Promotional activities of the non-genotoxic carcinogen bemitradine (SC-33643)

Bemitradine (SC‐33643), a diuretic antihypertensive agent, was studied for its carcinogenicity in a 2‐year bioassay in Charles River CD rats via dietary admix at dosages of 50, 150 and 450 mg kg−1 for up to 97 weeks (after which they were followed for eight additional weeks without treatment). Body...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of applied toxicology 1992-06, Vol.12 (3), p.157-164
Hauptverfasser: Gad, Shayne C., Burton, Earl, Chengelis, Christopher P., Levin, Stuart, Piper, Charles E., Oshiro, Yuki, Semler, David E.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 164
container_issue 3
container_start_page 157
container_title Journal of applied toxicology
container_volume 12
creator Gad, Shayne C.
Burton, Earl
Chengelis, Christopher P.
Levin, Stuart
Piper, Charles E.
Oshiro, Yuki
Semler, David E.
description Bemitradine (SC‐33643), a diuretic antihypertensive agent, was studied for its carcinogenicity in a 2‐year bioassay in Charles River CD rats via dietary admix at dosages of 50, 150 and 450 mg kg−1 for up to 97 weeks (after which they were followed for eight additional weeks without treatment). Body weights were decreased compared to controls: 5–15% in the female and 10–12% in the male dosage groups by week 105 of the study. Prolactin values were significantly increased in 150 and 450 mg kg−1 females. The compound caused significant increased incidences of liver, thyroid (both sexes) and mammary (females only) neoplasms. The metabolism of bemitradine was studied in both rats and man. Bemitradine and its primary metabolite (SC‐36741; desethylbemitradine) were tested and found to be non‐genotoxic in Ames, rat primary hepatocyte UDS, CHO/HGPRT, CHO cytogenetics, in vivo mouse micronucleus and mouse lymphoma TK+/− (bemitradine only) assays. Finally, in an altered hepatic foci (Y‐glutamyl transpeptidase positive) promotion assay in female Charles River CD rats, bemitradine was found to be a promotor, though not as potent as phenobarbital. We concluded that bemitradine (which has been dropped from development) is a non‐genotoxic carcinogen which appears to act by a hormonally modulated promotional activity in inducing tumors in the liver and mammary glands. Tumors seen in the thyroid were probably secondary to the effects of bemitradine on metabolism.
doi_str_mv 10.1002/jat.2550120303
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_16541637</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>14284066</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3843-44cd2b89616b1f731a797b57576c01548e62bd943d601abeabe16fc3d60a247f3</originalsourceid><addsrcrecordid>eNqFkM1v1DAQxS0EKtvClRtSDgjBIYvHH-PkWK1ooVpKgSJ6sxzHAZckLra3tP89WWXVilMlS5bn_d4b6xHyAugSKGXvLk1eMikpMMopf0QWQOu6BIb8MVlQhrQUXF08JfspXVI6aazaI3uArJYAC_LpLIYhZB9G0xfGZn_ts3epCF2Rf7liDGP5040hhxtvC2ui9WOYBkXjBp-jaf3oijffViXnKPjbZ-RJZ_rknu_uA_L96P356kO5_nz8cXW4Li2vBC-FsC1rqhoBG-gUB6Nq1UglFVoKUlQOWdPWgrdIwTRuOoCd3T4NE6rjB-T1nHsVw5-NS1kPPlnX92Z0YZM0oBSAXD0MClYJijiByxm0MaQUXaevoh9MvNVA9bZoPRWt74ueDC93yZtmcO09Pjc76a92uknW9F00o_XpDpMMZc22WD1jf33vbh9Yqk8Oz__7Qjl7fcru5s5r4m-Niiupf5wea_x6-uVofXGiz_g_QDGjqw</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>14284066</pqid></control><display><type>article</type><title>Promotional activities of the non-genotoxic carcinogen bemitradine (SC-33643)</title><source>MEDLINE</source><source>Wiley Online Library All Journals</source><creator>Gad, Shayne C. ; Burton, Earl ; Chengelis, Christopher P. ; Levin, Stuart ; Piper, Charles E. ; Oshiro, Yuki ; Semler, David E.</creator><creatorcontrib>Gad, Shayne C. ; Burton, Earl ; Chengelis, Christopher P. ; Levin, Stuart ; Piper, Charles E. ; Oshiro, Yuki ; Semler, David E.</creatorcontrib><description>Bemitradine (SC‐33643), a diuretic antihypertensive agent, was studied for its carcinogenicity in a 2‐year bioassay in Charles River CD rats via dietary admix at dosages of 50, 150 and 450 mg kg−1 for up to 97 weeks (after which they were followed for eight additional weeks without treatment). Body weights were decreased compared to controls: 5–15% in the female and 10–12% in the male dosage groups by week 105 of the study. Prolactin values were significantly increased in 150 and 450 mg kg−1 females. The compound caused significant increased incidences of liver, thyroid (both sexes) and mammary (females only) neoplasms. The metabolism of bemitradine was studied in both rats and man. Bemitradine and its primary metabolite (SC‐36741; desethylbemitradine) were tested and found to be non‐genotoxic in Ames, rat primary hepatocyte UDS, CHO/HGPRT, CHO cytogenetics, in vivo mouse micronucleus and mouse lymphoma TK+/− (bemitradine only) assays. Finally, in an altered hepatic foci (Y‐glutamyl transpeptidase positive) promotion assay in female Charles River CD rats, bemitradine was found to be a promotor, though not as potent as phenobarbital. We concluded that bemitradine (which has been dropped from development) is a non‐genotoxic carcinogen which appears to act by a hormonally modulated promotional activity in inducing tumors in the liver and mammary glands. Tumors seen in the thyroid were probably secondary to the effects of bemitradine on metabolism.</description><identifier>ISSN: 0260-437X</identifier><identifier>EISSN: 1099-1263</identifier><identifier>DOI: 10.1002/jat.2550120303</identifier><identifier>PMID: 1629511</identifier><identifier>CODEN: JJATDK</identifier><language>eng</language><publisher>Chichester: John Wiley &amp; Sons, Ltd</publisher><subject>Animals ; Biological and medical sciences ; carcinogenicity ; Carcinogens - toxicity ; CHO Cells ; Chromosome Aberrations ; Cricetinae ; Drug toxicity and drugs side effects treatment ; genotoxicity ; Hypoxanthine Phosphoribosyltransferase - genetics ; In Vitro Techniques ; Liver Neoplasms, Experimental - chemically induced ; Liver Neoplasms, Experimental - pathology ; Lymphoma - genetics ; Medical sciences ; Mice ; Micronucleus Tests ; Miscellaneous (drug allergy, mutagens, teratogens...) ; mutagenicity ; Mutagenicity Tests ; Mutagens - toxicity ; Pharmacology. Drug treatments ; promotion ; Pyrimidines - pharmacokinetics ; Pyrimidines - toxicity ; Rats ; Salmonella typhimurium - genetics ; Triazoles - pharmacokinetics ; Triazoles - toxicity</subject><ispartof>Journal of applied toxicology, 1992-06, Vol.12 (3), p.157-164</ispartof><rights>Copyright © 1992 John Wiley &amp; Sons, Ltd.</rights><rights>1992 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3843-44cd2b89616b1f731a797b57576c01548e62bd943d601abeabe16fc3d60a247f3</citedby><cites>FETCH-LOGICAL-c3843-44cd2b89616b1f731a797b57576c01548e62bd943d601abeabe16fc3d60a247f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjat.2550120303$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjat.2550120303$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,781,785,1418,27929,27930,45579,45580</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=5265921$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1629511$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gad, Shayne C.</creatorcontrib><creatorcontrib>Burton, Earl</creatorcontrib><creatorcontrib>Chengelis, Christopher P.</creatorcontrib><creatorcontrib>Levin, Stuart</creatorcontrib><creatorcontrib>Piper, Charles E.</creatorcontrib><creatorcontrib>Oshiro, Yuki</creatorcontrib><creatorcontrib>Semler, David E.</creatorcontrib><title>Promotional activities of the non-genotoxic carcinogen bemitradine (SC-33643)</title><title>Journal of applied toxicology</title><addtitle>J. Appl. Toxicol</addtitle><description>Bemitradine (SC‐33643), a diuretic antihypertensive agent, was studied for its carcinogenicity in a 2‐year bioassay in Charles River CD rats via dietary admix at dosages of 50, 150 and 450 mg kg−1 for up to 97 weeks (after which they were followed for eight additional weeks without treatment). Body weights were decreased compared to controls: 5–15% in the female and 10–12% in the male dosage groups by week 105 of the study. Prolactin values were significantly increased in 150 and 450 mg kg−1 females. The compound caused significant increased incidences of liver, thyroid (both sexes) and mammary (females only) neoplasms. The metabolism of bemitradine was studied in both rats and man. Bemitradine and its primary metabolite (SC‐36741; desethylbemitradine) were tested and found to be non‐genotoxic in Ames, rat primary hepatocyte UDS, CHO/HGPRT, CHO cytogenetics, in vivo mouse micronucleus and mouse lymphoma TK+/− (bemitradine only) assays. Finally, in an altered hepatic foci (Y‐glutamyl transpeptidase positive) promotion assay in female Charles River CD rats, bemitradine was found to be a promotor, though not as potent as phenobarbital. We concluded that bemitradine (which has been dropped from development) is a non‐genotoxic carcinogen which appears to act by a hormonally modulated promotional activity in inducing tumors in the liver and mammary glands. Tumors seen in the thyroid were probably secondary to the effects of bemitradine on metabolism.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>carcinogenicity</subject><subject>Carcinogens - toxicity</subject><subject>CHO Cells</subject><subject>Chromosome Aberrations</subject><subject>Cricetinae</subject><subject>Drug toxicity and drugs side effects treatment</subject><subject>genotoxicity</subject><subject>Hypoxanthine Phosphoribosyltransferase - genetics</subject><subject>In Vitro Techniques</subject><subject>Liver Neoplasms, Experimental - chemically induced</subject><subject>Liver Neoplasms, Experimental - pathology</subject><subject>Lymphoma - genetics</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Micronucleus Tests</subject><subject>Miscellaneous (drug allergy, mutagens, teratogens...)</subject><subject>mutagenicity</subject><subject>Mutagenicity Tests</subject><subject>Mutagens - toxicity</subject><subject>Pharmacology. Drug treatments</subject><subject>promotion</subject><subject>Pyrimidines - pharmacokinetics</subject><subject>Pyrimidines - toxicity</subject><subject>Rats</subject><subject>Salmonella typhimurium - genetics</subject><subject>Triazoles - pharmacokinetics</subject><subject>Triazoles - toxicity</subject><issn>0260-437X</issn><issn>1099-1263</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1992</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkM1v1DAQxS0EKtvClRtSDgjBIYvHH-PkWK1ooVpKgSJ6sxzHAZckLra3tP89WWXVilMlS5bn_d4b6xHyAugSKGXvLk1eMikpMMopf0QWQOu6BIb8MVlQhrQUXF08JfspXVI6aazaI3uArJYAC_LpLIYhZB9G0xfGZn_ts3epCF2Rf7liDGP5040hhxtvC2ui9WOYBkXjBp-jaf3oijffViXnKPjbZ-RJZ_rknu_uA_L96P356kO5_nz8cXW4Li2vBC-FsC1rqhoBG-gUB6Nq1UglFVoKUlQOWdPWgrdIwTRuOoCd3T4NE6rjB-T1nHsVw5-NS1kPPlnX92Z0YZM0oBSAXD0MClYJijiByxm0MaQUXaevoh9MvNVA9bZoPRWt74ueDC93yZtmcO09Pjc76a92uknW9F00o_XpDpMMZc22WD1jf33vbh9Yqk8Oz__7Qjl7fcru5s5r4m-Niiupf5wea_x6-uVofXGiz_g_QDGjqw</recordid><startdate>199206</startdate><enddate>199206</enddate><creator>Gad, Shayne C.</creator><creator>Burton, Earl</creator><creator>Chengelis, Christopher P.</creator><creator>Levin, Stuart</creator><creator>Piper, Charles E.</creator><creator>Oshiro, Yuki</creator><creator>Semler, David E.</creator><general>John Wiley &amp; Sons, Ltd</general><general>Wiley</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7ST</scope><scope>C1K</scope><scope>SOI</scope><scope>7U7</scope></search><sort><creationdate>199206</creationdate><title>Promotional activities of the non-genotoxic carcinogen bemitradine (SC-33643)</title><author>Gad, Shayne C. ; Burton, Earl ; Chengelis, Christopher P. ; Levin, Stuart ; Piper, Charles E. ; Oshiro, Yuki ; Semler, David E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3843-44cd2b89616b1f731a797b57576c01548e62bd943d601abeabe16fc3d60a247f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1992</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>carcinogenicity</topic><topic>Carcinogens - toxicity</topic><topic>CHO Cells</topic><topic>Chromosome Aberrations</topic><topic>Cricetinae</topic><topic>Drug toxicity and drugs side effects treatment</topic><topic>genotoxicity</topic><topic>Hypoxanthine Phosphoribosyltransferase - genetics</topic><topic>In Vitro Techniques</topic><topic>Liver Neoplasms, Experimental - chemically induced</topic><topic>Liver Neoplasms, Experimental - pathology</topic><topic>Lymphoma - genetics</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Micronucleus Tests</topic><topic>Miscellaneous (drug allergy, mutagens, teratogens...)</topic><topic>mutagenicity</topic><topic>Mutagenicity Tests</topic><topic>Mutagens - toxicity</topic><topic>Pharmacology. Drug treatments</topic><topic>promotion</topic><topic>Pyrimidines - pharmacokinetics</topic><topic>Pyrimidines - toxicity</topic><topic>Rats</topic><topic>Salmonella typhimurium - genetics</topic><topic>Triazoles - pharmacokinetics</topic><topic>Triazoles - toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gad, Shayne C.</creatorcontrib><creatorcontrib>Burton, Earl</creatorcontrib><creatorcontrib>Chengelis, Christopher P.</creatorcontrib><creatorcontrib>Levin, Stuart</creatorcontrib><creatorcontrib>Piper, Charles E.</creatorcontrib><creatorcontrib>Oshiro, Yuki</creatorcontrib><creatorcontrib>Semler, David E.</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Environment Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Environment Abstracts</collection><collection>Toxicology Abstracts</collection><jtitle>Journal of applied toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gad, Shayne C.</au><au>Burton, Earl</au><au>Chengelis, Christopher P.</au><au>Levin, Stuart</au><au>Piper, Charles E.</au><au>Oshiro, Yuki</au><au>Semler, David E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Promotional activities of the non-genotoxic carcinogen bemitradine (SC-33643)</atitle><jtitle>Journal of applied toxicology</jtitle><addtitle>J. Appl. Toxicol</addtitle><date>1992-06</date><risdate>1992</risdate><volume>12</volume><issue>3</issue><spage>157</spage><epage>164</epage><pages>157-164</pages><issn>0260-437X</issn><eissn>1099-1263</eissn><coden>JJATDK</coden><abstract>Bemitradine (SC‐33643), a diuretic antihypertensive agent, was studied for its carcinogenicity in a 2‐year bioassay in Charles River CD rats via dietary admix at dosages of 50, 150 and 450 mg kg−1 for up to 97 weeks (after which they were followed for eight additional weeks without treatment). Body weights were decreased compared to controls: 5–15% in the female and 10–12% in the male dosage groups by week 105 of the study. Prolactin values were significantly increased in 150 and 450 mg kg−1 females. The compound caused significant increased incidences of liver, thyroid (both sexes) and mammary (females only) neoplasms. The metabolism of bemitradine was studied in both rats and man. Bemitradine and its primary metabolite (SC‐36741; desethylbemitradine) were tested and found to be non‐genotoxic in Ames, rat primary hepatocyte UDS, CHO/HGPRT, CHO cytogenetics, in vivo mouse micronucleus and mouse lymphoma TK+/− (bemitradine only) assays. Finally, in an altered hepatic foci (Y‐glutamyl transpeptidase positive) promotion assay in female Charles River CD rats, bemitradine was found to be a promotor, though not as potent as phenobarbital. We concluded that bemitradine (which has been dropped from development) is a non‐genotoxic carcinogen which appears to act by a hormonally modulated promotional activity in inducing tumors in the liver and mammary glands. Tumors seen in the thyroid were probably secondary to the effects of bemitradine on metabolism.</abstract><cop>Chichester</cop><pub>John Wiley &amp; Sons, Ltd</pub><pmid>1629511</pmid><doi>10.1002/jat.2550120303</doi><tpages>8</tpages></addata></record>
fulltext fulltext
identifier ISSN: 0260-437X
ispartof Journal of applied toxicology, 1992-06, Vol.12 (3), p.157-164
issn 0260-437X
1099-1263
language eng
recordid cdi_proquest_miscellaneous_16541637
source MEDLINE; Wiley Online Library All Journals
subjects Animals
Biological and medical sciences
carcinogenicity
Carcinogens - toxicity
CHO Cells
Chromosome Aberrations
Cricetinae
Drug toxicity and drugs side effects treatment
genotoxicity
Hypoxanthine Phosphoribosyltransferase - genetics
In Vitro Techniques
Liver Neoplasms, Experimental - chemically induced
Liver Neoplasms, Experimental - pathology
Lymphoma - genetics
Medical sciences
Mice
Micronucleus Tests
Miscellaneous (drug allergy, mutagens, teratogens...)
mutagenicity
Mutagenicity Tests
Mutagens - toxicity
Pharmacology. Drug treatments
promotion
Pyrimidines - pharmacokinetics
Pyrimidines - toxicity
Rats
Salmonella typhimurium - genetics
Triazoles - pharmacokinetics
Triazoles - toxicity
title Promotional activities of the non-genotoxic carcinogen bemitradine (SC-33643)
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-10T13%3A45%3A26IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Promotional%20activities%20of%20the%20non-genotoxic%20carcinogen%20bemitradine%20(SC-33643)&rft.jtitle=Journal%20of%20applied%20toxicology&rft.au=Gad,%20Shayne%20C.&rft.date=1992-06&rft.volume=12&rft.issue=3&rft.spage=157&rft.epage=164&rft.pages=157-164&rft.issn=0260-437X&rft.eissn=1099-1263&rft.coden=JJATDK&rft_id=info:doi/10.1002/jat.2550120303&rft_dat=%3Cproquest_cross%3E14284066%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=14284066&rft_id=info:pmid/1629511&rfr_iscdi=true