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
Hauptverfasser: BAO TING ZHU, EZELL, E. L, LIEHR, J. G
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EZELL, E. L
LIEHR, J. G
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. 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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 &amp; 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&amp;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 &amp; 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. 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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 &amp; 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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ispartof The Journal of biological chemistry, 1994-01, Vol.269 (1), p.292-299
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source MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection
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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