Kinetic and inhibitor studies of 4-methylumbelliferone and 1-naphthol glucuronidation in human liver microsomes
The glucuronidation kinetics of 4-methylumbelliferone (4MU) and 1-naphthol (1NP) have been investigated in human liver microsomes to determine the validity of using these compounds as probes for specific UDP-glucuronosyltransferase (GT) activities in human liver. 4MU glucuronidation followed Michael...
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| Veröffentlicht in: | Biochemical pharmacology 1988-02, Vol.37 (4), p.665-671 |
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| creator | Miners, J.O. Lillywhite, K.J. Matthews, A.P. Jones, M.E. Birkett, D.J. |
| description | The glucuronidation kinetics of 4-methylumbelliferone (4MU) and 1-naphthol (1NP) have been investigated in human liver microsomes to determine the validity of using these compounds as probes for specific UDP-glucuronosyltransferase (GT) activities in human liver. 4MU glucuronidation followed Michaelis-Menten kinetics, whereas 1NP glucuronidation kinetics were biphasic. Cross inhibition studies were performed with 4MU and 1NP to determine the relationship between 4MU glucuronidation and the two phases of 1NP glucuronidation. 4MU glucuronidation was competitively inhibited by 1NP but 4MU inhibited only the high affinity component of 1NP glucuronidation. There was good agreement between the apparent
K
m values for 4MU and the high affinity component of 1NP glucuronidation and their respective apparent
K
i values determined in the cross inhibition studies. These data suggest that the same form(s) of human liver GT is involved in 4MU glucuronidation and the high affinity component of 1NP glucuronidation.
A number of compounds known to be specific substrates for purified rat liver GTs were screened for inhibitory effects on 4MU glucuronidation in human liver microsomes. 4-Nitrophenol, 2-aminophenol and androsterone inhibited 4MU glucuronidation whereas bilirubin, chloramphenicol, digitoxigenin monodigitoxoside, morphine, oestrone and testosterone had no effect. 4-Nitrophenol and 2-aminophenol were competitive inhibitors of 4MU glucuronidation but the inhibition of 4MU glucuronidation by androsterone followed atypical kinetics. Overall, the substrate specificity of the human liver 4MU/high affinity 1NP-GT activity appears to be broadly similar to that of the 3-methylcholanthrene inducible rat hepatic microsomal GT. |
| doi_str_mv | 10.1016/0006-2952(88)90140-2 |
| format | Article |
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K
m values for 4MU and the high affinity component of 1NP glucuronidation and their respective apparent
K
i values determined in the cross inhibition studies. These data suggest that the same form(s) of human liver GT is involved in 4MU glucuronidation and the high affinity component of 1NP glucuronidation.
A number of compounds known to be specific substrates for purified rat liver GTs were screened for inhibitory effects on 4MU glucuronidation in human liver microsomes. 4-Nitrophenol, 2-aminophenol and androsterone inhibited 4MU glucuronidation whereas bilirubin, chloramphenicol, digitoxigenin monodigitoxoside, morphine, oestrone and testosterone had no effect. 4-Nitrophenol and 2-aminophenol were competitive inhibitors of 4MU glucuronidation but the inhibition of 4MU glucuronidation by androsterone followed atypical kinetics. Overall, the substrate specificity of the human liver 4MU/high affinity 1NP-GT activity appears to be broadly similar to that of the 3-methylcholanthrene inducible rat hepatic microsomal GT.</description><identifier>ISSN: 0006-2952</identifier><identifier>EISSN: 1873-2968</identifier><identifier>DOI: 10.1016/0006-2952(88)90140-2</identifier><identifier>PMID: 3124857</identifier><identifier>CODEN: BCPCA6</identifier><language>eng</language><publisher>New York, NY: Elsevier Inc</publisher><subject>Biological and medical sciences ; General and cellular metabolism. Vitamins ; Glucuronates - metabolism ; Glucuronosyltransferase - analysis ; Humans ; Hymecromone - analogs & derivatives ; Hymecromone - metabolism ; In Vitro Techniques ; Kinetics ; Medical sciences ; Microsomes, Liver - metabolism ; Naphthols - metabolism ; Pharmacology. Drug treatments ; Substrate Specificity ; Umbelliferones - metabolism ; Uridine Diphosphate Glucuronic Acid - analysis</subject><ispartof>Biochemical pharmacology, 1988-02, Vol.37 (4), p.665-671</ispartof><rights>1988</rights><rights>1989 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c452t-d66601e5ab44a217226ea04daea38d76ec53d3e5811d5583749aae6cb1f5a7413</citedby><cites>FETCH-LOGICAL-c452t-d66601e5ab44a217226ea04daea38d76ec53d3e5811d5583749aae6cb1f5a7413</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/0006295288901402$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=7035802$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/3124857$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Miners, J.O.</creatorcontrib><creatorcontrib>Lillywhite, K.J.</creatorcontrib><creatorcontrib>Matthews, A.P.</creatorcontrib><creatorcontrib>Jones, M.E.</creatorcontrib><creatorcontrib>Birkett, D.J.</creatorcontrib><title>Kinetic and inhibitor studies of 4-methylumbelliferone and 1-naphthol glucuronidation in human liver microsomes</title><title>Biochemical pharmacology</title><addtitle>Biochem Pharmacol</addtitle><description>The glucuronidation kinetics of 4-methylumbelliferone (4MU) and 1-naphthol (1NP) have been investigated in human liver microsomes to determine the validity of using these compounds as probes for specific UDP-glucuronosyltransferase (GT) activities in human liver. 4MU glucuronidation followed Michaelis-Menten kinetics, whereas 1NP glucuronidation kinetics were biphasic. Cross inhibition studies were performed with 4MU and 1NP to determine the relationship between 4MU glucuronidation and the two phases of 1NP glucuronidation. 4MU glucuronidation was competitively inhibited by 1NP but 4MU inhibited only the high affinity component of 1NP glucuronidation. There was good agreement between the apparent
K
m values for 4MU and the high affinity component of 1NP glucuronidation and their respective apparent
K
i values determined in the cross inhibition studies. These data suggest that the same form(s) of human liver GT is involved in 4MU glucuronidation and the high affinity component of 1NP glucuronidation.
A number of compounds known to be specific substrates for purified rat liver GTs were screened for inhibitory effects on 4MU glucuronidation in human liver microsomes. 4-Nitrophenol, 2-aminophenol and androsterone inhibited 4MU glucuronidation whereas bilirubin, chloramphenicol, digitoxigenin monodigitoxoside, morphine, oestrone and testosterone had no effect. 4-Nitrophenol and 2-aminophenol were competitive inhibitors of 4MU glucuronidation but the inhibition of 4MU glucuronidation by androsterone followed atypical kinetics. Overall, the substrate specificity of the human liver 4MU/high affinity 1NP-GT activity appears to be broadly similar to that of the 3-methylcholanthrene inducible rat hepatic microsomal GT.</description><subject>Biological and medical sciences</subject><subject>General and cellular metabolism. Vitamins</subject><subject>Glucuronates - metabolism</subject><subject>Glucuronosyltransferase - analysis</subject><subject>Humans</subject><subject>Hymecromone - analogs & derivatives</subject><subject>Hymecromone - metabolism</subject><subject>In Vitro Techniques</subject><subject>Kinetics</subject><subject>Medical sciences</subject><subject>Microsomes, Liver - metabolism</subject><subject>Naphthols - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Substrate Specificity</subject><subject>Umbelliferones - metabolism</subject><subject>Uridine Diphosphate Glucuronic Acid - analysis</subject><issn>0006-2952</issn><issn>1873-2968</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1988</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE2P1SAUhonRjHdG_4EmLIwZF1WgQLmbSczErziJG10TCqf2mBauQCeZf2879-YuXRF4n_Pm8BDyirP3nHH9gTGmG7FX4tqYd3vGJWvEE7LjpmvXZ22ekt0ZeU4uS_mzXY3mF-Si5UIa1e1I-o4RKnrqYqAYR-yxpkxLXQJCoWmgspmhjg_TMvcwTThAThEecd5EdxjrmCb6e1r8sgYYXMUU1yY6LrOLdMJ7yHRGn1NJM5QX5NngpgIvT-cV-fX508_br83djy_fbj_eNV4qUZugtWYclOuldIJ3QmhwTAYHrjWh0-BVG1pQhvOglGk7uXcOtO_5oFwneXtF3h57Dzn9XaBUO2Px6wdchLQU2xnODGMbKI_gtmHJMNhDxtnlB8uZ3TzbzZrdJFpj7KNnK9ax16f-pZ8hnIdOYtf8zSl3xbtpyC56LGesY60ybKu5OWKwurhHyLZ4hOghYAZfbUj4_z3-AQsAmpI</recordid><startdate>19880215</startdate><enddate>19880215</enddate><creator>Miners, J.O.</creator><creator>Lillywhite, K.J.</creator><creator>Matthews, A.P.</creator><creator>Jones, M.E.</creator><creator>Birkett, D.J.</creator><general>Elsevier Inc</general><general>Elsevier Science</general><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>7X8</scope></search><sort><creationdate>19880215</creationdate><title>Kinetic and inhibitor studies of 4-methylumbelliferone and 1-naphthol glucuronidation in human liver microsomes</title><author>Miners, J.O. ; Lillywhite, K.J. ; Matthews, A.P. ; Jones, M.E. ; Birkett, D.J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c452t-d66601e5ab44a217226ea04daea38d76ec53d3e5811d5583749aae6cb1f5a7413</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1988</creationdate><topic>Biological and medical sciences</topic><topic>General and cellular metabolism. Vitamins</topic><topic>Glucuronates - metabolism</topic><topic>Glucuronosyltransferase - analysis</topic><topic>Humans</topic><topic>Hymecromone - analogs & derivatives</topic><topic>Hymecromone - metabolism</topic><topic>In Vitro Techniques</topic><topic>Kinetics</topic><topic>Medical sciences</topic><topic>Microsomes, Liver - metabolism</topic><topic>Naphthols - metabolism</topic><topic>Pharmacology. Drug treatments</topic><topic>Substrate Specificity</topic><topic>Umbelliferones - metabolism</topic><topic>Uridine Diphosphate Glucuronic Acid - analysis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Miners, J.O.</creatorcontrib><creatorcontrib>Lillywhite, K.J.</creatorcontrib><creatorcontrib>Matthews, A.P.</creatorcontrib><creatorcontrib>Jones, M.E.</creatorcontrib><creatorcontrib>Birkett, D.J.</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>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Biochemical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Miners, J.O.</au><au>Lillywhite, K.J.</au><au>Matthews, A.P.</au><au>Jones, M.E.</au><au>Birkett, D.J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Kinetic and inhibitor studies of 4-methylumbelliferone and 1-naphthol glucuronidation in human liver microsomes</atitle><jtitle>Biochemical pharmacology</jtitle><addtitle>Biochem Pharmacol</addtitle><date>1988-02-15</date><risdate>1988</risdate><volume>37</volume><issue>4</issue><spage>665</spage><epage>671</epage><pages>665-671</pages><issn>0006-2952</issn><eissn>1873-2968</eissn><coden>BCPCA6</coden><abstract>The glucuronidation kinetics of 4-methylumbelliferone (4MU) and 1-naphthol (1NP) have been investigated in human liver microsomes to determine the validity of using these compounds as probes for specific UDP-glucuronosyltransferase (GT) activities in human liver. 4MU glucuronidation followed Michaelis-Menten kinetics, whereas 1NP glucuronidation kinetics were biphasic. Cross inhibition studies were performed with 4MU and 1NP to determine the relationship between 4MU glucuronidation and the two phases of 1NP glucuronidation. 4MU glucuronidation was competitively inhibited by 1NP but 4MU inhibited only the high affinity component of 1NP glucuronidation. There was good agreement between the apparent
K
m values for 4MU and the high affinity component of 1NP glucuronidation and their respective apparent
K
i values determined in the cross inhibition studies. These data suggest that the same form(s) of human liver GT is involved in 4MU glucuronidation and the high affinity component of 1NP glucuronidation.
A number of compounds known to be specific substrates for purified rat liver GTs were screened for inhibitory effects on 4MU glucuronidation in human liver microsomes. 4-Nitrophenol, 2-aminophenol and androsterone inhibited 4MU glucuronidation whereas bilirubin, chloramphenicol, digitoxigenin monodigitoxoside, morphine, oestrone and testosterone had no effect. 4-Nitrophenol and 2-aminophenol were competitive inhibitors of 4MU glucuronidation but the inhibition of 4MU glucuronidation by androsterone followed atypical kinetics. Overall, the substrate specificity of the human liver 4MU/high affinity 1NP-GT activity appears to be broadly similar to that of the 3-methylcholanthrene inducible rat hepatic microsomal GT.</abstract><cop>New York, NY</cop><pub>Elsevier Inc</pub><pmid>3124857</pmid><doi>10.1016/0006-2952(88)90140-2</doi><tpages>7</tpages></addata></record> |
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| ispartof | Biochemical pharmacology, 1988-02, Vol.37 (4), p.665-671 |
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| subjects | Biological and medical sciences General and cellular metabolism. Vitamins Glucuronates - metabolism Glucuronosyltransferase - analysis Humans Hymecromone - analogs & derivatives Hymecromone - metabolism In Vitro Techniques Kinetics Medical sciences Microsomes, Liver - metabolism Naphthols - metabolism Pharmacology. Drug treatments Substrate Specificity Umbelliferones - metabolism Uridine Diphosphate Glucuronic Acid - analysis |
| title | Kinetic and inhibitor studies of 4-methylumbelliferone and 1-naphthol glucuronidation in human liver microsomes |
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