Toxic substance mechanisms最新文献

{"title":"CHOLESTASIS AND MITOCHONDRIAL DYSFUNCTION: A REVIEW","authors":"A. Rolo, C. Palmeira","doi":"10.1080/10769180052008878","DOIUrl":"https://doi.org/10.1080/10769180052008878","url":null,"abstract":"Although liver diseases such as cholestasis are a significant clinical problem, the cellular mechanisms disturbed during these pathophysiological processes are still controversial. Progress along several lines of research have revealed several possible lines of action, pointing to new approaches to medical treatment. Impairment of mitochondrial function seems to be a central biochemical pathway of cell dysfunction during disease. Additionally, perturbation of other cellular functions could play a pivotal role in triggering these pathological events. Our review provides an overview of probable events involved in the cholestatic disease process.","PeriodicalId":87425,"journal":{"name":"Toxic substance mechanisms","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88414046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"THE EFFECTS OF 5-AZA-2'-DEOXYCYTIDINE (D-AZA) ON SONIC HEDGEHOG EXPRESSION IN MOUSE EMBRYONIC LIMB BUDS.","authors":"Stacy Branch,&nbsp;Ida W Smoak","doi":"10.1080/10769180052008904","DOIUrl":"https://doi.org/10.1080/10769180052008904","url":null,"abstract":"<p><p>5-Aza-2'-deoxycytidine (d-AZA) causes temporally-related defects in the mouse. At 1.0 mg/kg on gestational day (GD) 10, d-AZA causes hindlimb phocomelia. Sonic hedgehog (Shh) plays a significant role in the normal development of limbs in rodent species. Sonic hedgehog peptides, found in the posterior mesenchyme of limb buds, are involved in patterning functions and in the regulation of both anterior-posterior polarity and proximal-distal outgrowth of the limb. The objective of the present study was to analyze alterations in Shh expression subsequent to d-AZA exposure. Pregnant mice were treated with d-AZA via intraperitonlal injection on GD 10. Controls were untreated. The reverse transcription-polymerase chain reaction (RT-PCR), whole mount in situ hybridization (ISH), and whole mount immunohistochemistry (WMI) were used to analyze expression patterns of Shh . For RT-PCR, embryonic hindlimb buds (buds) were taken 0, 4, 8, 12, or 24 hr after exposure. Cyclophilin was used as the baseline monitor. RNA was transcribed to cDNA and used as template with Shh specific primers for amplification. Whole embryos were collected 12 and 24 hr posttreatment for ISH. An antisense primer specific for Shh was used in an oligo-based ISH protocol. Whole embryos were collected 36 and 48 hr posttreatment for WMI. The antibody corresponding to the amino terminal subunit of the Shh peptide was used. There was a treatment related up-regulation of Shh transcripts by 12 and 24 hr posttreatment. The protein response of up-regulation was detectable by 36 and 48 hr posttreatment. Our data suggest that 5-aza-2'-deoxycytidine-induced hindlimb defects may be associated with alterations in the level of Shh expression. This may be part of a cascade of signaling events involved in d-AZA-induced hindlimb defects. Work is ongoing to determine the relationship of other gene species that may cooperate with Shh in the induction of the hindlimb defects.</p>","PeriodicalId":87425,"journal":{"name":"Toxic substance mechanisms","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/10769180052008904","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25995543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"REDUCTION OF CHROMIUM(VI) TO CHROMIUM(V) BY HUMAN MICROSOMAL ENZYMES: EFFECTS OF IRON AND QUINONES","authors":"C. Myers, J. Myers, B. P. Carstens, W. Antholine","doi":"10.1080/10769180051125734","DOIUrl":"https://doi.org/10.1080/10769180051125734","url":null,"abstract":"The NADPH- and NADH-dependent reduction of chromium(VI), a known carcinogen, by human hepatic and lung microsomes likely proceeds through cytochrome b 5 as the common mediator of electron transfer to Cr(VI). Consistent with the ability of cytochrome b 5 to transfer one electron at a time, Cr(V) was generated as a transient intermediate during human microsomal Cr(VI) reduction. The redox cycling of small amounts of iron or quinones significantly accelerated the rate of Cr(VI) reduction, which should accelerate Cr(V) formation. However, Cr(V) did not accumulate under these conditions, suggesting that Fe(II) and semiquinones also reduce Cr(V). This could accelerate the formation of Cr(IV), a highly reactive intermediate. An indirect electron paramagnetic resonance (EPR) method suggested that Cr(IV) was produced during microsomal Cr(VI) reduction. Since iron and quinones significantly altered the rates of formation of reactive Cr intermediates, they could potentially influence cytotoxic damage associated with these intermediates.","PeriodicalId":87425,"journal":{"name":"Toxic substance mechanisms","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87586969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ENDOCRINE DISRUPTION: A CRITICAL REVIEW OF ENVIRONMENTAL ESTROGENS FROM A MECHANISTIC PERSPECTIVE","authors":"R. Witorsch","doi":"10.1080/10769180051125752","DOIUrl":"https://doi.org/10.1080/10769180051125752","url":null,"abstract":"With the aid of such systems as the E-screen assay (MCF-7 human breast cancer cells) and/or estrogen receptor (ER) binding assays, estrogenic activity has been identiŽed in a wide variety of nonsteroidal substances, such as polychlorobiphenyls, alkylphenols, bisphenols, pesticides (e.g., DDT derivatives, methoxychlor, kepone), pharmaceutical agents (e.g., diethylstilbestrol [DES], tamoxifen, raloxifene), and phytoestrogens. With few exceptions (notably DES), most xenoestrogens show weak estrogenic and ER binding activity (e.g., 1/1000 to 1/1,000,000 that of the endogenous hormone, estradiol). A series of observations and episodes, some controversial, have led to the perception that endocrine disruption via hormonally active environmental substances is a hazard to wildlife and humans. As a result of Congressional legislation, the U.S. Environmental Protection Agency (EPA) formed the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) to develop and implement a multitiered program for the screening and testing of potentially 87,000 chemicals and mixtures for hormonal (primarily estrogenic) activity and endocrine disruptive effects. This review explores the issue of xenoestrogens from a mechanistic perspective. Many nonsteroidal substances can interact with the ligand binding domain of the ER, albeit weakly, because they share characteristics common to both estradiol and DES, these being a ring structure (preferably unencumbered phenolic) along with a hydrophobic center. However, ER binding does not explain the nature of the biological response. As exempliŽed by a diversity of estrogenic and antiestrogenic effects exhibited by estradiol, tamoxifen, and raloxifene and by the antiestrogenic effect of DDT in the tiger salamander, different ER ligands evoke distinct response proŽles that appear to be inuenced by the target tissue and species. These distinct proŽles are determined by the ligand itself and the diversity of ER isoforms (® or ̄), response elements, and individual coregulatory proteins that associate with ER. Endocrine disruption may also be inuenced by the role of plasma binding on the delivery of xenoestrogens to cells, chirality of xenoestrogens, cross-talk between ER signaling and other signaling systems (e.g., aryl hydrocarbon receptor), and alternate mechanisms (e.g., antiandrogen effects). In view of the complexities pertaining to mechanisms of action of xenoestrogens and knowledge yet to be obtained in this area, it would appear that the screening and testing approach undertaken by EDSTAC is premature at this time.","PeriodicalId":87425,"journal":{"name":"Toxic substance mechanisms","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73086314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AN ASSESSMENT OF IN VIVO ESTROGENIC ACTIVITY OF BUTYL BENZYL PHTHALATE AND ITS PRINCIPAL MAMMALIAN METABOLITES","authors":"A. Brady, G. Moffat, M. Hall, F. Martens, M. Martens, R. Nair","doi":"10.1080/10769180051125716","DOIUrl":"https://doi.org/10.1080/10769180051125716","url":null,"abstract":"Butyl benzyl phthalate (BBP) has been reported to exhibit weak estrogenic activity in a number of in vitro assays. The monoester metabolites of BBP have been shown to lack estrogenic activity in vitro. This work has evaluated the estrogenic activity of BBP in vivo by examining the ability of BBP and its primary monoester metabolites to stimulate uterine growth in sexually immature female rats. BBP has been administered by both oral and subcutaneous (sc) routes to address the possible differences in systemic exposure patterns and to analyze the pharmacokinetics. Groups of 6 immature female rats were administered BBP or its monoester metabolites daily for 3 days at a range of dose levels up to a maximum tolerated dose (MTD). Twenty-four hours after the last dose, the uteri were excised and weighed. Estradiol benzoate (EB, 0.5 1g/animal/day) was administered sc as a positive control. In all experiments, EB administration increased absolute and relative uterine weights by 3.4to 4.0-fold. BBP dosed orally at 56– 2240 mg/kg/day had no effects on absolute or relative uterine weight. Monobutyl phthalate (1–1000 mg/kg/day) or monobenzyl phthalate (50–1000 mg/kg/day) dosed orally did not increase absolute or relative uterine weight, although the latter produced a small decrease at highest dose levels. BBP dosed sc at 0.5– 5000 mg/kg/day had no effects on uterine weight. In a pharmacokinetic study, the levels of BBP and its monoester metabolites were measured in blood, plasma, and urine over a 24-h period following administration of BBP to immature female","PeriodicalId":87425,"journal":{"name":"Toxic substance mechanisms","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79245838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ROLE OF L-TYPE CALCIUM CHANNELS IN LEAD ACETATE-INDUCED ANTINOCICEPTIVE EFFECTS ON FORMALIN TEST IN MICE","authors":"M. Abdollahi, S. Nikfar, Maryam Kakouiee","doi":"10.1080/107691899229061","DOIUrl":"https://doi.org/10.1080/107691899229061","url":null,"abstract":"In this study, the interaction of three types of calcium channel blockers-nifedipine, diltiazem, and verapamil-on the effects of lead acetateon two types of pain (nociception and inflammation) induced by formalin in mice were examined. To study nociception, the formalin test was selected because of greater resemblance to clinical pain. Lead acetate (50, 75, 100, 125, 150 mg/kg) was administered intraperitoneally 90 min before form alin injection. Nifedipine (5mg/kg), diltiazem (10mg/kg), and verapamil (5mg/kg) alone or in combination with different doses of lead acetate were used. Lead acetate induced a dose-dependent antinociception in both phases of the formalin test. When animals were administered calcium channel blockers alone, diltiazem and verapamil did not induce any significant effect in either phase of the form alin test, but nifedipine induced anti-inflammatory effects in the late phase (p < .01). Pretreatment with nifedipine or diltiazem potentiated the lead acetate antinociceptive effect (e...","PeriodicalId":87425,"journal":{"name":"Toxic substance mechanisms","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1999-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90629275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LIPID PEROXIDATION AND PROTEIN OXIDATION IN AZOTOBACTER VINELANDII EXPOSED TO MERCURY, SILVER, CRUDE OIL, AND FENTON REAGENT","authors":"I. N. Onwurah","doi":"10.1080/107691899229052","DOIUrl":"https://doi.org/10.1080/107691899229052","url":null,"abstract":"A pure strain of Azotobacter vinelandii was isolated from soil samples with no known history of contamination by crude oil, mercury, silver or any other heavy metal salts. The isolate was grown to a density of 10 8 cells/ml as the primary culture, in an enriched mineral Azotobacter medium. From this, 90 ml was pipetted into each of 15 conical flasks divided into five sets of three replicates. A set was treated with mercury (II) chloride (2.5 mmol/l), silver chloride (4.6 mmol/l), Bonny light crude oil (1.0%, w/v), or Fenton reagent. A set with normal Azotobacter medium served as the control. The mean total cell protein harvested from the various flasks ranged from 0.503 to0.245 mg/ml within 48 hr of incubation. The differences in the mean total protein concentrations were statistically significant (p < .05). The protein carbonyl contents from the flasks also were significantly different but for the pair of control/Hg2+ -treated media. Lipid peroxidation levels in all the treated media were significantl...","PeriodicalId":87425,"journal":{"name":"Toxic substance mechanisms","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1999-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91277231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HERBICIDE-INDUCED MITOCHONDRIAL AND CELLULAR LIVER TOXICITY: A REVIEW OF PARAQUAT, DINOSEB, AND 2, 4-D EFFECTS","authors":"C. Palmeira","doi":"10.1080/107691899229070","DOIUrl":"https://doi.org/10.1080/107691899229070","url":null,"abstract":"This review articleis a synthesis of the toxic effects induced by dinoseb, 2, 4-D, and paraquat on liver mitochondrial bioenergetics and hepatic cells. Liver mitochondria and hepatocytes were used as models for toxicological studies, owing to the similarities of the organization and function among mammalian species and the particular role of the liver in cell detoxification mechanisms. The interactions of these herbicides, all of which belong to different chemical families, on mitochondrial respiration, membrane potential, redox complex activities, ATPase, and ATP synthase activities are reviewed and analyzed in detail. Additionally, the cytotoxic effects on isolated hepatocytes regarding cell viability, glutathione status, adenine and pyridine nucleotide contents, lipid peroxidation, protein thiols, and intracellular calcium are discussed. This review article calls attention to the role of mitochondria in the development of cellular toxicity by these herbicides.","PeriodicalId":87425,"journal":{"name":"Toxic substance mechanisms","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1999-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87835960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Testosterone pretreatment enhances cadmium-induced increases in c-myc and c-jun transcript levels in 16 myoblasts","authors":"H. Shimada, W. Achanzar, M. Waalkes, J. Hochadel","doi":"10.1080/107691899229098","DOIUrl":"https://doi.org/10.1080/107691899229098","url":null,"abstract":"Cadmium is a known carcinogen that often targets male reproductive tissues. In many cells cadmium induces expression of the proto-oncogenes c-myc and c-jun. Several steroid hormones can modify the effects of cadmium, including testosterone. Thus, we studied the effects of testosterone on cadmium toxicity or c-myc and c-jun expression in L6 cells. Testosterone at non-toxic doses (0-10 muM) did not modify either cadmium-induced cytotoxicity or expression of metallothionein, a protein involved in acquired cadmium tolerance. Cadmium (5 muM) increased c-myc and c-jun m RNA levels by 3.1-fold and 2.8-fold of control, respectively. Testosterone alone (10 muM) decreased basal levels of c-myc transcript but did not affect c-jun. Despite reducing transcript levels by itself, testosterone pretreatment increased cadmium-induced c-myc transcript accumulation to 5-fold over control. Testosterone pretreatment also enhanced cadmium induction of c-jun mRNA accumulation. Thus, it appears that testosterone increases cadmium...","PeriodicalId":87425,"journal":{"name":"Toxic substance mechanisms","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1999-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72706057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NAPHTHOQUINONES STIMULATE THE RATE OF REDUCTION OF HEXAVALENT CHROMIUM BY HUMAN MICROSOMES","authors":"C. Myers, B. Porgilsson, B. P. Carstens, J. Myers","doi":"10.1080/107691899229089","DOIUrl":"https://doi.org/10.1080/107691899229089","url":null,"abstract":"The NADPH-dependent reduction of chromium (VI), a known carcinogen, by human hepatic microsomes was significantly stimulated by 1,4-naphthoquinone (NQ) or 2-methyl-1,4-naphthoquinone (MNQ) under anaerobic conditions. The most pronounced stimulation occurred when quinone concentrations were increased from 1 to 5 muM. Additional, but smaller, increases were seen with subsequent increases in quinone concentration above 5 muM. These quinones also caused pronounced stimulation of chrom ium(VI) reduction by human lung microsomes. Azo and nitroaromatic compounds, as well as methylviologen (Paraquat), seemed to have little effect. Since marked stimulation occurred with levels of NQ and MNQ that were well below those of the initial chromium(VI) concentration, the quinones probably are being redox-cycled through their semiquinone radicals, and these radicals probably are reducing chromium(VI). In support of this occurrence, NQ and MNQ caused a marked stimulation of NADPH consumption under aerobic conditions, with t...","PeriodicalId":87425,"journal":{"name":"Toxic substance mechanisms","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1999-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87383942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}