The effect of age on the glucuronidation and toxicity of 4,4′-thiobis(6- t-butyl- m-cresol)
Age-related changes in glucuronidation may potentially lead to a decrease in excretion of reactive compounds, resulting in enhanced toxic effects. 4,4′-Thiobis(6- t-butyl- m-cresol) (TBBC), a major antioxidant in the rubber industry, was selected as a model compound to evaluate glucuronidation as a...
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| Veröffentlicht in: | Toxicology and applied pharmacology 1988-03, Vol.92 (3), p.453-466 |
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| creator | Borghoff, Susan J. Stefanski, Steven A. Birnbaum, Linda S. |
| description | Age-related changes in glucuronidation may potentially lead to a decrease in excretion of reactive compounds, resulting in enhanced toxic effects. 4,4′-Thiobis(6-
t-butyl-
m-cresol) (TBBC), a major antioxidant in the rubber industry, was selected as a model compound to evaluate glucuronidation as a function of age because it is directly conjugated to UDP-glucuronic acid (UDPGA) without requiring oxidative metabolism. To assess glucuronidation changes
in vivo, male F344 rats, 2.5, 16, and 26 months of age, were administered 5 mg [
14C]TBBC/kg (10 μCi/kg) iv and urine and feces were collected for 3 days. Bile was also collected for 6 hr from animals of the same age groups after iv doses of 5 and 25 mg/kg [
14C]TBBC. Total radioactivity was determined in all samples and the profile of metabolites in bile analyzed by HPLC. Along with a decrease in the older animal's ability to excrete TBBC-derived radioactivity in bile, feces, and urine, there was a decrease in the percentage of the dose eliminated in bile as glucuronide.
In vitro, the microsomal glucuronyltransferase activity using TBBC as a substrate decreased in the senescent animals. The hepatic concentration of the cofactor UDPGA also decreased from 2.5 to 28 months of age. The apparent
V
max for the enzyme decreased as a function of age while the apparent
K
m
decreased for the substrate (TBBC) but not for the cofactor (UDPGA) in the 26-month-old rats. These data suggest that with the decrease in the activity of the enzyme as well as a decrease in the available UDPGA, the ability of the senescent rats to conjugate and excrete TBBC may be altered. Thus, the
in vitro decline in TBBC glucuronidation is compatible with the decreased excretion of TBBC-derived radioactivity observed
in vivo in old rats. When toxicity was evaluated in 2.5-, 16-, and 26-month-old rats exposed to 0.25% TBBC in their diet for 14 days, no age-related change in the toxicity of TBBC was observed. However, there appeared to be an increase in leukemia in the treated senescent rats. |
| doi_str_mv | 10.1016/0041-008X(88)90185-8 |
| format | Article |
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t-butyl-
m-cresol) (TBBC), a major antioxidant in the rubber industry, was selected as a model compound to evaluate glucuronidation as a function of age because it is directly conjugated to UDP-glucuronic acid (UDPGA) without requiring oxidative metabolism. To assess glucuronidation changes
in vivo, male F344 rats, 2.5, 16, and 26 months of age, were administered 5 mg [
14C]TBBC/kg (10 μCi/kg) iv and urine and feces were collected for 3 days. Bile was also collected for 6 hr from animals of the same age groups after iv doses of 5 and 25 mg/kg [
14C]TBBC. Total radioactivity was determined in all samples and the profile of metabolites in bile analyzed by HPLC. Along with a decrease in the older animal's ability to excrete TBBC-derived radioactivity in bile, feces, and urine, there was a decrease in the percentage of the dose eliminated in bile as glucuronide.
In vitro, the microsomal glucuronyltransferase activity using TBBC as a substrate decreased in the senescent animals. The hepatic concentration of the cofactor UDPGA also decreased from 2.5 to 28 months of age. The apparent
V
max for the enzyme decreased as a function of age while the apparent
K
m
decreased for the substrate (TBBC) but not for the cofactor (UDPGA) in the 26-month-old rats. These data suggest that with the decrease in the activity of the enzyme as well as a decrease in the available UDPGA, the ability of the senescent rats to conjugate and excrete TBBC may be altered. Thus, the
in vitro decline in TBBC glucuronidation is compatible with the decreased excretion of TBBC-derived radioactivity observed
in vivo in old rats. When toxicity was evaluated in 2.5-, 16-, and 26-month-old rats exposed to 0.25% TBBC in their diet for 14 days, no age-related change in the toxicity of TBBC was observed. However, there appeared to be an increase in leukemia in the treated senescent rats.</description><identifier>ISSN: 0041-008X</identifier><identifier>EISSN: 1096-0333</identifier><identifier>DOI: 10.1016/0041-008X(88)90185-8</identifier><identifier>PMID: 3127943</identifier><identifier>CODEN: TXAPA9</identifier><language>eng</language><publisher>San Diego, CA: Elsevier Inc</publisher><subject>Age Factors ; Animals ; Antioxidants - metabolism ; Bile - metabolism ; Biological and medical sciences ; Chemical and industrial products toxicology. Toxic occupational diseases ; Cresols - metabolism ; Cresols - toxicity ; Glucuronates - metabolism ; Glucuronosyltransferase - analysis ; Leukemia, Experimental - chemically induced ; Male ; Medical sciences ; Rats ; Rats, Inbred F344 ; Toxicology ; Uridine Diphosphate Glucuronic Acid - analysis ; Various organic compounds</subject><ispartof>Toxicology and applied pharmacology, 1988-03, Vol.92 (3), p.453-466</ispartof><rights>1988</rights><rights>1989 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://www.sciencedirect.com/science/article/pii/0041008X88901858$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=7022036$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/3127943$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Borghoff, Susan J.</creatorcontrib><creatorcontrib>Stefanski, Steven A.</creatorcontrib><creatorcontrib>Birnbaum, Linda S.</creatorcontrib><title>The effect of age on the glucuronidation and toxicity of 4,4′-thiobis(6- t-butyl- m-cresol)</title><title>Toxicology and applied pharmacology</title><addtitle>Toxicol Appl Pharmacol</addtitle><description>Age-related changes in glucuronidation may potentially lead to a decrease in excretion of reactive compounds, resulting in enhanced toxic effects. 4,4′-Thiobis(6-
t-butyl-
m-cresol) (TBBC), a major antioxidant in the rubber industry, was selected as a model compound to evaluate glucuronidation as a function of age because it is directly conjugated to UDP-glucuronic acid (UDPGA) without requiring oxidative metabolism. To assess glucuronidation changes
in vivo, male F344 rats, 2.5, 16, and 26 months of age, were administered 5 mg [
14C]TBBC/kg (10 μCi/kg) iv and urine and feces were collected for 3 days. Bile was also collected for 6 hr from animals of the same age groups after iv doses of 5 and 25 mg/kg [
14C]TBBC. Total radioactivity was determined in all samples and the profile of metabolites in bile analyzed by HPLC. Along with a decrease in the older animal's ability to excrete TBBC-derived radioactivity in bile, feces, and urine, there was a decrease in the percentage of the dose eliminated in bile as glucuronide.
In vitro, the microsomal glucuronyltransferase activity using TBBC as a substrate decreased in the senescent animals. The hepatic concentration of the cofactor UDPGA also decreased from 2.5 to 28 months of age. The apparent
V
max for the enzyme decreased as a function of age while the apparent
K
m
decreased for the substrate (TBBC) but not for the cofactor (UDPGA) in the 26-month-old rats. These data suggest that with the decrease in the activity of the enzyme as well as a decrease in the available UDPGA, the ability of the senescent rats to conjugate and excrete TBBC may be altered. Thus, the
in vitro decline in TBBC glucuronidation is compatible with the decreased excretion of TBBC-derived radioactivity observed
in vivo in old rats. When toxicity was evaluated in 2.5-, 16-, and 26-month-old rats exposed to 0.25% TBBC in their diet for 14 days, no age-related change in the toxicity of TBBC was observed. However, there appeared to be an increase in leukemia in the treated senescent rats.</description><subject>Age Factors</subject><subject>Animals</subject><subject>Antioxidants - metabolism</subject><subject>Bile - metabolism</subject><subject>Biological and medical sciences</subject><subject>Chemical and industrial products toxicology. Toxic occupational diseases</subject><subject>Cresols - metabolism</subject><subject>Cresols - toxicity</subject><subject>Glucuronates - metabolism</subject><subject>Glucuronosyltransferase - analysis</subject><subject>Leukemia, Experimental - chemically induced</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Rats</subject><subject>Rats, Inbred F344</subject><subject>Toxicology</subject><subject>Uridine Diphosphate Glucuronic Acid - analysis</subject><subject>Various organic compounds</subject><issn>0041-008X</issn><issn>1096-0333</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1988</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kc9KxDAQh4Mouq6-gUIPIgpGZ5psk1wEEf-B4EXBi4Q0TTXSbbRJxb35TD6ST2JXlz0N_H4fAzMfITsIxwhYnABwpADy8UDKQwUoJ1SukBGCKigwxlbJaIlskM0YXwFAcY7rZJ1hLhRnI_J0_-IyV9fOpizUmXl2WWizNITPTW_7LrS-MskPmWmrLIVPb32azVF-xH--vml68aH08aCgWaJln2YNzabUdi6G5nCLrNWmiW57Mcfk4fLi_vya3t5d3Zyf3VLHckxUThjipFC5rYWQWHJb87KWeSml4sJixZRQVhmjODAui5yVUKHgQuWFkAzZmOz_733rwnvvYtJTH61rGtO60EeNXPGCCxjA3QXYl1NX6bfOT00304t_DP3eojfRmqbuTGt9XGIC8hxYMWCn_5gbjvrwrtPRetdaV_lu-KSugtcIeq5Jzx3ouQMtpf7TpCX7BfKYgS0</recordid><startdate>19880315</startdate><enddate>19880315</enddate><creator>Borghoff, Susan J.</creator><creator>Stefanski, Steven A.</creator><creator>Birnbaum, Linda S.</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>19880315</creationdate><title>The effect of age on the glucuronidation and toxicity of 4,4′-thiobis(6- t-butyl- m-cresol)</title><author>Borghoff, Susan J. ; Stefanski, Steven A. ; Birnbaum, Linda S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-e321t-853115692cf7781b4cf4bf82b88947c1d3979c9aa940348623b0d174792678313</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1988</creationdate><topic>Age Factors</topic><topic>Animals</topic><topic>Antioxidants - metabolism</topic><topic>Bile - metabolism</topic><topic>Biological and medical sciences</topic><topic>Chemical and industrial products toxicology. Toxic occupational diseases</topic><topic>Cresols - metabolism</topic><topic>Cresols - toxicity</topic><topic>Glucuronates - metabolism</topic><topic>Glucuronosyltransferase - analysis</topic><topic>Leukemia, Experimental - chemically induced</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Rats</topic><topic>Rats, Inbred F344</topic><topic>Toxicology</topic><topic>Uridine Diphosphate Glucuronic Acid - analysis</topic><topic>Various organic compounds</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Borghoff, Susan J.</creatorcontrib><creatorcontrib>Stefanski, Steven A.</creatorcontrib><creatorcontrib>Birnbaum, Linda S.</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>Borghoff, Susan J.</au><au>Stefanski, Steven A.</au><au>Birnbaum, Linda S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The effect of age on the glucuronidation and toxicity of 4,4′-thiobis(6- t-butyl- m-cresol)</atitle><jtitle>Toxicology and applied pharmacology</jtitle><addtitle>Toxicol Appl Pharmacol</addtitle><date>1988-03-15</date><risdate>1988</risdate><volume>92</volume><issue>3</issue><spage>453</spage><epage>466</epage><pages>453-466</pages><issn>0041-008X</issn><eissn>1096-0333</eissn><coden>TXAPA9</coden><abstract>Age-related changes in glucuronidation may potentially lead to a decrease in excretion of reactive compounds, resulting in enhanced toxic effects. 4,4′-Thiobis(6-
t-butyl-
m-cresol) (TBBC), a major antioxidant in the rubber industry, was selected as a model compound to evaluate glucuronidation as a function of age because it is directly conjugated to UDP-glucuronic acid (UDPGA) without requiring oxidative metabolism. To assess glucuronidation changes
in vivo, male F344 rats, 2.5, 16, and 26 months of age, were administered 5 mg [
14C]TBBC/kg (10 μCi/kg) iv and urine and feces were collected for 3 days. Bile was also collected for 6 hr from animals of the same age groups after iv doses of 5 and 25 mg/kg [
14C]TBBC. Total radioactivity was determined in all samples and the profile of metabolites in bile analyzed by HPLC. Along with a decrease in the older animal's ability to excrete TBBC-derived radioactivity in bile, feces, and urine, there was a decrease in the percentage of the dose eliminated in bile as glucuronide.
In vitro, the microsomal glucuronyltransferase activity using TBBC as a substrate decreased in the senescent animals. The hepatic concentration of the cofactor UDPGA also decreased from 2.5 to 28 months of age. The apparent
V
max for the enzyme decreased as a function of age while the apparent
K
m
decreased for the substrate (TBBC) but not for the cofactor (UDPGA) in the 26-month-old rats. These data suggest that with the decrease in the activity of the enzyme as well as a decrease in the available UDPGA, the ability of the senescent rats to conjugate and excrete TBBC may be altered. Thus, the
in vitro decline in TBBC glucuronidation is compatible with the decreased excretion of TBBC-derived radioactivity observed
in vivo in old rats. When toxicity was evaluated in 2.5-, 16-, and 26-month-old rats exposed to 0.25% TBBC in their diet for 14 days, no age-related change in the toxicity of TBBC was observed. However, there appeared to be an increase in leukemia in the treated senescent rats.</abstract><cop>San Diego, CA</cop><pub>Elsevier Inc</pub><pmid>3127943</pmid><doi>10.1016/0041-008X(88)90185-8</doi><tpages>14</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0041-008X |
| ispartof | Toxicology and applied pharmacology, 1988-03, Vol.92 (3), p.453-466 |
| issn | 0041-008X 1096-0333 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_14946470 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Age Factors Animals Antioxidants - metabolism Bile - metabolism Biological and medical sciences Chemical and industrial products toxicology. Toxic occupational diseases Cresols - metabolism Cresols - toxicity Glucuronates - metabolism Glucuronosyltransferase - analysis Leukemia, Experimental - chemically induced Male Medical sciences Rats Rats, Inbred F344 Toxicology Uridine Diphosphate Glucuronic Acid - analysis Various organic compounds |
| title | The effect of age on the glucuronidation and toxicity of 4,4′-thiobis(6- t-butyl- m-cresol) |
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