Nicotine N-glucuronidation relative to N-oxidation and C-oxidation and UGT2B10 genotype in five ethnic/racial groups

Nicotine metabolism influences smoking behavior and differences in metabolism probably contribute to ethnic variability in lung cancer risk. We report here on the proportion of nicotine metabolism by cytochrome P450 2A6-catalyzed C-oxidation, UDP-glucuronosyl transferase 2B10 (UGT2B10)-catalyzed N-g...

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Veröffentlicht in:Carcinogenesis (New York) 2014-11, Vol.35 (11), p.2526-2533
Hauptverfasser: Murphy, Sharon E, Park, Sung-Shim L, Thompson, Elizabeth F, Wilkens, Lynne R, Patel, Yesha, Stram, Daniel O, Le Marchand, Loic
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container_end_page 2533
container_issue 11
container_start_page 2526
container_title Carcinogenesis (New York)
container_volume 35
creator Murphy, Sharon E
Park, Sung-Shim L
Thompson, Elizabeth F
Wilkens, Lynne R
Patel, Yesha
Stram, Daniel O
Le Marchand, Loic
description Nicotine metabolism influences smoking behavior and differences in metabolism probably contribute to ethnic variability in lung cancer risk. We report here on the proportion of nicotine metabolism by cytochrome P450 2A6-catalyzed C-oxidation, UDP-glucuronosyl transferase 2B10 (UGT2B10)-catalyzed N-glucuronidation and flavin monooxygenase 3-catalyzed N-oxidation in five ethnic/racial groups and the role of UGT2B10 genotype on the metabolic patterns observed. Nicotine and its metabolites were quantified in urine from African American (AA, n = 364), Native Hawaiian (NH, n = 311), White (n = 437), Latino (LA, n = 453) and Japanese American (JA, n = 674) smokers. Total nicotine equivalents, the sum of nicotine and six metabolites, and nicotine metabolism phenotypes were calculated. The relationship of UGT2B10 genotype to nicotine metabolic pathways was determined for each group; geometric means were computed and adjusted for age, sex, creatinine, and body mass index. Nicotine metabolism patterns were unique across the groups, C-oxidation was lowest in JA and NH (P < 0.0001), and N-glucuronidation lowest in AA (P < 0.0001). There was no difference in C-oxidation among Whites and AA and LA. Nicotine and cotinine glucuronide ratios were 2- and 3-fold lower in AA compared with Whites. Two UGT variants, a missense mutation (Asp67Tyr, rs61750900) and a splice variant (rs116294140) accounted for 33% of the variation in glucuronidation. In AA, the splice variant accounted for the majority of the reduced nicotine glucuronidation. UGT2B10 variant allele carriers had increased levels of C-oxidation (P = 0.0099). Our data indicate that the relative importance of nicotine metabolic pathways varies by ethnicity, and all pathways should be considered when characterizing the role of nicotine metabolism on smoking behavior and cancer risk.
doi_str_mv 10.1093/carcin/bgu191
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We report here on the proportion of nicotine metabolism by cytochrome P450 2A6-catalyzed C-oxidation, UDP-glucuronosyl transferase 2B10 (UGT2B10)-catalyzed N-glucuronidation and flavin monooxygenase 3-catalyzed N-oxidation in five ethnic/racial groups and the role of UGT2B10 genotype on the metabolic patterns observed. Nicotine and its metabolites were quantified in urine from African American (AA, n = 364), Native Hawaiian (NH, n = 311), White (n = 437), Latino (LA, n = 453) and Japanese American (JA, n = 674) smokers. Total nicotine equivalents, the sum of nicotine and six metabolites, and nicotine metabolism phenotypes were calculated. The relationship of UGT2B10 genotype to nicotine metabolic pathways was determined for each group; geometric means were computed and adjusted for age, sex, creatinine, and body mass index. Nicotine metabolism patterns were unique across the groups, C-oxidation was lowest in JA and NH (P &lt; 0.0001), and N-glucuronidation lowest in AA (P &lt; 0.0001). There was no difference in C-oxidation among Whites and AA and LA. Nicotine and cotinine glucuronide ratios were 2- and 3-fold lower in AA compared with Whites. Two UGT variants, a missense mutation (Asp67Tyr, rs61750900) and a splice variant (rs116294140) accounted for 33% of the variation in glucuronidation. In AA, the splice variant accounted for the majority of the reduced nicotine glucuronidation. UGT2B10 variant allele carriers had increased levels of C-oxidation (P = 0.0099). Our data indicate that the relative importance of nicotine metabolic pathways varies by ethnicity, and all pathways should be considered when characterizing the role of nicotine metabolism on smoking behavior and cancer risk.</description><identifier>ISSN: 0143-3334</identifier><identifier>EISSN: 1460-2180</identifier><identifier>DOI: 10.1093/carcin/bgu191</identifier><identifier>PMID: 25233931</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Adolescent ; Adult ; Ethnic Groups - genetics ; Female ; Genotype ; Glucuronates - genetics ; Glucuronosyltransferase - genetics ; Glucuronosyltransferase - pharmacokinetics ; Hepatocytes - metabolism ; Humans ; Male ; Microsomes, Liver - drug effects ; Microsomes, Liver - metabolism ; Middle Aged ; Neoplasms - genetics ; Neoplasms - metabolism ; Neoplasms - pathology ; Nicotine - analogs &amp; derivatives ; Nicotine - genetics ; Nicotine - metabolism ; Original Manuscript ; Risk Factors ; Smoking - genetics</subject><ispartof>Carcinogenesis (New York), 2014-11, Vol.35 (11), p.2526-2533</ispartof><rights>The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.</rights><rights>The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c387t-6c40b3c3fc3ff2027f1395d2203b9724f638dd015e1e7d05816e2bc620f425873</citedby><cites>FETCH-LOGICAL-c387t-6c40b3c3fc3ff2027f1395d2203b9724f638dd015e1e7d05816e2bc620f425873</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25233931$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Murphy, Sharon E</creatorcontrib><creatorcontrib>Park, Sung-Shim L</creatorcontrib><creatorcontrib>Thompson, Elizabeth F</creatorcontrib><creatorcontrib>Wilkens, Lynne R</creatorcontrib><creatorcontrib>Patel, Yesha</creatorcontrib><creatorcontrib>Stram, Daniel O</creatorcontrib><creatorcontrib>Le Marchand, Loic</creatorcontrib><title>Nicotine N-glucuronidation relative to N-oxidation and C-oxidation and UGT2B10 genotype in five ethnic/racial groups</title><title>Carcinogenesis (New York)</title><addtitle>Carcinogenesis</addtitle><description>Nicotine metabolism influences smoking behavior and differences in metabolism probably contribute to ethnic variability in lung cancer risk. We report here on the proportion of nicotine metabolism by cytochrome P450 2A6-catalyzed C-oxidation, UDP-glucuronosyl transferase 2B10 (UGT2B10)-catalyzed N-glucuronidation and flavin monooxygenase 3-catalyzed N-oxidation in five ethnic/racial groups and the role of UGT2B10 genotype on the metabolic patterns observed. Nicotine and its metabolites were quantified in urine from African American (AA, n = 364), Native Hawaiian (NH, n = 311), White (n = 437), Latino (LA, n = 453) and Japanese American (JA, n = 674) smokers. Total nicotine equivalents, the sum of nicotine and six metabolites, and nicotine metabolism phenotypes were calculated. The relationship of UGT2B10 genotype to nicotine metabolic pathways was determined for each group; geometric means were computed and adjusted for age, sex, creatinine, and body mass index. Nicotine metabolism patterns were unique across the groups, C-oxidation was lowest in JA and NH (P &lt; 0.0001), and N-glucuronidation lowest in AA (P &lt; 0.0001). There was no difference in C-oxidation among Whites and AA and LA. Nicotine and cotinine glucuronide ratios were 2- and 3-fold lower in AA compared with Whites. Two UGT variants, a missense mutation (Asp67Tyr, rs61750900) and a splice variant (rs116294140) accounted for 33% of the variation in glucuronidation. In AA, the splice variant accounted for the majority of the reduced nicotine glucuronidation. UGT2B10 variant allele carriers had increased levels of C-oxidation (P = 0.0099). Our data indicate that the relative importance of nicotine metabolic pathways varies by ethnicity, and all pathways should be considered when characterizing the role of nicotine metabolism on smoking behavior and cancer risk.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Ethnic Groups - genetics</subject><subject>Female</subject><subject>Genotype</subject><subject>Glucuronates - genetics</subject><subject>Glucuronosyltransferase - genetics</subject><subject>Glucuronosyltransferase - pharmacokinetics</subject><subject>Hepatocytes - metabolism</subject><subject>Humans</subject><subject>Male</subject><subject>Microsomes, Liver - drug effects</subject><subject>Microsomes, Liver - metabolism</subject><subject>Middle Aged</subject><subject>Neoplasms - genetics</subject><subject>Neoplasms - metabolism</subject><subject>Neoplasms - pathology</subject><subject>Nicotine - analogs &amp; derivatives</subject><subject>Nicotine - genetics</subject><subject>Nicotine - metabolism</subject><subject>Original Manuscript</subject><subject>Risk Factors</subject><subject>Smoking - genetics</subject><issn>0143-3334</issn><issn>1460-2180</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdUFtLwzAUDqK4OX30VfIH6k5yen0RdOgUxnzZnkOapl2kS0baDvfv7agOFQ6cy3c58BFyy-CeQYZTJb0ydppXHcvYGRmzMIaAsxTOyRhYiAEihiNy1TQfACzGKLskIx5xxAzZmLRLo1xrrKbLoKo71XlnTSFb4yz1uu6Hvaat61H3-XOXtqCzf_t6vuJPDGilrWsPO02NpeVRq9uNNWrqpTKyppV33a65JhelrBt9890nZP3yvJq9Bov3-dvscREoTJM2iFUIOSos-yo58KRkmEUF54B5lvCwjDEtCmCRZjopIEpZrHmuYg5lyKM0wQl5GHx3Xb7VhdK29bIWO2-20h-Ek0b8RazZiMrtRchZDDH0BsFgoLxrGq_Lk5aBOMYvhvjFEH_Pv_v98MT-yRu_AJkEhKM</recordid><startdate>20141101</startdate><enddate>20141101</enddate><creator>Murphy, Sharon E</creator><creator>Park, Sung-Shim L</creator><creator>Thompson, Elizabeth F</creator><creator>Wilkens, Lynne R</creator><creator>Patel, Yesha</creator><creator>Stram, Daniel O</creator><creator>Le Marchand, Loic</creator><general>Oxford University Press</general><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>5PM</scope></search><sort><creationdate>20141101</creationdate><title>Nicotine N-glucuronidation relative to N-oxidation and C-oxidation and UGT2B10 genotype in five ethnic/racial groups</title><author>Murphy, Sharon E ; Park, Sung-Shim L ; Thompson, Elizabeth F ; Wilkens, Lynne R ; Patel, Yesha ; Stram, Daniel O ; Le Marchand, Loic</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c387t-6c40b3c3fc3ff2027f1395d2203b9724f638dd015e1e7d05816e2bc620f425873</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Ethnic Groups - genetics</topic><topic>Female</topic><topic>Genotype</topic><topic>Glucuronates - genetics</topic><topic>Glucuronosyltransferase - genetics</topic><topic>Glucuronosyltransferase - pharmacokinetics</topic><topic>Hepatocytes - metabolism</topic><topic>Humans</topic><topic>Male</topic><topic>Microsomes, Liver - drug effects</topic><topic>Microsomes, Liver - metabolism</topic><topic>Middle Aged</topic><topic>Neoplasms - genetics</topic><topic>Neoplasms - metabolism</topic><topic>Neoplasms - pathology</topic><topic>Nicotine - analogs &amp; derivatives</topic><topic>Nicotine - genetics</topic><topic>Nicotine - metabolism</topic><topic>Original Manuscript</topic><topic>Risk Factors</topic><topic>Smoking - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Murphy, Sharon E</creatorcontrib><creatorcontrib>Park, Sung-Shim L</creatorcontrib><creatorcontrib>Thompson, Elizabeth F</creatorcontrib><creatorcontrib>Wilkens, Lynne R</creatorcontrib><creatorcontrib>Patel, Yesha</creatorcontrib><creatorcontrib>Stram, Daniel O</creatorcontrib><creatorcontrib>Le Marchand, Loic</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Carcinogenesis (New York)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Murphy, Sharon E</au><au>Park, Sung-Shim L</au><au>Thompson, Elizabeth F</au><au>Wilkens, Lynne R</au><au>Patel, Yesha</au><au>Stram, Daniel O</au><au>Le Marchand, Loic</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nicotine N-glucuronidation relative to N-oxidation and C-oxidation and UGT2B10 genotype in five ethnic/racial groups</atitle><jtitle>Carcinogenesis (New York)</jtitle><addtitle>Carcinogenesis</addtitle><date>2014-11-01</date><risdate>2014</risdate><volume>35</volume><issue>11</issue><spage>2526</spage><epage>2533</epage><pages>2526-2533</pages><issn>0143-3334</issn><eissn>1460-2180</eissn><abstract>Nicotine metabolism influences smoking behavior and differences in metabolism probably contribute to ethnic variability in lung cancer risk. We report here on the proportion of nicotine metabolism by cytochrome P450 2A6-catalyzed C-oxidation, UDP-glucuronosyl transferase 2B10 (UGT2B10)-catalyzed N-glucuronidation and flavin monooxygenase 3-catalyzed N-oxidation in five ethnic/racial groups and the role of UGT2B10 genotype on the metabolic patterns observed. Nicotine and its metabolites were quantified in urine from African American (AA, n = 364), Native Hawaiian (NH, n = 311), White (n = 437), Latino (LA, n = 453) and Japanese American (JA, n = 674) smokers. Total nicotine equivalents, the sum of nicotine and six metabolites, and nicotine metabolism phenotypes were calculated. The relationship of UGT2B10 genotype to nicotine metabolic pathways was determined for each group; geometric means were computed and adjusted for age, sex, creatinine, and body mass index. Nicotine metabolism patterns were unique across the groups, C-oxidation was lowest in JA and NH (P &lt; 0.0001), and N-glucuronidation lowest in AA (P &lt; 0.0001). There was no difference in C-oxidation among Whites and AA and LA. Nicotine and cotinine glucuronide ratios were 2- and 3-fold lower in AA compared with Whites. Two UGT variants, a missense mutation (Asp67Tyr, rs61750900) and a splice variant (rs116294140) accounted for 33% of the variation in glucuronidation. In AA, the splice variant accounted for the majority of the reduced nicotine glucuronidation. UGT2B10 variant allele carriers had increased levels of C-oxidation (P = 0.0099). Our data indicate that the relative importance of nicotine metabolic pathways varies by ethnicity, and all pathways should be considered when characterizing the role of nicotine metabolism on smoking behavior and cancer risk.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>25233931</pmid><doi>10.1093/carcin/bgu191</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record>
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source MEDLINE; Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection
subjects Adolescent
Adult
Ethnic Groups - genetics
Female
Genotype
Glucuronates - genetics
Glucuronosyltransferase - genetics
Glucuronosyltransferase - pharmacokinetics
Hepatocytes - metabolism
Humans
Male
Microsomes, Liver - drug effects
Microsomes, Liver - metabolism
Middle Aged
Neoplasms - genetics
Neoplasms - metabolism
Neoplasms - pathology
Nicotine - analogs & derivatives
Nicotine - genetics
Nicotine - metabolism
Original Manuscript
Risk Factors
Smoking - genetics
title Nicotine N-glucuronidation relative to N-oxidation and C-oxidation and UGT2B10 genotype in five ethnic/racial groups
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