|Year : 2019 | Volume
| Issue : 10 | Page : 1319-1323
Roles of UGT2B7 C802T gene polymorphism on the efficacy of morphine treatment on cancer pain among the Chinese han population
M Ning, Y Tao, X Hu, L Guo, J Ni, J Hu, H Shen, Y Chen
Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
|Date of Acceptance||21-Jan-2019|
|Date of Web Publication||14-Oct-2019|
Dr. Y Chen
Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing-210 008
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Morphine is a common analgesic often used to manage chronic pain, especially for patients with pain due to malignancies. Since UGT2B7 plays an important role in the metabolism of morphine, UGT2B7 gene mutation may influence the efficacy of morphine in patients with cancer being treated by this medication. Aims: The aim of this study is to investigate the relationship between the polymorphisms of UGT2B7 and the efficacy of morphine treatment on cancer pain among the Chinese Han population. Materials and Methods: A total of 120 patients with cancer pain were enrolled in this study. Morphine was administrated through patient-controlled analgesia infusion pump, and the visual analog score (VAS) was used for pain assessment at 0.5, 4, 6, 12, 24, 48, and 72-h post morphine treatment, respectively. The plasma concentration of morphine and genetic polymorphism of UGT2B7 C802T and G221T was analyzed, respectively. Results: The frequencies of UGT2B7 C802T were CC: 13.33%, CT: 45% and TT: 41.67%, and the frequencies of UGT2B7 G221T were GG: 76.67%, GT: 22.5% and TT: 0.83%. Moreover, the VAS score of patients with either C802T CT or TT was significantly higher than that in patients with C802T CC. However, no difference of VAS scores was observed between patients carrying G221T GG and patients carrying G221T GT. The plasma concentration of morphine for patients with the C802T CC was significantly lower than that in patients carrying C802T CT or TT, while there was no significant difference in the level of morphine between patients with G221T GG and G221T GT. Conclusion: The polymorphism of UGT2B7 C802T, but not UGT2B7 G221T, has been associated with the efficacy of morphine treatment on cancer pain among Chinese Han population.
Keywords: Cancer pain, morphine, polymorphism, UGT2B7
|How to cite this article:|
Ning M, Tao Y, Hu X, Guo L, Ni J, Hu J, Shen H, Chen Y. Roles of UGT2B7 C802T gene polymorphism on the efficacy of morphine treatment on cancer pain among the Chinese han population. Niger J Clin Pract 2019;22:1319-23
|How to cite this URL:|
Ning M, Tao Y, Hu X, Guo L, Ni J, Hu J, Shen H, Chen Y. Roles of UGT2B7 C802T gene polymorphism on the efficacy of morphine treatment on cancer pain among the Chinese han population. Niger J Clin Pract [serial online] 2019 [cited 2020 Mar 29];22:1319-23. Available from: http://www.njcponline.com/text.asp?2019/22/10/1319/269019
| Introduction|| |
Pain due to cancer is a common symptom experienced by patients with various types of cancers. Cancer pain can either be due to the tumor itself or as an adverse effect of anti-cancer therapies, such as chemotherapy, surgery, and radiotherapy. Patients with cancer pain often present with mental and psychological problems which manifest as anxiety, depression, and negative feelings toward self, consequently leading to poor quality of life.
Morphine is a common analgesic often used to manage chronic pain. The metabolism of morphine mainly relies on the process of glucuronidation, which is responsible for eliminating about two-thirds of morphine from the human body. Through this process, 60% of morphine is converted into morphine-3-glucuronides (M3G), and the other 5%–10% of morphine is metabolized into morphine-6-glucuronides (M6G) by UDP- glucuronosyltransferases (UGTs). UGTs-regulated metabolism of morphine can be suppressed with the administration of an opioid, such as methadone. Besides modulating the metabolism of morphine, UGTs can also regulate the endogenous glucuronidation of opioids and xenobiotics.
The isozymes of UGTs can be divided into UGT1 and UGT2. UGT1 isozymes include: UGT1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9, 1A10 isozymes, and UGT2 isozymes include 2A1, 2B4, 2B7, 2B15, 2B17, and 2B28. In the human body, UGT2B7 is the predominant UGT isozyme in the glucuronidation of morphine. Previous studies demonstrated that UGT2B7 can react with morphine on the 3-OH or 6-OH position of morphine. UGT2B7 can regulate the metabolism of morphine by converting morphine to either M3G or M6G, and the level of M6G may reflect the activity of UGT2B7. Because UGT2B7 plays an important role in the metabolism of morphine, UGT2B7 gene mutation may influence the efficacy of morphine in patients being treated by this medication  Hitherto, the current information indicates that there is little that is known on the relationship between morphine metabolism and the genetic polymorphisms of UGT2B7. Thus, whether UGT2B7 genotype could affect the efficacy of morphine treatment on cancer pain remains to be determined.
In this present study, we investigated the relationship between the metabolism of morphine for pain relief in patients with cancer, and polymorphisms of UGT2B7 C802T and UGT2B7 G221T among the Chinese Han population. Our study provides new evidence for physicians in the use of morphine as an analgesic drug for the management of cancer pain.
| Materials and Methods|| |
In this study, we enrolled 120 patients with cancer pain from March 2016 to August 2016 in Nanjing Drum Tower Hospital. The clinical information of patients was as shown in [Table 1]. Morphine was administered through patient-controlled analgesia (PCA) infusion pump, and the visual analog score (VAS) was used for pain assessment at different time points. The research protocol was approved by the Human Ethics Committee of the Nanjing Drum Tower Hospital, and all the participants signed a written informed consent before getting involved in this study. Patients with a history of chronic pain and those with severe cardiopulmonary dysfunction and psychological depression were excluded from this study.
Determination of the concentration of plasma morphine
The level of morphine in plasma was quantified using the chemiluminescence method. The limit of the quantification was 0.1 nM for morphine.
Polymerase chain reaction and UGT2B7 polymorphism analysis
Genomic DNA was isolated from the peripheral blood of the patient, and polymerase chain reaction (PCR) was performed to amplify UGT2B7 C802T and UGT2B7 G221T. The primer sequences were as follows: C802T forward 5′-TCCAACTGATTGTTATGGTAGAT-3; reverse 5′-GCTGTTCCTTTCTGTCATTTCTC-3′ G211T, forward 5′-TGCTTTAGCTCTGGGAATTGT-3′ reverse 5′-TGCATGATGAAATTVTCCAAC-3′. The PCR products were analyzed by gene sequencing for genotyping.
Data were analyzed using the SPSS 19.0 (IBM SPSS, IBM, Armonk, NY, USA). Mann–Whitney test was used to compare allelic variation in genes between groups. Student's t-test or ANOVA was used to analyze associations between the different variables, allelic variation in genes UGT2B7 C802T and UGT2B7 G221T, and dose and concentration of morphine. P < 0.05 was considered statistically significant. The distribution of UGT2B7 C802T and G211T alleles from the Hardy–Weinberg equilibrium was tested by Chi-square test.
| Results|| |
Distribution of UGT2B7 C802T and G211T alleles
Genotyping analysis of UGT2B7 C802T and G211T alleles was performed among 120 enrolled patients using PCR and sequencing method. The frequencies of UGT2B7 C802T were CC: 13.33%, CT: 45%, and TT: 41.67%, while the frequencies of UGT2B7 G221T were GG: 76.67%, GT: 22.5%, and TT: 0.83% [Table 2]. The distribution of the both UGT2B7 C802T and G211T alleles was in accordance with Hardy–Weinberg equilibrium (P > 0.05).
The comparison of the dynamic visual analog scores post morphine treatment
The loading doses and the cumulative doses of morphine for PCA at each time point, as well as the VAS scores of patients at 0.5, 4, 6, 12, 24, 48, and 72 h post morphine treatment were recorded [Table 3] and [Table 4] to investigate the effect of C802T and G211T gene polymorphisms on the efficacy of morphine treatment. There were no significant differences between the loading dose and the cumulative dose of morphine for PCA at different time points among groups (P > 0.05). For the VAS scores, patients with C802T CT allele had a significantly higher VAS score than patients with C802T CC allele at each time point except for the 12 h (P < 0.05). Besides, patients with C802T TT allele had a significantly increased VAS score, compared with patients with C802T CC allele at each time point (P < 0.05). The VAS score of patients carrying either G211T GG or GT showed no significant difference (P > 0.05).
|Table 3: The loading dose and the cumulative dose of morphine from PCA at different time points|
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|Table 4: The comparison of Visual Analogue Score (VAS) at different time points among groups|
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The comparison of the plasma morphine concentration
The peripheral blood of patients at different time points was collected, and the concentration of plasma morphine was measured. The level of morphine was significantly lower in patients with C802T TT or CT allele, compared to patients with C802T CC allele at each time point (P < 0.05). On the other hand, the plasma concentration of morphine showed no significant difference between patients with G211T GG and GT allele (P > 0.05) [Table 4] and [Table 5].
|Table 5: Dynamic blood morphine concentrations at different time points among each group|
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| Discussion|| |
In this present study, we explored the relationship between the polymorphisms of UGT2B7 C802T and UGT2B7 G221T and the efficacy of morphine treatment in patients with cancer pain. We found out that UGT2B7 C802T, but not G221T polymorphism, is involved in the efficacy of morphine treatment for cancer pain among the Chinese Han population.
Morphine is a first-line drug recommended by the World Health Organization for pain management. However, significant variations were observed for the clinical efficacy of morphine among patients.,, For instance, it was reported that the morphine clearance rate and the accumulation of M3G and M6G were significantly higher among the Chinese Han population compared with that of the Caucasians. Previous studies indicated that the individual differences in morphine treatment may be caused by the genetic polymorphism of the metabolic enzymes, drug targets or receptors, and drug transporters. Campa et al. proved that ABCB1/MDR1 and OPRM1 gene polymorphisms were associated with the efficacy of morphine for pain relief; Candiotti et al. suggested that the CYP2D6 genetic polymorphisms may be a contributing factor to the postoperative consumption of morphine; Klepstad et al. also proved that the 118 A > G polymorphism of μ-opioid receptor may lead to an increased effective dose of morphine for patients with pain due to malignancies.
The results from clinical studies indicated that the polymorphisms of UGT gene may be associated with the metabolism of morphine in vivo.,, Bastami et al. reported that the polymorphism of UGT2B7 was strongly associated with the postoperative morphine consumption. In this present study, we explored the relationship between the polymorphisms of UGT2B7 on the efficacy of morphine treatment regarding cancer pain among Chinese Han population. Consistent with previous reports, PCR and sequencing results indicated that the distributions of UGT2B7 C802T were CC: 13.33%, CT: 45%, and TT: 41.67%, and the distributions of UGT2B7 G221T were GG: 76.67%, GT: 22.5% and TT: 0.83%. Moreover, during morphine treatment, patients with either C802T CT or TT allele had significantly higher VAS score compared with C802T CC allele required at each time point except for the 12 h (P < 0.05). In addition, the plasma concentration of morphine was significantly lower in patients with C802T TT or CT allele, compared with C802T CC allele at each time point (P < 0.05). Ideally, these results indicate that the C802T TT or CT mutation is strongly associated with the efficacy of morphine treatment for patients with cancer pain. On the other hand, the VAS score of patients with G211T GG and GT has no significant differences (P > 0.05), and the plasma concentration of morphine also showed no significant difference between patients with G211T GG and GT allele (P > 0.05). These results also indicated that the G211T polymorphism had no effect on the efficacy of morphine treatment for patients with cancer pain among the Chinese Han population.
| Conclusion|| |
To sum-up, the first time, we reported that the UGT2B7 C802T polymorphism can affect the efficacy of morphine treatment on cancer pain among the Chinese Han population. Our study may provide new insight for patients with cancer pain for morphine administration as the pain relief medication.
Financial support and sponsorship
This work was supported by the National Natural Science Foundation of China (81600201) and Nanjing Medical Science and technique Development Foundation (QRX17141) to YC.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Pachman DR, Barton DL, Swetz KM, Loprinzi CL. Troublesome symptoms in cancer survivors: Fatigue, insomnia, neuropathy, and pain. J Clin Oncol 2012;30:3687-96.
Kroenke K, Theobald D, Wu J, Loza JK, Carpenter JS, Tu W. The association of depression and pain with health-related quality of life, disability, and health care use in cancer patients. J Pain Symptom Manage 2010;40:327-41.
Nicholson B. Morphine sulfate extended-release capsules for the treatment of chronic, moderate-to-severe pain. Expert Opin Pharmacother 2008;9:1585-94.
Prommer EE. Pharmacological management of cancer-related pain. Cancer Control 2015;22:412-25.
Ahlers SJ, Välitalo PA, Peeters MY, Gulik LV, van Dongen EP, Dahan A, et al.
Morphine glucuronidation and elimination in intensive care patients: A Comparison with healthy volunteers. Anesth Analg 2015;121:1261-73.
Oda S, Fukami T, Yokoi T, Nakajima M. A comprehensive review of UDP-glucuronosyltransferase and esterases for drug development. Drug Metab Pharmacokinet 2015;30:30-51.
Wu B, Kulkarni K, Basu S, Zhang S, Hu M. First-pass metabolism via UDP-glucuronosyltransferase: A barrier to oral bioavailability of phenolics. J Pharm Sci 2011;100:3655-81.
Zhu L, Lu L, Zeng S, Luo F, Dai P, Wu P, et al.
UDP-glucuronosyltransferases 1A6 and 1A9 are the major isozymes responsible for the 7-O-glucuronidation of esculetin and 4-methylesculetin in human liver microsomes. Drug Metab Dispos 2015;43:977-83.
Coffman BL, Kearney WR, Goldsmith S, Knosp BM, Tephly TR. Opioids bind to the amino acids 84 to 118 of UDP-glucuronosyltransferase UGT2B7. Mol Pharmacol 2003;63:283-8.
Yang Z, Li L, Hu H, Xu M, Gu J, Wang ZJ, et al.
Reverse of acute and chronic morphine tolerance by lithocholic acid via
down-regulating UGT2B7. Front Pharmacol 2016;7:404.
Bastami S, Gupta A, Zackrisson AL, Ahlner J, Osman A, Uppugunduri S. Influence of UGT2B7, OPRM1 and ABCB1 gene polymorphisms on postoperative morphine consumption. Basic Clin Pharmacol Toxicol 2014;115:423-31.
Fitzgibbon D, Morgan D, Dockter D, Barry C, Kharasch ED. Initial pharmacokinetic, safety and efficacy evaluation of nasal morphine gluconate for breakthrough pain in cancer patients. Pain 2003;106:309-15.
Lee J, Lakha SF, Mailis A. Efficacy of low-dose oral liquid morphine for elderly patients with chronic non-cancer pain: Retrospective chart review. Drugs Real World Outcomes 2015;2:369-76.
Reyes-Gibby CC, Shete S, Rakvåg T, Bhat SV, Skorpen F, Bruera E, et al.
Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain 2007;130:25-30.
De Gregori S, De Gregori M, Ranzani GN, Allegri M, Minella C, Regazzi M. Morphine metabolism, transport and brain disposition. Metab Brain Dis 2012;27:1-5.
Campa D, Gioia A, Tomei A, Poli P, Barale R. Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther 2008;83:559-66.
Candiotti KA, Yang Z, Rodriguez Y, Crescimone A, Sanchez GC, Takacs P, et al.
The impact of CYP2D6 genetic polymorphisms on postoperative morphine consumption. Pain Med 2009;10:799-805.
Klepstad P, Rakvåg TT, Kaasa S, Holthe M, Dale O, Borchgrevink PC, et al.
The 118 A > ; G polymorphism in the human mu-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiol Scand 2004;48:1232-9.
Darbari DS, van Schaik RH, Capparelli EV, Rana S, McCarter R, van den Anker J. UGT2B7 promoter variant -840G and gt; A contributes to the variability in hepatic clearance of morphine in patients with sickle cell disease. Am J Hematol 2008;83:200-2.
Innocenti F, Liu W, Fackenthal D, Ramírez J, Chen P, Ye X, et al.
Single nucleotide polymorphism discovery and functional assessment of variation in the UDP-glucuronosyltransferase 2B7 gene. Pharmacogenet Genomics 2008;18:683-97.
Saeki M, Saito Y, Jinno H, Tanaka-Kagawa T, Ohno A, Ozawa S, et al.
Single nucleotide polymorphisms and haplotype frequencies of UGT2B4 and UGT2B7 in a Japanese population. Drug Metab Dispos 2004;32:1048-54.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]