the xenoestrogens was structure-dependent since resveratrol, kepone and HO-PCB-Cl(4) were inactive and only minimal activation of PKA was observed. CaMKIV was activated only by E2 and DES, and HO-PCB-Cl(4) was a potent inhibitor of CaMKIV-dependent activity. These results demonstrate that activation of estrogen receptor-alpha-mediated non-genomic pathways by estrogenic compounds in MCF-7 cells is structure-dependent and can result in activation or inhibition of kinase activities.
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PMID:Activation of kinase pathways in MCF-7 cells by 17beta-estradiol and structurally diverse estrogenic compounds. 1641 91

PCBs produce adverse effects in humans and animals by several modes of action. The first mode of action is binding of coplanar or mono-ortho-PCBs to the aryl hydrocarbon (Ah) receptor leading to effects associated with the activation of this receptor. The remaining PCB congeners do not activate this receptor and have different modes of action underlying their toxic effects. One mode of action that has been shown for di-ortho-substituted non-coplanar PCBs (PCB congeners with two or more chlorines in the ortho-positions) is the interference with intracellular signaling pathways dependent on Ca(2+) homeostasis and the resulting cellular, organ-level and organismal effects. The ortho-substituted non-coplanar congeners produce other cellular or organ-level effects including changes in protein kinase C translocation, changes in cellular dopamine (DA) uptake, formation of reactive oxygen species, and thyroid effects. Here, we propose a scheme for developing relative potency estimates (REP) for the PCB congeners not considered in the TEF scheme used to assess the toxicity of coplanar and mono-ortho-PCBs and chlorinated dioxins and furans. Because a number of the modes of action listed here for the ortho-substituted non-coplanar PCB congeners have been implicated in the neurotoxic effects of these PCBs congeners, this relative potency scheme is referred to here as the Neurotoxic Equivalent (NEQ) scheme for estimating toxicity of PCB mixtures. The Neurotoxic Equivalent (NEQ) values are developed in a way similar in concept to the derivation of the well-known TEF congener values. Although this scheme is in its infancy and the set of NEQ values are limited by the current data, there are several compelling reasons for proposing such a scheme now. First, it should open discussions as to how different modes of action can be utilized to predict congener potency differences for the effects they produce. Second, consideration and evaluation of the ability of the proposed NEQ scheme to predict the toxicity of PCB mixtures will assist in the identification of the specific modes of action relevant to the effects produced by non-coplanar PCBs. If other modes of action are suggested and subsequently identified, then other schemes of relative potency could be developed specifically for those modes of action, distinct from either the TEF scheme or the NEQ scheme. Knowing these other modes of action and the relative toxicity of the various congeners would advance our understanding of PCB toxicology and thereby ultimately improve our ability to estimate the toxic potency of PCB mixtures for each identified mode of action. Third, a quantitative scheme for assessing the toxicity of the non-coplanar PCB congeners present in a mixture has the potential to improve significantly future risk assessments of PCB mixtures.
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PMID:Development of a neurotoxic equivalence scheme of relative potency for assessing the risk of PCB mixtures. 1747 78