Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the interaction of bisphenol A (BPA, an estrogenic environmental contaminant used in the manufacture of plastics) with the estrogen receptor alpha (ERalpha) transfected into the human HepG2 hepatoma cell line and expanded the study in vivo to examine the effect of BPA on the immature rat uterus. Bisphenol A was 26-fold less potent in activating ER-WT and was a partial agonist with the ERalpha compared to E2. The use of ERalpha mutants in which the AF1 or AF2 regions were inactivated has permitted the classification of ER ligands into mechanistically distinct groups. The pattern of activity of BPA with the ERalpha mutants differed from the activity observed with weak estrogens (estrone and estriol), partial ERalpha agonists (raloxifene or 4-OH-tamoxifen), or a pure antagonist (ICI 182, 780). Intact immature female Sprague-Dawley rats were exposed to BPA alone or with E2 for 3 days. Unlike E2, BPA had no effect on uterine weight; however, like E2, both peroxidase activity and PR levels were elevated, though not to the level induced by E2. Following simultaneous administration, BPA antagonized the E2 stimulatory effects on both peroxidase activity and PR levels but did not inhibit E2-induced increases of uterine weight. These results demonstrate that BPA is not merely a weak estrogen mimic but exhibits a distinct mechanism of action at the ERalpha.
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PMID:Bisphenol A interacts with the estrogen receptor alpha in a distinct manner from estradiol. 978 16

Previous studies have shown that alpha-fetoprotein (AFP) interferes with estrogen (E2)-stimulated growth, including E2-stimulated breast cancer growth. In an effort to localize the antiestrotrophic portion of the molecule, the C-terminal one-third (200 amino acids) of human AFP, known as Domain III, was produced in a baculovirus expression system as a fusion protein containing an amino terminal histidine tag. The histidine tag was included to facilitate purification by metal ion affinity chromatography. The purified recombinant Domain III fusion protein was functionally similar to full-length natural AFP isolated from human cord sera or from cultured human hepatoma cells (HepG2) in that they all produced significant and quantitatively similar inhibition of E2-stimulated growth of immature mouse uterus. Furthermore, the dose-response profiles of the recombinant Domain III AFP and natural full-length AFP were similar. Preincubation of either protein in a molar excess of E2 lowered the minimally effective antiestrotrophic dose and produced a difference spectrum consistent with a change in conformation. These findings indicate that the antiestrotrophic activity of AFP is contained within the third domain of the molecule, and they have obvious implications for the production of biologically active peptides derived from this portion of the AFP molecule.
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PMID:The recombinant third domain of human alpha-fetoprotein retains the antiestrotrophic activity found in the full-length molecule. 1021 47

Factor I (FI) is a regulatory serine protease of the complement system which cleaves three peptide bonds in the alpha-chain of C3b and two bonds in the alpha-chain of C4b thereby inactivating these proteins. The human protein and the recently characterized mouse factor I are heterodimers of about 88,000 MW which consist of a non-catalytic heavy chain of 50,000 MW which is linked to a catalytic light chain of 38,000 MW by a disulphide bond. For the screening of a rat liver cDNA library we used a hybridization probe produced by polymerase chain reaction (PCR) using degenerated primers which corresponded to conserved parts of the human and the murine factor I nucleotide sequences. One of the identified sequences, which had a length of 2243 base pairs (bp), contained the complete coding region and the whole 3' untranslated region. The length of the coding region in rat consisted of 1812 bp followed by a 3' untranslated region of 207 bp including the polyadenylation signal and the beginning of the poly A tail. Comparison of the rat cDNA-derived coding sequence revealed identities of 87% to the mouse and of 78% to the human FI nucleotide sequence. The translation product of rat FI mRNA was 604 amino acid residues (aa) in length with an identity of 85% to the mouse (603 aa) and 69% to the human protein (583 aa). The comparison of the molecular mass predicted by the primary structure and derived from rat FI isolated from rat serum as detected in immunoblot analyses suggested a glycosylation of more than 20% of the total mass of the FI protein. Expression studies using reverse transcription (RT)-PCR assays indicated that FI-specific mRNA could neither be identified in B cells, nor in T cells, monocytes or granulocytes from rat and human peripheral blood nor in rat peritoneal macrophages. These data were in agreement with the results of RT-PCR obtained with several human lymphoma cell lines (Jurkat, MOLT-4, HUT102, Wil 2-NS, Ramos, Raji, U937) all of which were devoid of FI-specific mRNA. In accord with our data from two rat hepatoma cell lines (FAO and H4IIE) and one from man (HepG2) only isolated rat hepatocytes (HC) but neither Kupffer cells (KC), hepatic stellate cells (HSC; Ito cells) nor sinusoidal endothelial cells (SEC) expressed FI-specific mRNA. FI mRNA was also detected in human umbilical vein endothelial cells (HUVEC) and in the uterus and small intestine of the rat. Spleen and lymph nodes did not contain any detectable FI-specific mRNA.
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PMID:Rat complement factor I: molecular cloning, sequencing and expression in tissues and isolated cells. 1058 9

Twenty-one monkeys (cynomolgus, rhesus, African green) were fed cyclamate (100 mg/kg and 500 mg/kg) in the diet five times per week from a few days after birth and continuing for up to 24 years. Malignant tumors were diagnosed in three 24-year-old cyclamate monkeys; these were metastatic colon carcinoma (rhesus; 500 mg/kg), metastatic hepatocellular carcinoma (cynomolgus; 500 mg/kg), and a small, well differentiated adenocarcinoma of the prostate (cynomolgus; 100 mg/kg). Benign tumors were found at necropsy in three females; these were adenoma of the thyroid gland (rhesus; 100 mg/kg) and two cases of leiomyoma of the uterus (rhesus; 100 mg/kg and 500 mg/kg). No tumors were detected in an age-matched control group of 16 monkeys. Examination of the testes revealed complete testicular atrophy in one of the old cyclamate monkeys, and focal germ cell aplasia (Sertoli-only tubules) in two other cyclamate monkeys. Focal spermatogenic interruption (maturation arrest) at various germ cell levels mixed with normal spermatogenesis was observed in both the cyclamate-treated and the control monkeys, all of which were over 20 years old. Measurements of terminal cyclohexylamine concentrations showed that three of the males dosed with cyclamate at 500 mg/kg were high converters, with plasma concentrations comparable to the levels that produce testicular atrophy in rats. However, only one of the three high converters showed histologic evidence of irregular spermatogenesis. The overall conclusion is that the testicular abnormalities and the sporadic cases of different malignancies found after more than 20 years of dosing do not provide clear evidence of a toxic or carcinogenic effect of sodium cyclamate in monkeys.
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PMID:Long-term toxicity and carcinogenicity study of cyclamate in nonhuman primates. 1065 18

A full-length cDNA clone encoding the retinol binding protein (RBP) was isolated from a mouse liver cDNA library by hybridization screening. The nucleotide sequence of murine RBP is 85 and 95% homologous to that of human and rat RBP, respectively, with a deduced amino acid sequence > or = 83% homologous to both species. Analysis of the tissue expression pattern of RBP mRNA in the female mouse indicated relatively abundant expression in the liver, with lesser amounts in extrahepatic tissues including adipose, kidney, spleen and uterus, suggesting that these tissues may have a significant role in retinol homeostasis. Mouse liver cell RBP regulation by retinoids was also investigated. Both all-trans retinoic acid (AT-RA) and 9-cis retinoic acid (9c-RA) induced RBP mRNA expression in a dose- and time-dependent manner. Maximal levels (up to 4-fold above controls) were observed at > or = 48 h following treatment of both mouse hepatoma cells in vitro and in vivo in mice receiving a single, oral dose of either retinoid. Interestingly, 9c-RA was more potent at RBP induction in both in vivo and in vitro systems. Given the extent and temporal pattern of RBP induction, we suggest that the RA-mediated increase in liver RBP is part of a cellular protection mechanism. Increased levels of RBP would facilitate sequestration and possibly cellular export of RA in cells receiving prolonged exposure to high levels of RA, thus minimizing toxicity.
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PMID:Mouse retinol binding protein gene: cloning, expression and regulation by retinoic acid. 1105 51

An ovarian hepatoid carcinoma associated with minimal alpha-fetoprotein (AFP) production is described. The tumor involved both ovaries, and had metastasized to the omentum, uterus and retroperitoneal lymph nodes. The neoplastic cells were arranged in sheets, had abundant eosinophilic cytoplasm, central nuclei and distinct cellular borders. Despite the morphologic similarity to the histology of a hepatocellular carcinoma, elevation of the serum AFP level was minimal, at 74.0 ng ml-1 (normal range: under 20 ng ml-1), and the value normalized after surgery and subsequent chemotherapy. An immunohistochemical technique revealed focal staining for albumin in the tumor tissue and AFP in the uterine metastasis. Since the primary tumor itself did not stain for AFP, it is suggested that there may be hepatoid ovarian carcinomas without AFP production, a situation found in some hepatocellular carcinomas.
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PMID:Ovarian hepatoid carcinoma without staining for alpha-fetoprotein in the primary site. 1157 97

It has been hypothesized that environmental contaminants that modulate endocrine signaling pathways may be causally linked to adverse health effects in humans. There has been particular concern regarding synthetic estrogens and their role in disrupting normal development of the male reproductive tract. Most estrogenic industrial compounds, such as bisphenol A (BPA) and nonylphenol, typically bind estrogen receptors alpha (ERalpha) and beta (ERbeta) and induce transactivation of estrogen-responsive genes/reporter genes, but their potencies are usually > or = 1,000-fold lower than observed for 17beta-estradiol (E2). Selective estrogen receptor modulators (SERMs) represent another class of synthetic estrogens that are being developed for treatment of hormone-dependent problems. The SERMs differentially activate wild-type ERalpha and variant forms expressing activation function 1 (ER-AF1) and AF2 (ER-AF2) in human HepG2 hepatoma cells transfected with a pC3-luciferase construct, and these in vitro differences reflect their unique in vivo biologies. The HepG2 cell assay has also been used in our laboratories to investigate the estrogenic activities of the following structurally diverse synthetic and phytoestrogens: 4'-hydroxytamoxifen; BPA; 2',4',6'-trichloro-4-biphenylol; 2',3',4',5'-tetrachloro-4-biphenylol; p-t-octylphenol; p-nonylphenol; naringenin; kepone; resveratrol; and 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE). The results show that synthetic and phytoestrogens induce distinct patterns of gene activation in HepG2 and U2 osteogenic sarcoma cells, suggesting that these compounds will induce tissue-specific in vivo ER agonist or antagonist activities. The predicted differences between these compounds, based on results of the in vitro bioassay, have been confirmed. For example, BPA inhibits E2-induced responses in the rodent uterus, and HPTE and structurally related compounds are ERalpha agonists and ERbeta antagonists in assays carried out in HepG2 and other cancer cell lines.
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PMID:Toxicology of environmental estrogens. 1180 Jan 69

Nitropolycyclic aromatic hydrocarbons (NPAHs) are found in diesel exhaust and ambient air. NPAHs as well as polycyclic aromatic hydrocarbons (PAHs) are known to have mutagenicity, carcinogenicity, and endocrine-disruptive effects. In the present study, the inducibility of the human cytochrome P450-1 (CYP1) family by NPAHs was compared with those produced by their parent PAHs and some reductive metabolites, amino-PAHs. Furthermore, to investigate the differences in the inducibility of the CYP1 family in human tissues, various human tissue-derived cell lines, namely HepG2 (hepatocellular carcinoma), ACHN (renal carcinoma), A549 (lung carcinoma), MCF-7 (breast carcinoma), LS-180 (colon carcinoma), HT-1197 (bladder carcinoma), HeLa (cervix of uterus adenocarcinoma), OMC-3 (ovarian carcinoma), and NEC14 (testis embryonal carcinoma), were treated with NPAHs, PAHs, or amino-PAHs. The mRNA levels of CYP1A1, CYP1A2, and CYP1B1 were determined with reverse transcription-polymerase chain reaction (RT-PCR). The cell lines were classified into two groups: CYP1 inducible cell lines, comprising HepG2, MCF-7, LS-180, and OMC-3 cells, and CYP1 non-inducible cell lines, comprising ACHN, A549, HT-1197, HeLa, and NEC14 cells. In inducible cell lines, the induction profile of chemical specificity was similar for CYP1A1, CYP1A2, and CYP1B1, although the extent of induction differed among the cell lines and for the CYP isoforms. Pyrene, 1-nitropyrene, 1-aminopyrene, 1,3-, 1,6-, and 1,8-dinitropyrenes slightly induced CYP1 mRNAs, but 1,3-dinitropyrene produced a 6-fold induction of CYP1A1 mRNA in MCF-7 cells. 2-Nitrofluoranthene and 3-nitrofluoranthene exhibited stronger inducibility than fluoranthene in the inducible cell lines. 6-Nitrochrysene induced CYP1 mRNAs to the same extent or more potently than chrysene. The induction potencies of 6-nitrobenzo[ a]pyrene and 7-nitrobenz[ a]anthracene were weaker than those of their parents benzo[ a]pyrene and benz[ a]anthracene, respectively. This study demonstrated that NPAHs as well as PAHs induced human CYP1A1, CYP1A2, and CYP1B1 in a chemical-, CYP isoform-, and cell-specific manner. Furthermore, the cell-specific induction of the CYP1 family was not related to the expression levels of aryl hydrocarbon receptor, aryl hydrocarbon nuclear translocator, or estrogen receptors alpha and beta.
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PMID:Induction of CYP1A1, CYP1A2, and CYP1B1 mRNAs by nitropolycyclic aromatic hydrocarbons in various human tissue-derived cells: chemical-, cytochrome P450 isoform-, and cell-specific differences. 1210 46

Theophylline is an alkaloid found in tea (Thea sinensis) and chocolate and is structurally related to caffeine and theobromine. Theophylline is used as a pharmaceutical agent. It stimulates the heart and central nervous system, relaxes the smooth muscles of the bronchi and blood vessels, and causes diuresis. The drug is used mainly as a bronchodilator in obstructive airway diseases, such as bronchial asthma, and for myocardial stimulation. Theophylline was nominated for toxicologic and carcinogenicity testing as a representative of the purine structural subclass, particularly because of its relationship to purines such as caffeine, 1-methyl-3-hydroxyguanine, and 3-hydroxy-1-methylxanthine, the latter two compounds having been shown to induce sarcomas in rats. Additional reasons for testing theophylline included its widespread use in humans as a pharmaceutical agent, its possible genotoxicity in vitro, and the lack of information on its potential toxicity and/or carcinogenicity under conditions of chronic oral usage. Based on reported teratogenicity and testicular toxicity, it was also recommended that reproductive studies be included in the evaluation of theophylline. The oral route of administration was selected because it is the primary route of human exposure, and the gavage route was selected because it mimics the pharmaceutical use of theophylline in humans. Male and female F344/N rats and B6C3F1 mice were given theophylline (greater than 99% pure) in feed or in corn oil by gavage for 16 days or 14 weeks or in corn oil by gavage for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, mouse bone marrow, and mouse peripheral blood. 16-DAY FEED STUDY IN RATS: Groups of five male and five female F344/N rats were given 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm theophylline in feed for 16 days, which resulted in approximate daily doses of 50, 100, 250, 450, or 1,000 mg theophylline/kg body weight to males and 75, 150, 250, 450, or 1,100 mg/kg to females. All rats survived until the end of the study. The final mean body weights and body weight gains of 8,000 ppm males and females were significantly less than those of the controls. The absolute and relative testis weights of 4,000 ppm males were significantly greater than those of the controls. Increased incidences of uterine hypoplasia were observed microscopically in exposed groups of females. 16-DAY GAVAGE STUDY IN RATS: Groups of five male and five female F344/N rats were given 0, 12.5 (twice daily), 25 (once daily), 50 (once daily), 50 (twice daily), 100 (once daily), 200 (once daily), 200 (twice daily), or 400 (once daily) mg theophylline/kg body weight in corn oil by gavage. All rats receiving 400 mg/kg once daily and all but one female receiving 200 mg/kg twice daily died during the study. In groups dosed once daily, final mean body weights and body weight gains of males receiving 100 or 200 mg/kg and mean body weight gains of females receiving 50, 100, or 200 mg/kg were less than those of controls. The final mean body weights and body weight gains of groups receiving theophylline twice daily were generally similar to those of groups receiving the same daily dosages once daily. Clinical findings included rapid or labored respiration, hunched posture, and squinting. In groups dosed once daily, absolute and relative uterus weights of females receiving 100 or 200 mg/kg once daily were significantly less than those of the controls, and the absolute and relative uterus weights of females receiving 100 mg/kg once daily were significantly less than those of females receiving 50 mg/kg twice daily. Uterine atrophy was observed in three females receiving 200 mg/kg twice daily. Periarteritis of the mesenteric arteries was observed in two males and two females receiving 400 mg/kg once daily. 16-DAY FEED STUDY IN MICE: Groups of five male and five female B6C3F1 mice were given 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm theophylline in feed for 16 days, resulting in approximate daily doses of 250, 475, 950, 1,800, or800, or 2,000 mg theophylline/kg body weight to males and 300, 450, 1,225, 2,000, or 4,375 mg/kg to females. All mice survived until the end of the study. Final mean body weights of 4,000 and 8,000 ppm females and mean body weight gains of 2,000, 4,000, and 8,000 ppm females were significantly greater than those of the controls. Feed consumption by exposed groups was similar to that by the controls, except that by the 8,000 ppm males, which was approximately 40% the amount of feed consumed by the control group. Histopathologic examinations were not performed due to the absence of mortality and significant exposure-related lesions. 16-DAY GAVAGE STUDY IN MICE: Groups of five male and five female B6C3F1 mice were given 0, 12.5 (twice daily), 25 (once daily), 50 (once daily), 50 (twice daily), 100 (once daily), 200 (once daily), 200 (twice daily), or 400 (once daily) mg theophylline/kg body weight in corn oil by gavage. Three males and all females receiving 400 mg/kg once daily died on day 1. There were no significant differences in final mean body weights or body weight gains. There were no histopathologic findings attributed directly to theophylline. 14-WEEK FEED STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were given 0, 1,000, 2,000, or 4,000 ppm theophylline in feed for 14 weeks, which resulted in approximate daily doses of 75, 125, or 250 mg theophylline/kg body weight to males and 75, 125, or 275 mg/kg to females. The final mean body weight of 1,000 ppm females was significantly greater than that of the control group. Feed consumption by exposed groups was similar to that by the controls. Mean cell volume and mean cell hemoglobin were significantly greater in males exposed to 2,000 or 4,000 ppm than those in the control group. Segmented neutrophil counts of all groups of exposed females were significantly greater than that of the control group. The absolute and relative kidney weights of 4,000 ppm males were significantly greater than those of the controls, and there was an exposure-related increase in the severity of nephropathy in males. Exposure-related increases in the incidences of mesenteric and/or pancreatic periarteritis were observed in males and females. 14-WEEK GAVAGE STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were given 0, 37.5, 75, or 150 mg theophylline/kg body weight in corn oil by gavage for 14 weeks. One male and one female receiving 150 mg/kg died before the end of the study. The mean body weight gain of 150 mg/kg females was significantly greater than that of the controls. Mean cell volume of 150 mg/kg males and mean cell hemoglobin of all groups of dosed males were significantly greater than those of the control group. There were slight dose-dependent increases in the incidences of mesenteric periarteritis in dosed males and females. 14-WEEK FEED STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were given 0, 1,000, 2,000, or 4,000 ppm theophylline in feed for 14 weeks, resulting in approximate daily doses of 175, 400, or 800 mg theophylline/kg body weight to males and 225, 425, or 850 mg/kg to females. All mice survived until the end of the study. The final mean body weights and body weight gains of all exposed groups of males and females were significantly less than those of the controls. Feed consumption by exposed groups was similar to that by the controls. Leukocyte, segmented neutrophil, and lymphocyte counts of 4,000 ppm males were significantly greater than those of the controls. Leukocyte and segmented neutrophil counts of 2,000 or 4,000 ppm females were significantly greater than those of the controls. There were no histopathologic findings attributed directly to theophylline exposure. 14-WEEK GAVAGE STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were given 0, 75, 150, or 300 mg theophylline/kg body weight in corn oil by gavage for 14 weeks. Three males and all females receiving 300 mg/kg, one 75 mg/kg male, and one control female died before the end of the study. Final mean body weights and body weight gains of 150 and 300 mg/kg males were significantly less than those of the controls. Mean cell volume and mean cell hemoglobin of 300 mg/kg males were significantly greater than those of the controls. There were no histopathologic findings attributed directly to theophylline treatment. 2-YEAR GAVAGE STUDY IN RATS: Groups of 50 male and 50 female rats were given 7.5, 25, or 75 mg theophylline/kg body weight in corn oil by gavage for 2 years. Survival and Body Weights: There were no significant differences in survival between dosed and control groups. Final mean body weights of all groups of dosed males and females were significantly less than those of the controls. Pathology Findings: There were no significantly increased incidences of neoplasms in dosed rats. The incidence of chronic inflammation of the mesenteric arteries was significantly increased in males receiving 75 mg/kg compared to the controls. There were doserelated negative trends in the incidences of mammary gland fibroadenoma and fibroadenoma or carcinoma (combined) in females; these differences correlated with decreased body weights. 2-YEAR GAVAGE STUDY IN MICE: Groups of 50 male B6C3F1 mice were given 0, 15, 50, or 150 mg theophylline/kg body weight and groups of 50 female B6C3F1 mice were given 0, 7.5, 25, or 75 mg/kg in corn oil by gavage for 2 years. Survival and Body Weights: Survival of 150 mg/kg males was significantly less than that of the controls. The final mean body weights of 150 mg/kg males, 25 mg/kg females, and 75 mg/kg females were significantly less than those of the control groups. Pathology Findings: There were no treatment-related increases in incidences of nonneoplastic lesions or neoplasms. In males and females, there were decreased incidences of hepatocellular adenoma and of the combined incidences of hepatocellular adenoma or carcinoma compared to the controls. Male mice had a pattern of nonneoplastic liver lesions along with silver-staining helical organisms in the liver consistent with Helicobacter hepaticus infection. The incidences of these liver lesions in 150 mg/kg males were significantly lower than those in control males. Increases in the incidences of hepatocellular neoplasms in male mice have been shown to be associated with H. hepaticus infection when hepatitis is also present. Because of this association, interpretation of the decreased incidence of liver neoplasms in male mice was more difficult. Incidences of lesions at other sites in this study were not considered to have been significantly impacted by H. hepaticus infection or its associated hepatitis. GENETIC TOXICOLOGY: Theophylline was not mutagenic in Salmonella typhimurium, with or without metabolic activation (S9). It induced sister chromatid exchanges but not chromosomal aberrations in cultured Chinese hamster ovary cells. The positive sister chromatid exchange response was noted only in the absence of S9. In vivo, a mouse bone marrow sister chromatid exchange test showed positive results at a standard 23-hour harvest time; however, this test was not repeated and the response is unconfirmed. An in vivo mouse bone marrow chromosomal aberrations test, that employed both standard and extended exposure protocols, gave negative results. The frequency of micronucleated erythrocytes was determined in peripheral blood of male and female mice exposed to theophylline in dosed feed or in corn oil by gavage for 14 weeks. No significant increases in the frequencies of micronucleated cells were seen in male or female mice in either of the studies. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of theophylline in male or female F344/N rats administered 7.5, 25, or 75 mg/kg. There was no evidence of carcinogenic activity of theophylline in male B6C3F1 mice administered 15, 50, or 150 mg/kg or female B6C3F1 mice administered 7.5, 25, or 75 mg/kg. Gavage administration of theophylline caused chronic inflammation of the mesenteric arteries in dosed male rats. Decreased incidences of mammary neoplasms in female rats were likely associated with lower body weights. There were dose-related decreases in the incidences of hepatocellular adenoma and hepatocellular carcinoma in male and female mice. Synonyms: 3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione; 1,3-dimethylxanthine; 1H-purine-2,6-dione; NSC 2066; pseusdotheophylline; theocin; theophyllin; theophylline, anhydrous Trade names: Accurbron; Aerobin; Aerolate III; Afonilum; Aminophylline; Aquaphyllin; Armophylline; Asmalix; Bilordyl; Bronchoretard; Bronkodyl; Cetraphylline; Constant-T; Diffumal; Duraphyl; Duraphyllin; Elixicon; Elixophyllin; Euphylline L.A.; Euphylong; LaBID; Labophylline; Lanophyllin; Lasma; Liquophylline; Optiphyllin; Parkophyllin; Phylocontin; Physpan; Pro-Vent; PulmiDur; Pulmo-Timelets; Quibron; Respbid; Rona-Phyllin; Sabidal; Slo-bid; Slo-Phyllin; Solosin; Sustaire; Tefamin; Teobid; Teofyllamin; Tesona; Theal tablets; Theo-24; Theobid; Theocap; Theochron; Theoclear; Theocontin; Theo-Dur; Theofol; Theograd; Theolair; Theolan; Theolix; Theophyl; Theoplus; Theo-Sav; Theosol; Theospan; Theostat; Theovent; TheoX; T-Phyl; Truphylline; Uni-Dur; Unifyl; Uniphyl; Uniphyllin; Xanthium
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PMID:NTP Toxicology and Carcinogenesis Studies of Theophylline (CAS No. 58-55-9) in F344/N Rats and B6C3F1 Mice (Feed and Gavage Studies). 1257 77

Arsenic is a known human carcinogen, but development of rodent models of inorganic arsenic carcinogenesis has been problematic. Since gestation is often a period of high sensitivity to chemical carcinogenesis, we performed a transplacental carcinogenicity study in mice using inorganic arsenic. Groups (n = 10) of pregnant C3H mice were given drinking water containing sodium arsenite (NaAsO(2)) at 0 (control), 42.5, and 85 ppm arsenite ad libitum from day 8 to 18 of gestation. These doses were well tolerated and body weights of the dams during gestation and of the offspring subsequent to birth were not reduced. Dams were allowed to give birth, and offspring were weaned at 4 weeks and then put into separate gender-based groups (n = 25) according to maternal exposure level. The offspring received no additional arsenic treatment. The study lasted 74 weeks in males and 90 weeks in females. A complete necropsy was performed on all mice and tissues were examined by light microscopy in a blind fashion. In male offspring, there was a marked increase in hepatocellular carcinoma incidence in a dose- related fashion (control, 12%; 42.5 ppm, 38%; 85 ppm, 61%) and in liver tumor multiplicity (tumors per liver; 5.6-fold over control at 85 ppm). In males, there was also a dose-related increase in adrenal tumor incidence and multiplicity. In female offspring, dose-related increases occurred in ovarian tumor incidence (control, 8%; 42.5 ppm, 26%; 85 ppm, 38%) and lung carcinoma incidence (control, 0%; 42.5 ppm, 4%; 85 ppm, 21%). Arsenic exposure also increased the incidence of proliferative lesions of the uterus and oviduct. These results demonstrate that oral inorganic arsenic exposure, as a single agent, can induce tumor formation in rodents and establishes inorganic arsenic as a complete transplacental carcinogen in mice. The development of this rodent model of inorganic arsenic carcinogenesis has important implications in defining the mechanism of action for this common environmental carcinogen.
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PMID:Transplacental carcinogenicity of inorganic arsenic in the drinking water: induction of hepatic, ovarian, pulmonary, and adrenal tumors in mice. 1258 88


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