Catechol-O-methyltransferase-catalyzed rapid O-methylation of mutagenic flavonoids: metabolic inactivation as a possible reason for their lack of carcinogenicity in vivo
Quercetin is highly mutagenic in vitro, yet is not carcinogenic when administered chronically at large doses to rodents for 12 months. We hypothesized that catechol-O-methyltransferase-catalyzed O-methylation of quercetin and other mutagenic catechol-containing flavonoids may provide an efficient in...
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Veröffentlicht in: | The Journal of biological chemistry 1994-01, Vol.269 (1), p.292-299 |
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description | Quercetin is highly mutagenic in vitro, yet is not carcinogenic when administered chronically at large doses to rodents for 12 months. We hypothesized that catechol-O-methyltransferase-catalyzed O-methylation of quercetin and other mutagenic catechol-containing flavonoids may provide an efficient inactivation in vivo and may therefore prevent tumor induction by these flavonoids. After one intraperitoneal administration of 50 mg/kg quercetin to hamsters, a urinary ether extract contained 2% quercetin and 97% 3'-O-methylquercetin. When the urine was treated first with beta-glucuronidase and sulfatase, 13% quercetin and 87% 3'-O-methylquercetin were recovered. Quercetin was rapidly O-methylated by either porcine liver or hamster kidney catechol-O-methyltransferase, with Km values of 6.1 and 6.9 micromolars and Vmax values of 14,870 and 200 pmol/mg of protein/min, respectively. S-Adenosyl-L-homocysteine exhibited a potent feedback inhibition of the catechol-O-methyltransferase-catalyzed O-methylation of quercetin by a competitive mechanism with respect to S-adenosyl-L-methionine and by a competitive plus noncompetitive mechanism with respect to the substrate. A comparison of the O-methylation rates and kinetic characteristics (Km, Vmax, and Vmax/Km) demonstrated that rates of O-methylation of quercetin and fisetin were up to three orders of magnitude higher than those of catechol estrogens and catecholamines. In conclusion, the rapid metabolic inactivation of mutagenic flavonoids catalyzed by catechol-O-methyltransferase may be a major reason for the lack of their carcinogenic activities in vivo. |
doi_str_mv | 10.1016/S0021-9258(17)42348-9 |
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L ; LIEHR, J. G</creator><creatorcontrib>BAO TING ZHU ; EZELL, E. L ; LIEHR, J. G</creatorcontrib><description>Quercetin is highly mutagenic in vitro, yet is not carcinogenic when administered chronically at large doses to rodents for 12 months. We hypothesized that catechol-O-methyltransferase-catalyzed O-methylation of quercetin and other mutagenic catechol-containing flavonoids may provide an efficient inactivation in vivo and may therefore prevent tumor induction by these flavonoids. After one intraperitoneal administration of 50 mg/kg quercetin to hamsters, a urinary ether extract contained 2% quercetin and 97% 3'-O-methylquercetin. When the urine was treated first with beta-glucuronidase and sulfatase, 13% quercetin and 87% 3'-O-methylquercetin were recovered. Quercetin was rapidly O-methylated by either porcine liver or hamster kidney catechol-O-methyltransferase, with Km values of 6.1 and 6.9 micromolars and Vmax values of 14,870 and 200 pmol/mg of protein/min, respectively. S-Adenosyl-L-homocysteine exhibited a potent feedback inhibition of the catechol-O-methyltransferase-catalyzed O-methylation of quercetin by a competitive mechanism with respect to S-adenosyl-L-methionine and by a competitive plus noncompetitive mechanism with respect to the substrate. A comparison of the O-methylation rates and kinetic characteristics (Km, Vmax, and Vmax/Km) demonstrated that rates of O-methylation of quercetin and fisetin were up to three orders of magnitude higher than those of catechol estrogens and catecholamines. In conclusion, the rapid metabolic inactivation of mutagenic flavonoids catalyzed by catechol-O-methyltransferase may be a major reason for the lack of their carcinogenic activities in vivo.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1016/S0021-9258(17)42348-9</identifier><identifier>PMID: 8276810</identifier><identifier>CODEN: JBCHA3</identifier><language>eng</language><publisher>Bethesda, MD: American Society for Biochemistry and Molecular Biology</publisher><subject>actividad enzimatica ; activite enzymatique ; Animals ; Biological and medical sciences ; Biotransformation ; Catalysis ; Catechol O-Methyltransferase - metabolism ; Catecholamines - metabolism ; Cell physiology ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; cerdo ; Cricetinae ; desintoxicacion ; detoxification ; enzymic activity ; Estrogens - metabolism ; flavonoide ; flavonoides ; flavonoids ; foie ; Fundamental and applied biological sciences. Psychology ; hamster ; hamsters ; higado ; kidneys ; Kinetics ; liver ; Male ; metabolism ; metabolisme ; metabolismo ; Methylation ; metilacion ; Molecular and cellular biology ; Mutagens - metabolism ; Mutagens - toxicity ; neoplasmas ; neoplasme ; neoplasms ; porcin ; Quercetin - analogs & derivatives ; Quercetin - metabolism ; Quercetin - toxicity ; Quercetin - urine ; rein ; rinones ; S-Adenosylhomocysteine - metabolism ; swine ; transferasas ; transferase ; transferases</subject><ispartof>The Journal of biological chemistry, 1994-01, Vol.269 (1), p.292-299</ispartof><rights>1994 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c460t-d58d650c5a57b4fd41ddaf6e1c629d94a7b156c9f360d6f6c2a9f02d8191d6963</citedby><cites>FETCH-LOGICAL-c460t-d58d650c5a57b4fd41ddaf6e1c629d94a7b156c9f360d6f6c2a9f02d8191d6963</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786,27931,27932</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3962891$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8276810$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>BAO TING ZHU</creatorcontrib><creatorcontrib>EZELL, E. L</creatorcontrib><creatorcontrib>LIEHR, J. G</creatorcontrib><title>Catechol-O-methyltransferase-catalyzed rapid O-methylation of mutagenic flavonoids: metabolic inactivation as a possible reason for their lack of carcinogenicity in vivo</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Quercetin is highly mutagenic in vitro, yet is not carcinogenic when administered chronically at large doses to rodents for 12 months. We hypothesized that catechol-O-methyltransferase-catalyzed O-methylation of quercetin and other mutagenic catechol-containing flavonoids may provide an efficient inactivation in vivo and may therefore prevent tumor induction by these flavonoids. After one intraperitoneal administration of 50 mg/kg quercetin to hamsters, a urinary ether extract contained 2% quercetin and 97% 3'-O-methylquercetin. When the urine was treated first with beta-glucuronidase and sulfatase, 13% quercetin and 87% 3'-O-methylquercetin were recovered. Quercetin was rapidly O-methylated by either porcine liver or hamster kidney catechol-O-methyltransferase, with Km values of 6.1 and 6.9 micromolars and Vmax values of 14,870 and 200 pmol/mg of protein/min, respectively. S-Adenosyl-L-homocysteine exhibited a potent feedback inhibition of the catechol-O-methyltransferase-catalyzed O-methylation of quercetin by a competitive mechanism with respect to S-adenosyl-L-methionine and by a competitive plus noncompetitive mechanism with respect to the substrate. A comparison of the O-methylation rates and kinetic characteristics (Km, Vmax, and Vmax/Km) demonstrated that rates of O-methylation of quercetin and fisetin were up to three orders of magnitude higher than those of catechol estrogens and catecholamines. In conclusion, the rapid metabolic inactivation of mutagenic flavonoids catalyzed by catechol-O-methyltransferase may be a major reason for the lack of their carcinogenic activities in vivo.</description><subject>actividad enzimatica</subject><subject>activite enzymatique</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Biotransformation</subject><subject>Catalysis</subject><subject>Catechol O-Methyltransferase - metabolism</subject><subject>Catecholamines - metabolism</subject><subject>Cell physiology</subject><subject>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</subject><subject>cerdo</subject><subject>Cricetinae</subject><subject>desintoxicacion</subject><subject>detoxification</subject><subject>enzymic activity</subject><subject>Estrogens - metabolism</subject><subject>flavonoide</subject><subject>flavonoides</subject><subject>flavonoids</subject><subject>foie</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>hamster</subject><subject>hamsters</subject><subject>higado</subject><subject>kidneys</subject><subject>Kinetics</subject><subject>liver</subject><subject>Male</subject><subject>metabolism</subject><subject>metabolisme</subject><subject>metabolismo</subject><subject>Methylation</subject><subject>metilacion</subject><subject>Molecular and cellular biology</subject><subject>Mutagens - metabolism</subject><subject>Mutagens - toxicity</subject><subject>neoplasmas</subject><subject>neoplasme</subject><subject>neoplasms</subject><subject>porcin</subject><subject>Quercetin - analogs & derivatives</subject><subject>Quercetin - metabolism</subject><subject>Quercetin - toxicity</subject><subject>Quercetin - urine</subject><subject>rein</subject><subject>rinones</subject><subject>S-Adenosylhomocysteine - metabolism</subject><subject>swine</subject><subject>transferasas</subject><subject>transferase</subject><subject>transferases</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1994</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kduKFDEQhoMo6-zqI6xEENGL1iTdne54J8N6gIW9WBe8C9U5TEfTnTHJjIxv5FuaOTi5CVR99RXJj9A1Je8oofz9PSGMVoK1_RvavW1Y3fSVeIQWlPR1Vbf0-2O0OCNP0WVKP0g5jaAX6KJnHe8pWaC_S8hGjcFXd9Vk8rjzOcKcrImQTKUgg9_9MRpHWDuN_zOQXZhxsHjaZFiZ2SlsPWzDHJxOH3CBYAi-VN0MKrvtkYeEAa9DSm7wBkcDqRRtiDiPxkXsQf3cOxVE5eZw0Lq8Kw68ddvwDD2x4JN5frqv0MOnm2_LL9Xt3eevy4-3lWo4yZVue81bolpou6GxuqFag-WGKs6EFg10A225ErbmRHPLFQNhCdM9FVRzwesr9ProXcfwa2NSlpNLyngPswmbJCnva9KzuoDtEVSxvCkaK9fRTRB3khK5j0geIpL7_5e0k4eIpChz16cFm2Ey-jx1yqT0X536kBR4W_JQLp2xWnDWC1qwl0dsdKvxt4tGDi6o0UyScSGpZIIV5sWRsRAkrGLRPNxTIVpCasI7Vv8DPMayBw</recordid><startdate>19940107</startdate><enddate>19940107</enddate><creator>BAO TING ZHU</creator><creator>EZELL, E. L</creator><creator>LIEHR, J. G</creator><general>American Society for Biochemistry and Molecular Biology</general><scope>FBQ</scope><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>7U7</scope><scope>C1K</scope></search><sort><creationdate>19940107</creationdate><title>Catechol-O-methyltransferase-catalyzed rapid O-methylation of mutagenic flavonoids: metabolic inactivation as a possible reason for their lack of carcinogenicity in vivo</title><author>BAO TING ZHU ; EZELL, E. L ; LIEHR, J. G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c460t-d58d650c5a57b4fd41ddaf6e1c629d94a7b156c9f360d6f6c2a9f02d8191d6963</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1994</creationdate><topic>actividad enzimatica</topic><topic>activite enzymatique</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Biotransformation</topic><topic>Catalysis</topic><topic>Catechol O-Methyltransferase - metabolism</topic><topic>Catecholamines - metabolism</topic><topic>Cell physiology</topic><topic>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</topic><topic>cerdo</topic><topic>Cricetinae</topic><topic>desintoxicacion</topic><topic>detoxification</topic><topic>enzymic activity</topic><topic>Estrogens - metabolism</topic><topic>flavonoide</topic><topic>flavonoides</topic><topic>flavonoids</topic><topic>foie</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>hamster</topic><topic>hamsters</topic><topic>higado</topic><topic>kidneys</topic><topic>Kinetics</topic><topic>liver</topic><topic>Male</topic><topic>metabolism</topic><topic>metabolisme</topic><topic>metabolismo</topic><topic>Methylation</topic><topic>metilacion</topic><topic>Molecular and cellular biology</topic><topic>Mutagens - metabolism</topic><topic>Mutagens - toxicity</topic><topic>neoplasmas</topic><topic>neoplasme</topic><topic>neoplasms</topic><topic>porcin</topic><topic>Quercetin - analogs & derivatives</topic><topic>Quercetin - metabolism</topic><topic>Quercetin - toxicity</topic><topic>Quercetin - urine</topic><topic>rein</topic><topic>rinones</topic><topic>S-Adenosylhomocysteine - metabolism</topic><topic>swine</topic><topic>transferasas</topic><topic>transferase</topic><topic>transferases</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>BAO TING ZHU</creatorcontrib><creatorcontrib>EZELL, E. L</creatorcontrib><creatorcontrib>LIEHR, J. G</creatorcontrib><collection>AGRIS</collection><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>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>BAO TING ZHU</au><au>EZELL, E. L</au><au>LIEHR, J. G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Catechol-O-methyltransferase-catalyzed rapid O-methylation of mutagenic flavonoids: metabolic inactivation as a possible reason for their lack of carcinogenicity in vivo</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>1994-01-07</date><risdate>1994</risdate><volume>269</volume><issue>1</issue><spage>292</spage><epage>299</epage><pages>292-299</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><coden>JBCHA3</coden><abstract>Quercetin is highly mutagenic in vitro, yet is not carcinogenic when administered chronically at large doses to rodents for 12 months. We hypothesized that catechol-O-methyltransferase-catalyzed O-methylation of quercetin and other mutagenic catechol-containing flavonoids may provide an efficient inactivation in vivo and may therefore prevent tumor induction by these flavonoids. After one intraperitoneal administration of 50 mg/kg quercetin to hamsters, a urinary ether extract contained 2% quercetin and 97% 3'-O-methylquercetin. When the urine was treated first with beta-glucuronidase and sulfatase, 13% quercetin and 87% 3'-O-methylquercetin were recovered. Quercetin was rapidly O-methylated by either porcine liver or hamster kidney catechol-O-methyltransferase, with Km values of 6.1 and 6.9 micromolars and Vmax values of 14,870 and 200 pmol/mg of protein/min, respectively. S-Adenosyl-L-homocysteine exhibited a potent feedback inhibition of the catechol-O-methyltransferase-catalyzed O-methylation of quercetin by a competitive mechanism with respect to S-adenosyl-L-methionine and by a competitive plus noncompetitive mechanism with respect to the substrate. A comparison of the O-methylation rates and kinetic characteristics (Km, Vmax, and Vmax/Km) demonstrated that rates of O-methylation of quercetin and fisetin were up to three orders of magnitude higher than those of catechol estrogens and catecholamines. In conclusion, the rapid metabolic inactivation of mutagenic flavonoids catalyzed by catechol-O-methyltransferase may be a major reason for the lack of their carcinogenic activities in vivo.</abstract><cop>Bethesda, MD</cop><pub>American Society for Biochemistry and Molecular Biology</pub><pmid>8276810</pmid><doi>10.1016/S0021-9258(17)42348-9</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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subjects | actividad enzimatica activite enzymatique Animals Biological and medical sciences Biotransformation Catalysis Catechol O-Methyltransferase - metabolism Catecholamines - metabolism Cell physiology Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes cerdo Cricetinae desintoxicacion detoxification enzymic activity Estrogens - metabolism flavonoide flavonoides flavonoids foie Fundamental and applied biological sciences. Psychology hamster hamsters higado kidneys Kinetics liver Male metabolism metabolisme metabolismo Methylation metilacion Molecular and cellular biology Mutagens - metabolism Mutagens - toxicity neoplasmas neoplasme neoplasms porcin Quercetin - analogs & derivatives Quercetin - metabolism Quercetin - toxicity Quercetin - urine rein rinones S-Adenosylhomocysteine - metabolism swine transferasas transferase transferases |
title | Catechol-O-methyltransferase-catalyzed rapid O-methylation of mutagenic flavonoids: metabolic inactivation as a possible reason for their lack of carcinogenicity in vivo |
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