The role of p-aminophenol in acetaminophen-induced nephrotoxicity: Effect of bis( p-nitrophenyl) phosphate on acetaminophen and p-aminophenol nephrotoxicity and metabolism in Fischer 344 rats
Acetaminophen (APAP) produces proximal tubular necrosis in Fischer 344 (F344) rats. Recently, p-aminophenol (PAP), a known potent nephrotoxicant, was identified as a metabolite of APAP in F344 rats. The purpose of this study was to determine if PAP formation is a requisite step in APAP-induced nephr...
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| Veröffentlicht in: | Toxicology and applied pharmacology 1985, Vol.81 (3), p.416-430 |
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| container_title | Toxicology and applied pharmacology |
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| creator | Newton, J.F. Kuo, C-H. DeShone, G.M. Hoefle, D. Bernstein, J. Hook, J.B. |
| description | Acetaminophen (APAP) produces proximal tubular necrosis in Fischer 344 (F344) rats. Recently,
p-aminophenol (PAP), a known potent nephrotoxicant, was identified as a metabolite of APAP in F344 rats. The purpose of this study was to determine if PAP formation is a requisite step in APAP-induced nephrotoxicity. Therefore, the effect of bis(
p-nitrophenyl) phosphate (BNPP), an acylamidase inhibitor, on APAP and PAP nephrotoxicity and metabolism was determined. BNPP (1 to 8 m
m) reduced APAP deacetylation and covalent binding in F344 renal cortical homogenates in a concentration-dependent manner. Pretreatment of animals with BNPP prior to APAP or PAP administration resulted in marked reduction of APAP (900 mg/kg) nephrotoxicity but not PAP nephrotoxicity. This result was not due to altered disposition of either APAP or acetylated metabolites in plasma or renal cortical and hepatic tissue. Rather, BNPP pretreatment reduced the fraction of APAP excreted as PAP by 64 and 75% after APAP doses of 750 and 900 mg/kg. BNPP did not alter the excretion of APAP or any of its non-deacetylated metabolites nor did BNPP alter excretion of PAP or its metabolites after PAP doses of 150 and 300 mg/kg. Therefore, the BNPP-induced reduction in APAP-induced nephrotoxicity appears to be due to inhibition of APAP deacetylation. It is concluded that PAP formation,
in vivo, accounts, at least in part, for APAP-induced renal tubular necrosis. |
| doi_str_mv | 10.1016/0041-008X(85)90413-2 |
| format | Article |
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p-aminophenol (PAP), a known potent nephrotoxicant, was identified as a metabolite of APAP in F344 rats. The purpose of this study was to determine if PAP formation is a requisite step in APAP-induced nephrotoxicity. Therefore, the effect of bis(
p-nitrophenyl) phosphate (BNPP), an acylamidase inhibitor, on APAP and PAP nephrotoxicity and metabolism was determined. BNPP (1 to 8 m
m) reduced APAP deacetylation and covalent binding in F344 renal cortical homogenates in a concentration-dependent manner. Pretreatment of animals with BNPP prior to APAP or PAP administration resulted in marked reduction of APAP (900 mg/kg) nephrotoxicity but not PAP nephrotoxicity. This result was not due to altered disposition of either APAP or acetylated metabolites in plasma or renal cortical and hepatic tissue. Rather, BNPP pretreatment reduced the fraction of APAP excreted as PAP by 64 and 75% after APAP doses of 750 and 900 mg/kg. BNPP did not alter the excretion of APAP or any of its non-deacetylated metabolites nor did BNPP alter excretion of PAP or its metabolites after PAP doses of 150 and 300 mg/kg. Therefore, the BNPP-induced reduction in APAP-induced nephrotoxicity appears to be due to inhibition of APAP deacetylation. It is concluded that PAP formation,
in vivo, accounts, at least in part, for APAP-induced renal tubular necrosis.</description><identifier>ISSN: 0041-008X</identifier><identifier>EISSN: 1096-0333</identifier><identifier>DOI: 10.1016/0041-008X(85)90413-2</identifier><identifier>PMID: 4082192</identifier><identifier>CODEN: TXAPA9</identifier><language>eng</language><publisher>San Diego, CA: Elsevier Inc</publisher><subject>Acetaminophen - metabolism ; Acetaminophen - toxicity ; Acetaminophen - urine ; Aminophenols - metabolism ; Aminophenols - toxicity ; Animals ; Biological and medical sciences ; Body Weight - drug effects ; Drug toxicity and drugs side effects treatment ; Injections, Intraperitoneal ; Kidney Cortex Necrosis - chemically induced ; Kidney Cortex Necrosis - metabolism ; Kidney Cortex Necrosis - pathology ; Male ; Medical sciences ; Nitrophenols - pharmacology ; Organ Size - drug effects ; Pharmacology. Drug treatments ; Rats ; Rats, Inbred F344 ; Toxicity: urogenital system</subject><ispartof>Toxicology and applied pharmacology, 1985, Vol.81 (3), p.416-430</ispartof><rights>1985</rights><rights>1986 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/0041-008X(85)90413-2$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,781,785,3551,4025,27925,27926,27927,45997</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=8651543$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/4082192$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Newton, J.F.</creatorcontrib><creatorcontrib>Kuo, C-H.</creatorcontrib><creatorcontrib>DeShone, G.M.</creatorcontrib><creatorcontrib>Hoefle, D.</creatorcontrib><creatorcontrib>Bernstein, J.</creatorcontrib><creatorcontrib>Hook, J.B.</creatorcontrib><title>The role of p-aminophenol in acetaminophen-induced nephrotoxicity: Effect of bis( p-nitrophenyl) phosphate on acetaminophen and p-aminophenol nephrotoxicity and metabolism in Fischer 344 rats</title><title>Toxicology and applied pharmacology</title><addtitle>Toxicol Appl Pharmacol</addtitle><description>Acetaminophen (APAP) produces proximal tubular necrosis in Fischer 344 (F344) rats. Recently,
p-aminophenol (PAP), a known potent nephrotoxicant, was identified as a metabolite of APAP in F344 rats. The purpose of this study was to determine if PAP formation is a requisite step in APAP-induced nephrotoxicity. Therefore, the effect of bis(
p-nitrophenyl) phosphate (BNPP), an acylamidase inhibitor, on APAP and PAP nephrotoxicity and metabolism was determined. BNPP (1 to 8 m
m) reduced APAP deacetylation and covalent binding in F344 renal cortical homogenates in a concentration-dependent manner. Pretreatment of animals with BNPP prior to APAP or PAP administration resulted in marked reduction of APAP (900 mg/kg) nephrotoxicity but not PAP nephrotoxicity. This result was not due to altered disposition of either APAP or acetylated metabolites in plasma or renal cortical and hepatic tissue. Rather, BNPP pretreatment reduced the fraction of APAP excreted as PAP by 64 and 75% after APAP doses of 750 and 900 mg/kg. BNPP did not alter the excretion of APAP or any of its non-deacetylated metabolites nor did BNPP alter excretion of PAP or its metabolites after PAP doses of 150 and 300 mg/kg. Therefore, the BNPP-induced reduction in APAP-induced nephrotoxicity appears to be due to inhibition of APAP deacetylation. It is concluded that PAP formation,
in vivo, accounts, at least in part, for APAP-induced renal tubular necrosis.</description><subject>Acetaminophen - metabolism</subject><subject>Acetaminophen - toxicity</subject><subject>Acetaminophen - urine</subject><subject>Aminophenols - metabolism</subject><subject>Aminophenols - toxicity</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Body Weight - drug effects</subject><subject>Drug toxicity and drugs side effects treatment</subject><subject>Injections, Intraperitoneal</subject><subject>Kidney Cortex Necrosis - chemically induced</subject><subject>Kidney Cortex Necrosis - metabolism</subject><subject>Kidney Cortex Necrosis - pathology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Nitrophenols - pharmacology</subject><subject>Organ Size - drug effects</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Rats, Inbred F344</subject><subject>Toxicity: urogenital system</subject><issn>0041-008X</issn><issn>1096-0333</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1985</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdks9q3DAQxkVpSbdp36AFHUpIDk71z7aUQ6CEpA0EekmhNyHLY6xiS66kLd2n66tV3iwLzUlI85tvRt8MQu8puaSENp8IEbQiRP44l_WFKhdesRdoQ4lqKsI5f4k2R-Q1epPST0KIEoKeoBNBJKOKbdDfxxFwDBPgMOClMrPzYRnBhwk7j42FfHyqnO-3FnrsYRljyOGPsy7vrvDtMIDNq0Dn0nlR8S7HfcpuusDLGNIymlwqPBPExvfPav4vvQfmktGFyaV57ejOJTtCxFwIHE1Ob9GrwUwJ3h3OU_T97vbx5mv18O3L_c3nhwoYb3KleEfpIFvSdFRySsXAqTSqt6LvWs5U2zLBBaG0rZWsW2mZIIIbYSRAUxh-is6edJcYfm0hZT2XTmCajIewTZoKrorxrIAfDuC2m6HXS3SziTt9cLzEPx7iJlkzDdF469IRk01Na8ELdv2EQfnUbwdRJ-vAF_tdLGbrPjhNiV4XQa9T1uuUtaz1fhE04_8AWRam1A</recordid><startdate>1985</startdate><enddate>1985</enddate><creator>Newton, J.F.</creator><creator>Kuo, C-H.</creator><creator>DeShone, G.M.</creator><creator>Hoefle, D.</creator><creator>Bernstein, J.</creator><creator>Hook, J.B.</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7U7</scope><scope>C1K</scope></search><sort><creationdate>1985</creationdate><title>The role of p-aminophenol in acetaminophen-induced nephrotoxicity: Effect of bis( p-nitrophenyl) phosphate on acetaminophen and p-aminophenol nephrotoxicity and metabolism in Fischer 344 rats</title><author>Newton, J.F. ; Kuo, C-H. ; DeShone, G.M. ; Hoefle, D. ; Bernstein, J. ; Hook, J.B.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-e236t-93b11f8706b183114f318a9dc4db73297724340117598578c24043a4a8ee64db3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1985</creationdate><topic>Acetaminophen - metabolism</topic><topic>Acetaminophen - toxicity</topic><topic>Acetaminophen - urine</topic><topic>Aminophenols - metabolism</topic><topic>Aminophenols - toxicity</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Body Weight - drug effects</topic><topic>Drug toxicity and drugs side effects treatment</topic><topic>Injections, Intraperitoneal</topic><topic>Kidney Cortex Necrosis - chemically induced</topic><topic>Kidney Cortex Necrosis - metabolism</topic><topic>Kidney Cortex Necrosis - pathology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Nitrophenols - pharmacology</topic><topic>Organ Size - drug effects</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Rats, Inbred F344</topic><topic>Toxicity: urogenital system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Newton, J.F.</creatorcontrib><creatorcontrib>Kuo, C-H.</creatorcontrib><creatorcontrib>DeShone, G.M.</creatorcontrib><creatorcontrib>Hoefle, D.</creatorcontrib><creatorcontrib>Bernstein, J.</creatorcontrib><creatorcontrib>Hook, J.B.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Toxicology and applied pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Newton, J.F.</au><au>Kuo, C-H.</au><au>DeShone, G.M.</au><au>Hoefle, D.</au><au>Bernstein, J.</au><au>Hook, J.B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The role of p-aminophenol in acetaminophen-induced nephrotoxicity: Effect of bis( p-nitrophenyl) phosphate on acetaminophen and p-aminophenol nephrotoxicity and metabolism in Fischer 344 rats</atitle><jtitle>Toxicology and applied pharmacology</jtitle><addtitle>Toxicol Appl Pharmacol</addtitle><date>1985</date><risdate>1985</risdate><volume>81</volume><issue>3</issue><spage>416</spage><epage>430</epage><pages>416-430</pages><issn>0041-008X</issn><eissn>1096-0333</eissn><coden>TXAPA9</coden><abstract>Acetaminophen (APAP) produces proximal tubular necrosis in Fischer 344 (F344) rats. Recently,
p-aminophenol (PAP), a known potent nephrotoxicant, was identified as a metabolite of APAP in F344 rats. The purpose of this study was to determine if PAP formation is a requisite step in APAP-induced nephrotoxicity. Therefore, the effect of bis(
p-nitrophenyl) phosphate (BNPP), an acylamidase inhibitor, on APAP and PAP nephrotoxicity and metabolism was determined. BNPP (1 to 8 m
m) reduced APAP deacetylation and covalent binding in F344 renal cortical homogenates in a concentration-dependent manner. Pretreatment of animals with BNPP prior to APAP or PAP administration resulted in marked reduction of APAP (900 mg/kg) nephrotoxicity but not PAP nephrotoxicity. This result was not due to altered disposition of either APAP or acetylated metabolites in plasma or renal cortical and hepatic tissue. Rather, BNPP pretreatment reduced the fraction of APAP excreted as PAP by 64 and 75% after APAP doses of 750 and 900 mg/kg. BNPP did not alter the excretion of APAP or any of its non-deacetylated metabolites nor did BNPP alter excretion of PAP or its metabolites after PAP doses of 150 and 300 mg/kg. Therefore, the BNPP-induced reduction in APAP-induced nephrotoxicity appears to be due to inhibition of APAP deacetylation. It is concluded that PAP formation,
in vivo, accounts, at least in part, for APAP-induced renal tubular necrosis.</abstract><cop>San Diego, CA</cop><pub>Elsevier Inc</pub><pmid>4082192</pmid><doi>10.1016/0041-008X(85)90413-2</doi><tpages>15</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Toxicology and applied pharmacology, 1985, Vol.81 (3), p.416-430 |
| issn | 0041-008X 1096-0333 |
| language | eng |
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| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | Acetaminophen - metabolism Acetaminophen - toxicity Acetaminophen - urine Aminophenols - metabolism Aminophenols - toxicity Animals Biological and medical sciences Body Weight - drug effects Drug toxicity and drugs side effects treatment Injections, Intraperitoneal Kidney Cortex Necrosis - chemically induced Kidney Cortex Necrosis - metabolism Kidney Cortex Necrosis - pathology Male Medical sciences Nitrophenols - pharmacology Organ Size - drug effects Pharmacology. Drug treatments Rats Rats, Inbred F344 Toxicity: urogenital system |
| title | The role of p-aminophenol in acetaminophen-induced nephrotoxicity: Effect of bis( p-nitrophenyl) phosphate on acetaminophen and p-aminophenol nephrotoxicity and metabolism in Fischer 344 rats |
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