<i>UGT2B7</i>
            Genetic Polymorphisms are Associated with the Withdrawal Symptoms in Methadone Maintenance Patients

Tian, Jia-Ni; Ho, Ing-Kang; Tsou, Hsiao-Hui; Fang, Chiu‐Ping; Chen, Chia‐Hui; Tan, Happy Kuy‐Lok; Lin, Linen; Wu, Chi‐Shin; Su, Lien-Wen; Huang, Chieh-Liang; Yang, Yi-Hong; Liu, Ming-Lun; Chen, Yuting; Liu, Shu Chih; Hsu, Ya-Ting; Kuo, Hsin‐Wei; Liu, Chen Ting; Yang, Yiting; Chen, Andrew Ch; Shih, Yu-Huei; Liu, Yuli

doi:10.2217/pgs.12.69

Cited by 32 publications

(22 citation statements)

References 30 publications

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“…This LD has been confirmed and extended in both directions spanning the gene from the 2-kb proximal promoter to the terminal exon (Hirota et al, 2003;Holthe et al, 2003;Sawyer et al, 2003;Duguay et al, 2004;Saeki et al, 2004;Saito et al, 2006;Innocenti et al, 2008;Nakamura et al, 2008;Hwang et al, 2010;Tian et al, 2012). This LD has been reported in different ethnic groups, including Caucasian (Holthe et al, 2003;Duguay et al, 2004;Innocenti et al, 2008), Chinese (Tian et al, 2012), Korean (Hwang et al, 2010), and Japanese populations (Hirota et al, 2003;Saeki et al, 2004;Saito et al, 2006;Nakamura et al, 2008). The present study further extended this LD in the 59-upstream direction spanning the 22000-to 24000-bp distal promoter region.…”

Section: Resultssupporting

confidence: 83%

“…Most studies show that this SNP has little impact on substrate selectivity and enzyme activity (Coffman et al, 1997(Coffman et al, , 1998Bhasker et al, 2000;Holthe et al, 2002;Court et al, 2003;Sawyer et al, 2003;Wiener et al, 2004;Lin et al, 2005;Thibaudeau et al, 2006;Innocenti et al, 2008;Court, 2010). Further studies on polymorphisms in the promoter and elsewhere in the UGT2B7 gene have led to the discovery of a tight linkage disequilibrium (LD) covering the region from the proximal 2-kb promoter to the 16-kb entire gene, including all exons and introns (Sawyer et al, 2003;Duguay et al, 2004;Nakamura et al, 2008;Tian et al, 2012). Two SNPs were identified in the promoter that negatively (2138A.G, rs7668258) (Duguay et al, 2004) or positively (2900A.G, rs7438135) (Duguay et al, 2004;Nakamura et al, 2008) regulate UGT2B7 promoter activity; however, the underlying molecular mechanisms remain undefined.…”

Section: Introductionmentioning

confidence: 99%

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Polymorphisms and Haplotypes of the UDP-Glucuronosyltransferase 2B7 Gene Promoter

Meech

et al. 2014

Drug Metab Dispos

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Identification of functional polymorphisms in the UDP-glucuronosyltransferase 2B7 (UGT2B7) gene predicting interpatient variability in the glucuronidation of drugs that are primarily metabolized by UGT2B7 has been the subject of many studies. These studies have shown linkage disequilibrium (LD) covering the region from 22 kb to 16 kb of the UGT2B7 gene. We identified three novel single-nucleotide polymorphisms (SNPs) and extended this LD in the 59-upstream direction to cover an additional nine prevalent polymorphisms in the distal 22600-to 24000-base pair (bp) promoter. We further showed complete LD between these distal promoter SNPs and the SNP (802C>T) in exon 2 in a panel of 26 livers. Because of this LD, we showed that all of the 23 prevalent polymorphisms in the 4-kb UGT2B7 promoter are linked together, defining two major haplotypes (i.e., I and II). The addition of the minor allele of a rare polymorphism and allele exchanges between haplotypes I and II generated subhaplotypes of I and II. We demonstrated a higher promoter activity of haplotype II over haplotype I, and this higher activity was abolished by an A-to-G change at a single SNP (2900A>G). This mutation changed a consensus activating protein-1 (AP-1) site (TGAGTCA) as occurred in haplotype II to a mutated AP-1 site (TGAGTCG) as occurred in haplotype I. Finally, we showed that the previously reported Alu element resides exclusively in haplotype I and is a highly conserved CG-rich Alu Y element.

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Section: Resultssupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Polymorphisms and Haplotypes of the UDP-Glucuronosyltransferase 2B7 Gene Promoter

Meech

et al. 2014

Drug Metab Dispos

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“…The morphine screen test was performed via a kinetic interaction of microparticles (KIMS) on an Integra 800 device (Roche Diagnostics, Basel, Switzerland). In our present analyses and previous reports [2,6,7], the urine morphine test was used as a surrogate measurement for the methadone treatment outcome.…”

Section: Methodsmentioning

confidence: 99%

Pharmacogenomics study in a Taiwanese methadone maintenance cohort

Wang

Tsou

et al. 2013

Journal of Food and Drug Analysis

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Pharmacogenomics is research to study the drug treatment responses in subgroups of patients according to their genetic variants or genetic expression information. Methadone maintenance treatment, which is usually prescribed for patients with heroin dependence, was launched in Taiwan by the government in 2006. In this study, 366 patients who had taken methadone continually in the previous 7 days were examined. Data from administration of the Treatment Outcomes Profile (TOP), Severity of Dependence Scale (SDS), Clinical Opioid Withdrawal Scale (COWS), and Treatment Emergent Symptoms Scale (TESS) were obtained from patients' report records. Genes encoding the liver cytochrome P-450 (CYP) enzymes that are involved with the metabolism of methadone (CYP2B6, 3A4 and 2C19) were selected and genotyped in this cohort. We found that the SNPs on CYP2B6 were associated with plasma S-methadone concentration; SNPs on CYP3A4 were associated with withdrawal symptoms and side effects; and SNPs on CYP2C19 were associated with methadone dose. SNPs in the genes encoding the morphine phase II metabolic enzyme, UGT2B7, were associated with withdrawal symptom scores. In pharmacodynamic genes, the SNPs on OPRM1 were associated with insomnia and change in libido side effects. We conclude that SNP markers may be useful for future methadone dosage adjustment and to reduce adverse reactions.

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“…Moreover, another in vivo study demonstrated that methadone is associated with inhibition of CYP2D6 and UDP-glucuronosyl transferase (UGT) 2B4 and 2B7 (Gelston et al, 2012). The inhibitory effect on UGT2B7 is shown to have an important role in opiate withdrawal symptoms, including pupil size and tremor (Tian et al, 2012).…”

Section: Metabolismmentioning

confidence: 99%

Metabolomics of methadone: clinical and forensic toxicological implications and variability of dose response

Dinis-Oliveira

2016

Drug Metabolism Reviews

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Methadone is a full μ-opioid receptor agonist used in the treatment of heroin addiction. It is commercialized as a racemic mixture with considerable variability in the pharmacokinetics and pharmacodynamics between individuals that can affect dose-response and toxicological profile. This review aims to discuss metabolomics of methadone, namely by presenting all major and minor metabolites and pharmacokinetic drug interactions. The main mechanism for methadone metabolism is hepatic through the cytochrome P450, specifically isoenzymes 2B6, 3A4 and 2D6. Firstly, methadone is N-demethylated and cyclize to form its major 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyraline (EMDP) metabolites. Several alternate minor pathways have been described namely various methadol metabolites, which proved to be active. It is expected that knowing the metabolomics of methadone may provide further insights, attempting a personalized therapy aiming to attain effective blood concentrations. The historical record is therefore especially important when investigating clinical and forensic cases related to methadone administration, since interindividual responses are known to vary considerably.

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UGT2B7 Genetic Polymorphisms are Associated with the Withdrawal Symptoms in Methadone Maintenance Patients

Abstract: These results suggest that SNPs of the UGT2B7 gene may play important roles in opiate withdrawal symptoms.

Cited by 32 publications

References 30 publications

Polymorphisms and Haplotypes of the UDP-Glucuronosyltransferase 2B7 Gene Promoter

Polymorphisms and Haplotypes of the UDP-Glucuronosyltransferase 2B7 Gene Promoter

Pharmacogenomics study in a Taiwanese methadone maintenance cohort

Metabolomics of methadone: clinical and forensic toxicological implications and variability of dose response

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