4-methylthiobenzoic acid reduces cisplatin nephrotoxicity in rats without compromising anti-tumour activity
Administration of 4-methylthiobenzoic acid (MTBA) (100 mg/kg) strongly reduced cisplatin nephrotoxicity (7.5 mg/kg, 20 min after MTBA) in rats as determined by histopathology and blood urea nitrogen. Anti-tumour activity against a colonie adenocarcinoma, CC 531, that was implanted in rats, was unaff...
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| Veröffentlicht in: | Biochemical pharmacology 1991-06, Vol.41 (12), p.1997-2003 |
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| container_issue | 12 |
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| container_title | Biochemical pharmacology |
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| creator | Boogaard, Pieter J. Lempers, Edwin L.M. Mulder, Gerard J. Meerman, John H.N. |
| description | Administration of 4-methylthiobenzoic acid (MTBA) (100 mg/kg) strongly reduced cisplatin nephrotoxicity (7.5 mg/kg, 20 min after MTBA) in rats as determined by histopathology and blood urea nitrogen. Anti-tumour activity against a colonie adenocarcinoma, CC 531, that was implanted in rats, was unaffected by MTBA pretreatment. Studies with isolated renal proximal tubular cells (PTC) demonstrated that preincubation of the cells with MTBA diminished cisplatin nephrotoxicity
in vitro as it did
in vivo. Preincubation of the PTC with probenecid completely abolished the protective effect of MTBA against cisplatin toxicity. These data indicate that MTBA is actively transported into the PTC. The mechanism of action of MTBA was investigated by NMR studies which showed that cisplatin and
cis-diamminediaquaplatinum(II), its hydrolysis product, reacted with the methylthio-sulphur. We suggest that MTBA after selective accumulation in the kidney inactivates cisplatin intracellularly by nucleophilic attack of the methylthio-sulphur to the Pt-moiety, Since MTBA shows no acute toxicity in the rat, even if administered at very high doses, it may be useful to suppress the nephrotoxic side effects of cisplatin anti-tumour therapy. |
| doi_str_mv | 10.1016/0006-2952(91)90141-Q |
| format | Article |
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in vitro as it did
in vivo. Preincubation of the PTC with probenecid completely abolished the protective effect of MTBA against cisplatin toxicity. These data indicate that MTBA is actively transported into the PTC. The mechanism of action of MTBA was investigated by NMR studies which showed that cisplatin and
cis-diamminediaquaplatinum(II), its hydrolysis product, reacted with the methylthio-sulphur. We suggest that MTBA after selective accumulation in the kidney inactivates cisplatin intracellularly by nucleophilic attack of the methylthio-sulphur to the Pt-moiety, Since MTBA shows no acute toxicity in the rat, even if administered at very high doses, it may be useful to suppress the nephrotoxic side effects of cisplatin anti-tumour therapy.</description><identifier>ISSN: 0006-2952</identifier><identifier>EISSN: 1873-2968</identifier><identifier>DOI: 10.1016/0006-2952(91)90141-Q</identifier><identifier>PMID: 1674872</identifier><language>eng</language><publisher>England: Elsevier Inc</publisher><subject>Adenocarcinoma - drug therapy ; Adenocarcinoma - pathology ; Alanine Transaminase - metabolism ; Animals ; Aspartate Aminotransferases - metabolism ; Cisplatin - therapeutic use ; Cisplatin - toxicity ; Colonic Neoplasms - drug therapy ; Colonic Neoplasms - pathology ; Drug Interactions ; gamma-Glutamyltransferase - metabolism ; Kidney - drug effects ; Kidney - enzymology ; Kidney - physiology ; Kidney Tubules, Proximal - drug effects ; Kidney Tubules, Proximal - metabolism ; Liver - drug effects ; Liver - enzymology ; Liver - physiology ; Magnetic Resonance Spectroscopy ; Male ; Neoplasm Transplantation ; Rats ; Rats, Inbred Strains ; Sulfides - metabolism ; Sulfides - pharmacology</subject><ispartof>Biochemical pharmacology, 1991-06, Vol.41 (12), p.1997-2003</ispartof><rights>1991</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c303t-7dae983bba63ca04a8cc70d82f65ba0ee7f04166e73368c0c160dac975f4e60b3</citedby><cites>FETCH-LOGICAL-c303t-7dae983bba63ca04a8cc70d82f65ba0ee7f04166e73368c0c160dac975f4e60b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/000629529190141Q$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1674872$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Boogaard, Pieter J.</creatorcontrib><creatorcontrib>Lempers, Edwin L.M.</creatorcontrib><creatorcontrib>Mulder, Gerard J.</creatorcontrib><creatorcontrib>Meerman, John H.N.</creatorcontrib><title>4-methylthiobenzoic acid reduces cisplatin nephrotoxicity in rats without compromising anti-tumour activity</title><title>Biochemical pharmacology</title><addtitle>Biochem Pharmacol</addtitle><description>Administration of 4-methylthiobenzoic acid (MTBA) (100 mg/kg) strongly reduced cisplatin nephrotoxicity (7.5 mg/kg, 20 min after MTBA) in rats as determined by histopathology and blood urea nitrogen. Anti-tumour activity against a colonie adenocarcinoma, CC 531, that was implanted in rats, was unaffected by MTBA pretreatment. Studies with isolated renal proximal tubular cells (PTC) demonstrated that preincubation of the cells with MTBA diminished cisplatin nephrotoxicity
in vitro as it did
in vivo. Preincubation of the PTC with probenecid completely abolished the protective effect of MTBA against cisplatin toxicity. These data indicate that MTBA is actively transported into the PTC. The mechanism of action of MTBA was investigated by NMR studies which showed that cisplatin and
cis-diamminediaquaplatinum(II), its hydrolysis product, reacted with the methylthio-sulphur. We suggest that MTBA after selective accumulation in the kidney inactivates cisplatin intracellularly by nucleophilic attack of the methylthio-sulphur to the Pt-moiety, Since MTBA shows no acute toxicity in the rat, even if administered at very high doses, it may be useful to suppress the nephrotoxic side effects of cisplatin anti-tumour therapy.</description><subject>Adenocarcinoma - drug therapy</subject><subject>Adenocarcinoma - pathology</subject><subject>Alanine Transaminase - metabolism</subject><subject>Animals</subject><subject>Aspartate Aminotransferases - metabolism</subject><subject>Cisplatin - therapeutic use</subject><subject>Cisplatin - toxicity</subject><subject>Colonic Neoplasms - drug therapy</subject><subject>Colonic Neoplasms - pathology</subject><subject>Drug Interactions</subject><subject>gamma-Glutamyltransferase - metabolism</subject><subject>Kidney - drug effects</subject><subject>Kidney - enzymology</subject><subject>Kidney - physiology</subject><subject>Kidney Tubules, Proximal - drug effects</subject><subject>Kidney Tubules, Proximal - metabolism</subject><subject>Liver - drug effects</subject><subject>Liver - enzymology</subject><subject>Liver - physiology</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Male</subject><subject>Neoplasm Transplantation</subject><subject>Rats</subject><subject>Rats, Inbred Strains</subject><subject>Sulfides - metabolism</subject><subject>Sulfides - pharmacology</subject><issn>0006-2952</issn><issn>1873-2968</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1991</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE9P3DAQxa2qiC6034BKOVXlEGrHieNckBAqfyQkhNSeLWcy6Q5N4sV2FpZPXy-Lyo3TaGbeex7_GDsS_ERwoX5wzlVeNFXxvRHHDRelyO8-sIXQtUxjpT-yxX_JJ3YQwv221Urss32h6lLXxYL9LfMR43IzxCW5FqdnR5BZoC7z2M2AIQMKq8FGmrIJV0vvonsioLjJ0sTbGLJHiks3xwzcuPJupEDTn8xOkfI4j272KS7SOjk-s73eDgG_vNZD9vvi56_zq_zm9vL6_OwmB8llzOvOYqNl21olwfLSaoCad7roVdVajlj3vBRKYS2l0sBBKN5ZaOqqL1HxVh6yb7vcdM7DjCGadBTgMNgJ3RyMqJpKi0ImYbkTgncheOzNytNo_cYIbraMzZaY2QI0jTAvjM1dsn19zZ_bEbs30w5q2p_u9pg-uSb0JgDhBNiRR4imc_T-A_8AMs6OwQ</recordid><startdate>19910615</startdate><enddate>19910615</enddate><creator>Boogaard, Pieter J.</creator><creator>Lempers, Edwin L.M.</creator><creator>Mulder, Gerard J.</creator><creator>Meerman, John H.N.</creator><general>Elsevier Inc</general><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>7U7</scope><scope>C1K</scope></search><sort><creationdate>19910615</creationdate><title>4-methylthiobenzoic acid reduces cisplatin nephrotoxicity in rats without compromising anti-tumour activity</title><author>Boogaard, Pieter J. ; Lempers, Edwin L.M. ; Mulder, Gerard J. ; Meerman, John H.N.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c303t-7dae983bba63ca04a8cc70d82f65ba0ee7f04166e73368c0c160dac975f4e60b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1991</creationdate><topic>Adenocarcinoma - drug therapy</topic><topic>Adenocarcinoma - pathology</topic><topic>Alanine Transaminase - metabolism</topic><topic>Animals</topic><topic>Aspartate Aminotransferases - metabolism</topic><topic>Cisplatin - therapeutic use</topic><topic>Cisplatin - toxicity</topic><topic>Colonic Neoplasms - drug therapy</topic><topic>Colonic Neoplasms - pathology</topic><topic>Drug Interactions</topic><topic>gamma-Glutamyltransferase - metabolism</topic><topic>Kidney - drug effects</topic><topic>Kidney - enzymology</topic><topic>Kidney - physiology</topic><topic>Kidney Tubules, Proximal - drug effects</topic><topic>Kidney Tubules, Proximal - metabolism</topic><topic>Liver - drug effects</topic><topic>Liver - enzymology</topic><topic>Liver - physiology</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Male</topic><topic>Neoplasm Transplantation</topic><topic>Rats</topic><topic>Rats, Inbred Strains</topic><topic>Sulfides - metabolism</topic><topic>Sulfides - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Boogaard, Pieter J.</creatorcontrib><creatorcontrib>Lempers, Edwin L.M.</creatorcontrib><creatorcontrib>Mulder, Gerard J.</creatorcontrib><creatorcontrib>Meerman, John H.N.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Biochemical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Boogaard, Pieter J.</au><au>Lempers, Edwin L.M.</au><au>Mulder, Gerard J.</au><au>Meerman, John H.N.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>4-methylthiobenzoic acid reduces cisplatin nephrotoxicity in rats without compromising anti-tumour activity</atitle><jtitle>Biochemical pharmacology</jtitle><addtitle>Biochem Pharmacol</addtitle><date>1991-06-15</date><risdate>1991</risdate><volume>41</volume><issue>12</issue><spage>1997</spage><epage>2003</epage><pages>1997-2003</pages><issn>0006-2952</issn><eissn>1873-2968</eissn><abstract>Administration of 4-methylthiobenzoic acid (MTBA) (100 mg/kg) strongly reduced cisplatin nephrotoxicity (7.5 mg/kg, 20 min after MTBA) in rats as determined by histopathology and blood urea nitrogen. Anti-tumour activity against a colonie adenocarcinoma, CC 531, that was implanted in rats, was unaffected by MTBA pretreatment. Studies with isolated renal proximal tubular cells (PTC) demonstrated that preincubation of the cells with MTBA diminished cisplatin nephrotoxicity
in vitro as it did
in vivo. Preincubation of the PTC with probenecid completely abolished the protective effect of MTBA against cisplatin toxicity. These data indicate that MTBA is actively transported into the PTC. The mechanism of action of MTBA was investigated by NMR studies which showed that cisplatin and
cis-diamminediaquaplatinum(II), its hydrolysis product, reacted with the methylthio-sulphur. We suggest that MTBA after selective accumulation in the kidney inactivates cisplatin intracellularly by nucleophilic attack of the methylthio-sulphur to the Pt-moiety, Since MTBA shows no acute toxicity in the rat, even if administered at very high doses, it may be useful to suppress the nephrotoxic side effects of cisplatin anti-tumour therapy.</abstract><cop>England</cop><pub>Elsevier Inc</pub><pmid>1674872</pmid><doi>10.1016/0006-2952(91)90141-Q</doi><tpages>7</tpages></addata></record> |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Adenocarcinoma - drug therapy Adenocarcinoma - pathology Alanine Transaminase - metabolism Animals Aspartate Aminotransferases - metabolism Cisplatin - therapeutic use Cisplatin - toxicity Colonic Neoplasms - drug therapy Colonic Neoplasms - pathology Drug Interactions gamma-Glutamyltransferase - metabolism Kidney - drug effects Kidney - enzymology Kidney - physiology Kidney Tubules, Proximal - drug effects Kidney Tubules, Proximal - metabolism Liver - drug effects Liver - enzymology Liver - physiology Magnetic Resonance Spectroscopy Male Neoplasm Transplantation Rats Rats, Inbred Strains Sulfides - metabolism Sulfides - pharmacology |
| title | 4-methylthiobenzoic acid reduces cisplatin nephrotoxicity in rats without compromising anti-tumour activity |
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