Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Effects of chronic exposure to PCBs on the microsomal cytochrome P450 (CYP) enzymes in liver and testis of bulls (Bos taurus) were determined by comparing the constitutive and PCB-induced alkoxyresorufin O-dealkylase and testosterone hydroxylase activities. Specific inductions of the prevailing hepatic ethoxyresorufin O-deethylation and 6 beta-hydroxylation of testosterone are suggestive of the induction of CYP1A1 and CYP3A-like enzymes by PCBs. A high level of PCB-inducible androstenedione formation was also found. The hepatic CYP2B activities (i.e. pentoxyresorufin O-depentylase and testosterone 16 beta-hydroxylase) and CYP2C11-like testosterone 2 alpha-hydroxylase were increased only weakly. The testicular microsomal CYP activities were non-specifically reduced by the PCB exposure, except for the androstenedione formation and 16 beta-hydroxylation of testosterone. The inhibition of the activity of mitochondrial CYP11A, as the rate-limiting enzyme of steroidogenesis measured with resorufin 3 beta-hydroxy-22,23-bisnor-5-cholenyl ether as the fluorogenic substrate, exceeded 50% in testes of the PCB-contaminated bulls. The latter activity as well as the hepatic testosterone 6 beta-hydroxylation and hepatic and testicular androstenedione formation may significantly contribute to the decrease in testosterone levels after the PCB intake.
Comp Biochem Physiol A Mol Integr Physiol 1998 May
PMID:Effects of chronic exposure to PCBs on cytochrome P450 systems and steroidogenesis in liver and testis of bulls (Bos taurus). 977 99

Locust Ion Transport Peptide (ITP) a member of the arthropod neuropeptide family which includes hyperglycemic, vitellogenesis-inhibiting, and moult-inhibiting hormones (CHH, VIH, MIH, respectively) was synthesized as proposed by Meredith et al. (1996) with terminal amidation of amino acid residue 72 and with 3 disulphide bridges. This is the first member of this family to be synthesized. Biological activities of synthetic ITP (synITP) were very similar to those previously reported for ITP purified from Schistocerca corpora cardiaca (ScgITP) and partially sequenced by Audsley et al. (1992a, b). Dose-response curves for both synITP and ScgITP on ileal transport of Cl- (measured as increased short-circuit current, delta Isc), were similar with a EC50 of 1-2 nM. The Isc time course and maximum delta Isc across ileal epithelia at different dosages of synITP and ScgITP had similar patterns as did changes in transepithelial open-circuit potential (Vt) and resistance (Rt), reflecting changes in salt transport which drives fluid absorption. Disulphide bridges were shown to be required for biological activity of synITP, which caused the same 4-fold increase in ileal fluid transport rate (Jv) as previously reported for ScgITP. Both synITP and ScgITP caused only partial stimulation of rectal Isc and had no significant effect on rectal Jv. These results indicate that the structure of ITP predicted earlier from cDNA is correct.
Insect Biochem Mol Biol 1999 Jan
PMID:Biological actions of synthetic locust ion transport peptide (ITP). 1007 Jul 40

PCBs adversely affect various reproductive functions. Little is known about the embryo- toxic effects during the preimplantation period in mammals. In the present study the effects of various mixtures of highly purified PCB-congeners on embryo morphology, blastocyst formation, embryo size and cell proliferation were investigated. For 24 hr, day 3 morulae and day 4 blastocysts were cultured in the presence/absence of coplanar congeners (PCB77, PCB126, and PCB169), non-coplanar congeners (PCB28, PCB52, PCB101, PCB118, PCB138, PCB153, PCB180) or both mixtures in concentrations ranging from 0.3 ng/mL to 60 microg/mL total PCB. The main effects were (1) degeneration of all embryos at 60 microg/mL, (2) reduction of cell proliferation in day 4 embryos only by coplanar PCB; in day 3 embryos, however, by all PCB-mixtures, and (3) reduction of cell proliferation in a non-linear dose response with the strongest impairment caused by the lowest concentration. Cell proliferation was decreased by 0.3 ng/mL coplanar PCB to 50% of the level in control blastocysts. Our results show that purified PCB congeners in the range of 0.3 ng/mL to 30 microg/mL affect the development of preimplantation embryos in a stage-specific and congener-specific manner. This study provides first evidence for an embryotoxic potential of coplanar PCB congeners.
Mol Reprod Dev 1999 Oct
PMID:Stage-specific effects of defined mixtures of polychlorinated biphenyls on in vitro development of rabbit preimplantation embryos. 1047 72

Several studies have shown that some organochlorine compounds act like estrogen in certain animals and in vitro cell culture systems, and therefore, there is a possibility that they could promote the process of tumorigenesis in breast cancer cells. In our previous study, two representative organochlorines, 1,1,1-trichloro 2-o-chlorophenyl-2'-p-chlorophenyl ethane (o,p'-DDT) and beta-1,2,3,4,5,6-hexachlorocyclohexane (beta HCH), were found to directly activate the protein tyrosine kinase of Neu (c-erbB-2 proto-oncogene product) immunoprecipitates isolated from MCF-7 breast cancer cells. In the current study, we also found that 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) at 1 nM and alpha-HCH isomers at 100 nM could also significantly activate protein tyrosine kinase of Neu immunoprecipitates in a cell-free system. We also found that organochlorines result in an increase of Neu protein tyrosine kinase after intact cell treatment in estrogen-depleted medium. This Neu kinase activation by beta-HCH (100 nM) was blocked when the cells were pretreated with Neu mRNA antisense oligonucleotide (p < 0.07, Student's t-test). Endogenously added alpha-, beta-, and gamma-HCH, o,p'-DDT, 2,2'-dichlorobiphenyl (2,2'-PCB), and 2,4,5-T at 100 nM were found to promote foci formation in postconfluent cultures of this cell line. This stimulatory effect caused by 17beta-estradiol, o,p'-DDT, and beta-HCH on foci formation was inhibited by coincubation with Neu monoclonal antibody (p < 0.05). Those two events induced by organochlorines (i.e., Neu kinase activation and foci formation) seemed causally correlated.
J Biochem Mol Toxicol 1999
PMID:Correlation between the activation of Neu tyrosine kinase and promotion of foci formation induced by selected organochlorine compounds in the MCF-7 model system. 1048 16

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that binds and mediates responses to many halogenated aromatic compounds (HACs). Exposure to mixtures of HACs frequently results in nonadditive behavior in both in vivo and in vitro assays. One cause is antagonism, which results when two or more ligands compete for a limited supply of the AhR; one interacts agonistically to induce a strong response, and the other interacts unproductively, eliciting little or no response. This study involves the mechanism by which HACs induce CYP 1A1. Agonistic (e.g., TCDD) and unproductive (e.g., PCB 153) HACs behaved similarly through the stages of initial AhR binding and conversion of the initial AhR-ligand complex to the form that possesses increased affinity for the bound ligand. They diverged in the ability of the AhR-HAC complex to bind to a synthetic oligonucleotide containing the consensus dioxin response enhancer sequence, as studied by the gel retardation assay. Competition for the Ah receptor was used to explain antagonistic behavior between TCDD and other HACs in both the gel retardation assay and the downstream response of CYP 1A1 induction in primary rat hepatocytes.
J Biochem Mol Toxicol 2000
PMID:Competitive behavior in the interactive toxicology of halogenated aromatic compounds. 1063 Apr 20

It is known that lower-chlorinated biphenyls are metabolically activated to electrophilic quinoid species capable of binding to DNA. Also, certain metabolites are capable of redox cycling, thereby increasing oxidative stress in biological systems. In the present study, we tested mono-, di-, tri-, tetra-, penta-, hexa-, and heptachlorinated biphenyls for their ability to bind with DNA and to induce oxidative DNA damage. We present additional evidence that several PCB congeners form DNA adducts after metabolic activation, which can be detected by the nuclease P1- or butanol-enrichment procedures of the (32)P-postlabeling technique. Butanol and nuclease P1 enrichments showed different adduct recoveries, depending on the level of chlorination of the biphenyls. Application of the nuclease P1 enrichment showed that the incubation of 2-chloro-; 3, 4-dichloro-; 2,4,4'-trichloro-; 3,4,5-trichloro-; and 2,2',5, 5'-tetrachlorobiphenyl with calf thymus DNA and liver microsomes from rats treated with phenobarbital, followed by oxidation with a peroxidase, produced five to eight different DNA adducts. For these lower-chlorinated biphenyls, butanol enrichment generally showed a lower recovery. For some higher substituted congeners (3,3',4,4', 5-pentachloro-, 2,2',3,4,4',5'-hexachloro-, 2,2',4,4',5, 5'-hexachloro-, and 2,2',3,4,4',5,5'-heptachlorobiphenyl), after butanol enrichment a single dominant spot was observed, which was absent in the nuclease P1 procedure. After incubation of calf thymus DNA with either higher- or lower-chlorinated PCB congeners, we were not able to detect significantly increased levels of oxidative DNA damage above background levels, measured as 8-oxo-7, 8-dihydro-2'deoxyguanosine. In view of the carcinogenicity of PCB mixtures in animals and the ability of PCB metabolites to bind covalently to DNA, rats were orally treated with a mixture of PCBs (Aroclor 1242). PCB-DNA adduct levels were analyzed in PCB target organs: liver, thymus, glandular stomach, spleen, testes, seminal vesicles and prostate DNA. In vivo PCB-DNA adducts could not be detected by either the butanol- or by the NP1-enrichment procedure in rat target tissue DNA. Also, no differences in oxidative DNA damage could be observed between PCB-treated rats and controls. These results indicate a lack of DNA reactivity of PCB mixtures in vivo.
Environ Mol Mutagen 2000
PMID:Induction of DNA adducts by several polychlorinated biphenyls. 1101 5

The induction of 7-ethoxyresorufin-o-deethylase (EROD) activity was examined in three rainbow trout pituitary cell lines: RTP-91E, RTP-91F and RTP-2. RTP-91E and RTP-91F were developed from the pituitary of a male and have epithelial-like and fibroblast-like morphologies, respectively. RTP-2, which was described previously, was developed from the pituitary of a female and has an epithelial-like shape. In all cell lines EROD activity was induced by 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD). Immunoblotting with the polyclonal antibody, anti-trout CYP1A1(277-294)/KLH, confirmed induction of a 58-kDa polypeptide. Potential inhibitors of the aryl hydrocarbon receptor, geldanamycin and alpha-naphthoflavone, inhibited EROD induction by TCDD. Other compounds inducing EROD activity were 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), and 3-methylcholanthrene (3MC). When judged by the concentration eliciting 50% of the maximal response (EC50), induction was similar in RTP-2 and RTP-91E, and less effective in RTP-91F. Regardless of the cell line, the rank order from most to least potent inducer on the basis of EC50 value was TCDD> or =PCDD>TCDF>PCB 126>>3MC. When induction potencies were expressed relative to TCDD, the values obtained with the pituitary cell lines were similar to previously published values derived with a rainbow trout liver cell line.
Comp Biochem Physiol A Mol Integr Physiol 2001 Feb
PMID:Induction of 7-ethoxyresorufin-O-deethylase activity by planar chlorinated hydrocarbons and polycyclic aromatic hydrocarbons in cell lines from the rainbow trout pituitary. 1122 80

Human sex hormone-binding globulin (SHBG) binds sex steroids with high affinity. In plasma, the number of SHBG steroid-binding sites far exceeds the molar concentrations of sex steroids, and will accommodate other ligands such as phytoestrogens and fatty acids. We have therefore developed a screening assay to identify ligands for SHBG, which exist in our diet or environment. This assay allows the binding of potential ligands to SHBG to be assessed under physiological conditions, and is sensitive to the effects of plasma constituents. Several classes of endocrine active compounds were tested, including hydroxy-polychlorinated biphenyls (HO-PCBs), phthalate esters, monoesters, chlorinated pesticides, as well as synthetic estrogens and phytoestrogens. The relative binding affinities (RBAs) of various compounds to SHBG were determined in competitive displacement assays, by comparison with 17 beta-estradiol (RBA=100). Synthetic estrogens bound SHBG with RBAs of 0.4 (ethinylestradiol)-0.2 (diethylstilbestrol), while some phytoestrogens bound with RBAs of 0.12 (coumestrol)-0.04 (naringenin). Many compounds did not bind to SHBG with sufficient affinity to allow RBA measurements, and these include: several phytoestrogens, such as genistein and kaempferol, polychlorinated biphenyls, phthalate esters and monoesters. Of nine HO-PCB congeners tested only 4-OH-2', 3', 4', 5'-tetraCB and 4-OH-2, 2', 3', 4', 5'-pentaCB bound SHBG in undiluted serum with RBAs of 0.05 and 0.11. Although all test compounds bound to SHBG with much lower affinity than endogenous sex steroids, these interactions may be physiologically relevant in situations where plasma SHBG levels are high and endogenous sex steroid levels are low, such as in pre-pubertal children and women taking oral contraceptives.
J Steroid Biochem Mol Biol 2000 Dec 15
PMID:Interactions between human plasma sex hormone-binding globulin and xenobiotic ligands. 1122 33

Exposure of Atlantic croaker (Micropogonias undulatus) to the polychlorinated biphenyl mixture (Aroclor 1254, PCB; 1 mg/kg body wt/day for 30 days) during the early-recrudescence phase of the gonadal cycle results in the impairment of LH secretion and gonadal growth. In order to determine whether impairment was due to disruption of the stimulatory GnRH neuroendocrine pathway, we compared various parameters of the GnRH-LH system in early recrudescing vs. spermiating (mature) fish. Seabream GnRH (GnRH) content in the preoptic anterior hypothalamic area (POAH) and pituitary, pituitary GnRH receptor concentrations, and basal and GnRH analog (GnRHa)-induced LH secretion were significantly higher in gonadally mature croaker compared to early-recrudescing fish. In a subsequent experiment, the effects of PCB on the same neuroendocrine indices were investigated during the gonadal recrudescence phase of croaker. PCB exposure during the period of testicular maturation prevented the natural increase in GnRH content in the POAH but not in the pituitary. This finding suggests that PCB may impair GnRH synthesis in the POAH. The number of pituitary GnRH receptors also remained significantly lower in the PCB-exposed group, which was likely due to an impairment of GnRH release. The GnRH content in the POAH, number of pituitary GnRH receptors, and LH secretion in the PCB-exposed group were comparable to those in early-recrudescing fish, suggesting an impairment of normal maturation of the GnRH-LH system during the gonadal recrudescence phase. This impairment may be due to a direct action of PCB on GnRH neurons and/or indirectly via interference with other neurotransmitter pathways that modulate GnRH function.
Comp Biochem Physiol B Biochem Mol Biol 2001 Jun
PMID:Alterations in the GnRH-LH system in relation to gonadal stage and Aroclor 1254 exposure in Atlantic croaker. 1139 57

Structure-dependent estrogen receptor alpha (ER alpha) agonist and antagonist activities of synthetic and natural estrogenic compounds were investigated in human HepG2, MDA-MB-231 and U2 cancer cell lines. Compounds used in this study include 4'-hydroxytamoxifen, ICI 182,780, bisphenol-A (BPA), 2',4',6'-trichloro-4-biphenylol (3Cl-PCB-OH), 2',3',4',5'-tetrachloro-4-biphenylol (4Cl-PCB-OH), p-t-octylphenol, p-nonylphenol, naringenin, kepone, resveratrol, and 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE). Cells were transfected with a construct (pERE(3)) containing three tandem estrogen responsive elements (EREs) and either wild-type estrogen receptor alpha (ER-wt) or variants expressing activation function-1 (ER-AF1) or AF-2 (ER-AF2). The ER agonist activities of the synthetic mono and dihydroxy aromatic compounds are comparable in all three-cell lines, whereas the activities of naringenin, kepone and resveratrol are dependent on cell context and expression of wild-type or variant forms of ER alpha. In contrast, the ER antagonist activities for these compounds were highly complex and, with the exception of 3Cl-PCB-OH, all compounds inhibited E2-induced wild-type or variant ER action. Results of this in vitro study suggest that the estrogenic and antiestrogenic activity of structurally diverse synthetic and natural estrogenic compounds is complex, and this is consistent with published data that often give contradictory results for these compounds.
J Steroid Biochem Mol Biol 2001 Jul
PMID:Differential activation of wild-type and variant forms of estrogen receptor alpha by synthetic and natural estrogenic compounds using a promoter containing three estrogen-responsive elements. 1153 Feb 81


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