Metabolism of [ 14C]acetylisoniazid and [ 14C]acetylhydrazine by the rat and rabbit
Male rats and rabbits were singly dosed with either 1-[ 14C]acetyl isoniazid (acetylisonicotinoylhydrazine, acetyl-INH, 200 mg/kg po) or 1-[ 14C]acetylhydrazine (50 or 100 mg/kg ip). Urine and expired 14CO 2 were collected, and after 6 hr the animals were killed for the analysis of tissue 14C concen...
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| Veröffentlicht in: | Fundam. Appl. Toxicol.; (United States) 1984-08, Vol.4 (4), p.646-653 |
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| container_title | Fundam. Appl. Toxicol.; (United States) |
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| creator | Thomas, Barry H. Whitehouse, Larry W. Zeitz, Walter |
| description | Male rats and rabbits were singly dosed with either 1-[
14C]acetyl isoniazid (acetylisonicotinoylhydrazine, acetyl-INH, 200 mg/kg po) or 1-[
14C]acetylhydrazine (50 or 100 mg/kg ip). Urine and expired
14CO
2 were collected, and after 6 hr the animals were killed for the analysis of tissue
14C concentrations and covalent binding of
14C to hepatic protein. Rats excreted proportionately more
14C in urine and had lower
14C levels in their tissues compared to rabbits. When acetyl-INH was administered, covalent hepatic protein binding of the acetyl moiety was greater in the rabbit than the rat, but the opposite was observed when acetylhydrazine was administered. Analysis of blood and urine by TLC revealed that the rabbit more rapidly metabolized both acetyl-INH to acetylhydrazine, and acetylhydrazine to diacetylhydrazine than did the rat. These observations suggest that higher amidase activity in the rabbit compared to the rat leads to faster conversion of acetyl-INH to acetylhydrazine which in turn leads to greater covalent binding and hepatotoxicity. |
| doi_str_mv | 10.1016/0272-0590(84)90056-3 |
| format | Article |
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14C]acetyl isoniazid (acetylisonicotinoylhydrazine, acetyl-INH, 200 mg/kg po) or 1-[
14C]acetylhydrazine (50 or 100 mg/kg ip). Urine and expired
14CO
2 were collected, and after 6 hr the animals were killed for the analysis of tissue
14C concentrations and covalent binding of
14C to hepatic protein. Rats excreted proportionately more
14C in urine and had lower
14C levels in their tissues compared to rabbits. When acetyl-INH was administered, covalent hepatic protein binding of the acetyl moiety was greater in the rabbit than the rat, but the opposite was observed when acetylhydrazine was administered. Analysis of blood and urine by TLC revealed that the rabbit more rapidly metabolized both acetyl-INH to acetylhydrazine, and acetylhydrazine to diacetylhydrazine than did the rat. These observations suggest that higher amidase activity in the rabbit compared to the rat leads to faster conversion of acetyl-INH to acetylhydrazine which in turn leads to greater covalent binding and hepatotoxicity.</description><identifier>ISSN: 0272-0590</identifier><identifier>EISSN: 1095-6832</identifier><identifier>DOI: 10.1016/0272-0590(84)90056-3</identifier><identifier>PMID: 6479511</identifier><language>eng</language><publisher>United States: Elsevier Science (USA)</publisher><subject>550501 - Metabolism- Tracer Techniques ; ANIMALS ; BASIC BIOLOGICAL SCIENCES ; BIOLOGICAL MATERIALS ; BIOLOGICAL WASTES ; Biotransformation ; BLOOD ; BODY ; BODY FLUIDS ; CARBON 14 COMPOUNDS ; CARBON COMPOUNDS ; CARBON DIOXIDE ; CARBON OXIDES ; Carbon Radioisotopes ; CHALCOGENIDES ; CHROMATOGRAPHY ; DIGESTIVE SYSTEM ; GLANDS ; HYDRAZIDES ; Hydrazines - metabolism ; Isoniazid - analogs & derivatives ; Isoniazid - metabolism ; Kinetics ; LABELLED COMPOUNDS ; LIVER ; Male ; MAMMALS ; MATERIALS ; METABOLISM ; ORGANIC COMPOUNDS ; ORGANIC NITROGEN COMPOUNDS ; ORGANS ; OXIDES ; OXYGEN COMPOUNDS ; PROTEINS ; RABBITS ; RATS ; Rats, Inbred Strains ; RODENTS ; SEPARATION PROCESSES ; Species Specificity ; THIN-LAYER CHROMATOGRAPHY ; Tissue Distribution ; URINE ; VERTEBRATES ; WASTES</subject><ispartof>Fundam. Appl. Toxicol.; (United States), 1984-08, Vol.4 (4), p.646-653</ispartof><rights>1984</rights><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/6479511$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/5982779$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Thomas, Barry H.</creatorcontrib><creatorcontrib>Whitehouse, Larry W.</creatorcontrib><creatorcontrib>Zeitz, Walter</creatorcontrib><creatorcontrib>Bureau of Drug Research, Health and Welfare Canada, Ottawa, Ontario</creatorcontrib><title>Metabolism of [ 14C]acetylisoniazid and [ 14C]acetylhydrazine by the rat and rabbit</title><title>Fundam. Appl. Toxicol.; (United States)</title><addtitle>Fundam Appl Toxicol</addtitle><description>Male rats and rabbits were singly dosed with either 1-[
14C]acetyl isoniazid (acetylisonicotinoylhydrazine, acetyl-INH, 200 mg/kg po) or 1-[
14C]acetylhydrazine (50 or 100 mg/kg ip). Urine and expired
14CO
2 were collected, and after 6 hr the animals were killed for the analysis of tissue
14C concentrations and covalent binding of
14C to hepatic protein. Rats excreted proportionately more
14C in urine and had lower
14C levels in their tissues compared to rabbits. When acetyl-INH was administered, covalent hepatic protein binding of the acetyl moiety was greater in the rabbit than the rat, but the opposite was observed when acetylhydrazine was administered. Analysis of blood and urine by TLC revealed that the rabbit more rapidly metabolized both acetyl-INH to acetylhydrazine, and acetylhydrazine to diacetylhydrazine than did the rat. These observations suggest that higher amidase activity in the rabbit compared to the rat leads to faster conversion of acetyl-INH to acetylhydrazine which in turn leads to greater covalent binding and hepatotoxicity.</description><subject>550501 - Metabolism- Tracer Techniques</subject><subject>ANIMALS</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>BIOLOGICAL MATERIALS</subject><subject>BIOLOGICAL WASTES</subject><subject>Biotransformation</subject><subject>BLOOD</subject><subject>BODY</subject><subject>BODY FLUIDS</subject><subject>CARBON 14 COMPOUNDS</subject><subject>CARBON COMPOUNDS</subject><subject>CARBON DIOXIDE</subject><subject>CARBON OXIDES</subject><subject>Carbon Radioisotopes</subject><subject>CHALCOGENIDES</subject><subject>CHROMATOGRAPHY</subject><subject>DIGESTIVE SYSTEM</subject><subject>GLANDS</subject><subject>HYDRAZIDES</subject><subject>Hydrazines - metabolism</subject><subject>Isoniazid - analogs & derivatives</subject><subject>Isoniazid - metabolism</subject><subject>Kinetics</subject><subject>LABELLED COMPOUNDS</subject><subject>LIVER</subject><subject>Male</subject><subject>MAMMALS</subject><subject>MATERIALS</subject><subject>METABOLISM</subject><subject>ORGANIC COMPOUNDS</subject><subject>ORGANIC NITROGEN COMPOUNDS</subject><subject>ORGANS</subject><subject>OXIDES</subject><subject>OXYGEN COMPOUNDS</subject><subject>PROTEINS</subject><subject>RABBITS</subject><subject>RATS</subject><subject>Rats, Inbred Strains</subject><subject>RODENTS</subject><subject>SEPARATION PROCESSES</subject><subject>Species Specificity</subject><subject>THIN-LAYER CHROMATOGRAPHY</subject><subject>Tissue Distribution</subject><subject>URINE</subject><subject>VERTEBRATES</subject><subject>WASTES</subject><issn>0272-0590</issn><issn>1095-6832</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1984</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkEtLw0AUhQdRaq3-A4XgShfRO5PMayNI8QUVF-pKZJjHLR1pE0lGIf56k7YIri7c83E4fIQcU7igQMUlMMly4BrOVHmuAbjIix0ypqB5LlTBdsn4D9knB237AUApL2FERqKUmlM6Js-PmKyrl7FdZfU8e8toOX23HlPXv-oq2p8YMluFf8miC00fVJi5LksLzBqb1lBjnYvpkOzN7bLFo-2dkNfbm5fpfT57unuYXs9yZAxSzkC5UgoMYk4LziRl_fLgZOm4daWm2nLhGVM6oBaWWSFB67kC8MIrBCwm5HTTW7cpmtbHhH7h66pCnwzXikmpe-hkA31-uRUG89nElW06szXQ51ebHPul3xGboQgrjyE2Q0-oo6FgBuNm0GkGnUaVZm3cFMUvv3Vvwg</recordid><startdate>198408</startdate><enddate>198408</enddate><creator>Thomas, Barry H.</creator><creator>Whitehouse, Larry W.</creator><creator>Zeitz, Walter</creator><general>Elsevier Science (USA)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>OTOTI</scope></search><sort><creationdate>198408</creationdate><title>Metabolism of [ 14C]acetylisoniazid and [ 14C]acetylhydrazine by the rat and rabbit</title><author>Thomas, Barry H. ; Whitehouse, Larry W. ; Zeitz, Walter</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-e220t-208b476ed6f1352712095db74b5ab4919a56c2289de96a2a67099f800c6c8e0e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1984</creationdate><topic>550501 - Metabolism- Tracer Techniques</topic><topic>ANIMALS</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>BIOLOGICAL MATERIALS</topic><topic>BIOLOGICAL WASTES</topic><topic>Biotransformation</topic><topic>BLOOD</topic><topic>BODY</topic><topic>BODY FLUIDS</topic><topic>CARBON 14 COMPOUNDS</topic><topic>CARBON COMPOUNDS</topic><topic>CARBON DIOXIDE</topic><topic>CARBON OXIDES</topic><topic>Carbon Radioisotopes</topic><topic>CHALCOGENIDES</topic><topic>CHROMATOGRAPHY</topic><topic>DIGESTIVE SYSTEM</topic><topic>GLANDS</topic><topic>HYDRAZIDES</topic><topic>Hydrazines - metabolism</topic><topic>Isoniazid - analogs & derivatives</topic><topic>Isoniazid - metabolism</topic><topic>Kinetics</topic><topic>LABELLED COMPOUNDS</topic><topic>LIVER</topic><topic>Male</topic><topic>MAMMALS</topic><topic>MATERIALS</topic><topic>METABOLISM</topic><topic>ORGANIC COMPOUNDS</topic><topic>ORGANIC NITROGEN COMPOUNDS</topic><topic>ORGANS</topic><topic>OXIDES</topic><topic>OXYGEN COMPOUNDS</topic><topic>PROTEINS</topic><topic>RABBITS</topic><topic>RATS</topic><topic>Rats, Inbred Strains</topic><topic>RODENTS</topic><topic>SEPARATION PROCESSES</topic><topic>Species Specificity</topic><topic>THIN-LAYER CHROMATOGRAPHY</topic><topic>Tissue Distribution</topic><topic>URINE</topic><topic>VERTEBRATES</topic><topic>WASTES</topic><toplevel>online_resources</toplevel><creatorcontrib>Thomas, Barry H.</creatorcontrib><creatorcontrib>Whitehouse, Larry W.</creatorcontrib><creatorcontrib>Zeitz, Walter</creatorcontrib><creatorcontrib>Bureau of Drug Research, Health and Welfare Canada, Ottawa, Ontario</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>OSTI.GOV</collection><jtitle>Fundam. Appl. Toxicol.; (United States)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Thomas, Barry H.</au><au>Whitehouse, Larry W.</au><au>Zeitz, Walter</au><aucorp>Bureau of Drug Research, Health and Welfare Canada, Ottawa, Ontario</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Metabolism of [ 14C]acetylisoniazid and [ 14C]acetylhydrazine by the rat and rabbit</atitle><jtitle>Fundam. Appl. Toxicol.; (United States)</jtitle><addtitle>Fundam Appl Toxicol</addtitle><date>1984-08</date><risdate>1984</risdate><volume>4</volume><issue>4</issue><spage>646</spage><epage>653</epage><pages>646-653</pages><issn>0272-0590</issn><eissn>1095-6832</eissn><abstract>Male rats and rabbits were singly dosed with either 1-[
14C]acetyl isoniazid (acetylisonicotinoylhydrazine, acetyl-INH, 200 mg/kg po) or 1-[
14C]acetylhydrazine (50 or 100 mg/kg ip). Urine and expired
14CO
2 were collected, and after 6 hr the animals were killed for the analysis of tissue
14C concentrations and covalent binding of
14C to hepatic protein. Rats excreted proportionately more
14C in urine and had lower
14C levels in their tissues compared to rabbits. When acetyl-INH was administered, covalent hepatic protein binding of the acetyl moiety was greater in the rabbit than the rat, but the opposite was observed when acetylhydrazine was administered. Analysis of blood and urine by TLC revealed that the rabbit more rapidly metabolized both acetyl-INH to acetylhydrazine, and acetylhydrazine to diacetylhydrazine than did the rat. These observations suggest that higher amidase activity in the rabbit compared to the rat leads to faster conversion of acetyl-INH to acetylhydrazine which in turn leads to greater covalent binding and hepatotoxicity.</abstract><cop>United States</cop><pub>Elsevier Science (USA)</pub><pmid>6479511</pmid><doi>10.1016/0272-0590(84)90056-3</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0272-0590 |
| ispartof | Fundam. Appl. Toxicol.; (United States), 1984-08, Vol.4 (4), p.646-653 |
| issn | 0272-0590 1095-6832 |
| language | eng |
| recordid | cdi_pubmed_primary_6479511 |
| source | MEDLINE; Oxford University Press Journals Digital Archive Legacy; Alma/SFX Local Collection |
| subjects | 550501 - Metabolism- Tracer Techniques ANIMALS BASIC BIOLOGICAL SCIENCES BIOLOGICAL MATERIALS BIOLOGICAL WASTES Biotransformation BLOOD BODY BODY FLUIDS CARBON 14 COMPOUNDS CARBON COMPOUNDS CARBON DIOXIDE CARBON OXIDES Carbon Radioisotopes CHALCOGENIDES CHROMATOGRAPHY DIGESTIVE SYSTEM GLANDS HYDRAZIDES Hydrazines - metabolism Isoniazid - analogs & derivatives Isoniazid - metabolism Kinetics LABELLED COMPOUNDS LIVER Male MAMMALS MATERIALS METABOLISM ORGANIC COMPOUNDS ORGANIC NITROGEN COMPOUNDS ORGANS OXIDES OXYGEN COMPOUNDS PROTEINS RABBITS RATS Rats, Inbred Strains RODENTS SEPARATION PROCESSES Species Specificity THIN-LAYER CHROMATOGRAPHY Tissue Distribution URINE VERTEBRATES WASTES |
| title | Metabolism of [ 14C]acetylisoniazid and [ 14C]acetylhydrazine by the rat and rabbit |
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