The contribution of common UGT2B10 and CYP2A6 alleles to variation in nicotine glucuronidation among european americans

A. Joseph Bloom, Linda B. Von Weymarn, Maribel Martinez, Laura J. Bierut, Alison Goate, Sharon E. Murphy

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background To develop a predictive genetic model of nicotine metabolism. UDP-glucuronosyltransferase-2B10 (UGT2B10) is the primary catalyst of nicotine glucuronidation. Materials and methods The conversion of deuterated (D 2)-nicotine to D2-nicotine-glucuronide, D 2-cotinine, D2-cotinine-glucuronide, and D 2-trans-3'-hydroxycotinine were quantified in 188 European Americans, and the contribution of UGT2B10 genotype to variability in first-pass nicotine glucuronidation assessed, following a procedure previously applied to nicotine C-oxidation. The proportion of total nicotine converted to nicotineglucuronide [D2-nicotine-glucuronide/(D2-nicotine+ D 2-nicotine-glucuronide+D2-cotinine +D2- cotinineglucuronide+ D2-trans-3'-hydroxycotinine)] was the primary phenotype. Results The variant, rs61750900T (D67Y) (minor allele frequency =10%), is confirmed to abolish nicotine glucuronidation activity. Another variant, rs112561475G (N397D) (minor allele frequency= 2%), is significantly associated with enhanced glucuronidation. rs112561475G is the ancestral allele of a well-conserved amino acid, indicating that the majority of human UGT2B10 alleles are derived hypomorphic alleles. Conclusion CYP2A6 and UGT2B10 genotype explain 53% of the variance in oral nicotine glucuronidation in this sample. CYP2A6 and UGT2B10 genetic variants are also significantly associated with undeuterated (D0) nicotine glucuronidation in individuals smoking ad libitum. We find no evidence for further common variation markedly influencing hepatic UGT2B10 expression in European Americans. Pharmacogenetics and Genomics 23:706-716

Original languageEnglish (US)
Pages (from-to)706-716
Number of pages11
JournalPharmacogenetics and Genomics
Volume23
Issue number12
DOIs
StatePublished - Dec 1 2013

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Glucuronosyltransferase
Nicotine
Alleles
Cotinine
Gene Frequency
Genotype
Pharmacogenetics
Genetic Models
Glucuronides
Genomics
Smoking
Phenotype
Amino Acids

Keywords

  • CYP2A6
  • Cotinine
  • Glucuronidation
  • Metabolism
  • Nicotine
  • UGT2B10

Cite this

The contribution of common UGT2B10 and CYP2A6 alleles to variation in nicotine glucuronidation among european americans. / Bloom, A. Joseph; Von Weymarn, Linda B.; Martinez, Maribel; Bierut, Laura J.; Goate, Alison; Murphy, Sharon E.

In: Pharmacogenetics and Genomics, Vol. 23, No. 12, 01.12.2013, p. 706-716.

Research output: Contribution to journalArticle

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title = "The contribution of common UGT2B10 and CYP2A6 alleles to variation in nicotine glucuronidation among european americans",
abstract = "Background To develop a predictive genetic model of nicotine metabolism. UDP-glucuronosyltransferase-2B10 (UGT2B10) is the primary catalyst of nicotine glucuronidation. Materials and methods The conversion of deuterated (D 2)-nicotine to D2-nicotine-glucuronide, D 2-cotinine, D2-cotinine-glucuronide, and D 2-trans-3'-hydroxycotinine were quantified in 188 European Americans, and the contribution of UGT2B10 genotype to variability in first-pass nicotine glucuronidation assessed, following a procedure previously applied to nicotine C-oxidation. The proportion of total nicotine converted to nicotineglucuronide [D2-nicotine-glucuronide/(D2-nicotine+ D 2-nicotine-glucuronide+D2-cotinine +D2- cotinineglucuronide+ D2-trans-3'-hydroxycotinine)] was the primary phenotype. Results The variant, rs61750900T (D67Y) (minor allele frequency =10{\%}), is confirmed to abolish nicotine glucuronidation activity. Another variant, rs112561475G (N397D) (minor allele frequency= 2{\%}), is significantly associated with enhanced glucuronidation. rs112561475G is the ancestral allele of a well-conserved amino acid, indicating that the majority of human UGT2B10 alleles are derived hypomorphic alleles. Conclusion CYP2A6 and UGT2B10 genotype explain 53{\%} of the variance in oral nicotine glucuronidation in this sample. CYP2A6 and UGT2B10 genetic variants are also significantly associated with undeuterated (D0) nicotine glucuronidation in individuals smoking ad libitum. We find no evidence for further common variation markedly influencing hepatic UGT2B10 expression in European Americans. Pharmacogenetics and Genomics 23:706-716",
keywords = "CYP2A6, Cotinine, Glucuronidation, Metabolism, Nicotine, UGT2B10",
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T1 - The contribution of common UGT2B10 and CYP2A6 alleles to variation in nicotine glucuronidation among european americans

AU - Bloom, A. Joseph

AU - Von Weymarn, Linda B.

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AU - Bierut, Laura J.

AU - Goate, Alison

AU - Murphy, Sharon E.

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N2 - Background To develop a predictive genetic model of nicotine metabolism. UDP-glucuronosyltransferase-2B10 (UGT2B10) is the primary catalyst of nicotine glucuronidation. Materials and methods The conversion of deuterated (D 2)-nicotine to D2-nicotine-glucuronide, D 2-cotinine, D2-cotinine-glucuronide, and D 2-trans-3'-hydroxycotinine were quantified in 188 European Americans, and the contribution of UGT2B10 genotype to variability in first-pass nicotine glucuronidation assessed, following a procedure previously applied to nicotine C-oxidation. The proportion of total nicotine converted to nicotineglucuronide [D2-nicotine-glucuronide/(D2-nicotine+ D 2-nicotine-glucuronide+D2-cotinine +D2- cotinineglucuronide+ D2-trans-3'-hydroxycotinine)] was the primary phenotype. Results The variant, rs61750900T (D67Y) (minor allele frequency =10%), is confirmed to abolish nicotine glucuronidation activity. Another variant, rs112561475G (N397D) (minor allele frequency= 2%), is significantly associated with enhanced glucuronidation. rs112561475G is the ancestral allele of a well-conserved amino acid, indicating that the majority of human UGT2B10 alleles are derived hypomorphic alleles. Conclusion CYP2A6 and UGT2B10 genotype explain 53% of the variance in oral nicotine glucuronidation in this sample. CYP2A6 and UGT2B10 genetic variants are also significantly associated with undeuterated (D0) nicotine glucuronidation in individuals smoking ad libitum. We find no evidence for further common variation markedly influencing hepatic UGT2B10 expression in European Americans. Pharmacogenetics and Genomics 23:706-716

AB - Background To develop a predictive genetic model of nicotine metabolism. UDP-glucuronosyltransferase-2B10 (UGT2B10) is the primary catalyst of nicotine glucuronidation. Materials and methods The conversion of deuterated (D 2)-nicotine to D2-nicotine-glucuronide, D 2-cotinine, D2-cotinine-glucuronide, and D 2-trans-3'-hydroxycotinine were quantified in 188 European Americans, and the contribution of UGT2B10 genotype to variability in first-pass nicotine glucuronidation assessed, following a procedure previously applied to nicotine C-oxidation. The proportion of total nicotine converted to nicotineglucuronide [D2-nicotine-glucuronide/(D2-nicotine+ D 2-nicotine-glucuronide+D2-cotinine +D2- cotinineglucuronide+ D2-trans-3'-hydroxycotinine)] was the primary phenotype. Results The variant, rs61750900T (D67Y) (minor allele frequency =10%), is confirmed to abolish nicotine glucuronidation activity. Another variant, rs112561475G (N397D) (minor allele frequency= 2%), is significantly associated with enhanced glucuronidation. rs112561475G is the ancestral allele of a well-conserved amino acid, indicating that the majority of human UGT2B10 alleles are derived hypomorphic alleles. Conclusion CYP2A6 and UGT2B10 genotype explain 53% of the variance in oral nicotine glucuronidation in this sample. CYP2A6 and UGT2B10 genetic variants are also significantly associated with undeuterated (D0) nicotine glucuronidation in individuals smoking ad libitum. We find no evidence for further common variation markedly influencing hepatic UGT2B10 expression in European Americans. Pharmacogenetics and Genomics 23:706-716

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