Correlation of UGT1A1 * 28 and * 6 polymorphisms with irinotecan-induced neutropenia in Thai colorectal cancer patients

Atasilp, Chalirmporn; Chansriwong, Phichai; Sirachainan, E.; Reungwetwattana, Thanyanan; Chamnanphon, Montri; Puangpetch, Apichaya; Wongwaisayawan, Sansanee; Sukasem, Chonlaphat

doi:10.1016/j.dmpk.2015.12.004

Cited by 28 publications

(23 citation statements)

References 24 publications

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“…Drug metabolic enzymes (DMEs) are divided into phase I and phase II DMEs. Uridine 5'‐diphospho (UDP)‐glucuronosyltransferases (UGTs) are the most important phase II DMEs and have been reported to participate in the metabolic elimination of many xenobiotics (e.g., drugs, herbs, and pollutants) (Atasilp et al , ) and endogenous substances (e.g., oestrogen, bilirubin, and bile acids) (Mu et al , ; Kallionpaa et al , ; Bock, ). The inhibition of UGTs' activity will significantly affect the plasma exposure of xenobiotics and endogenous substances.…”

Section: Introductionsupporting

confidence: 72%

The Inhibition of UDP‐Glucuronosyltransferase (UGT) Isoforms by Praeruptorin A and B

Liu

Chen

et al. 2016

Phytotherapy Research

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Praeruptorin A (PA) and B (PB) are two important compounds isolated from Bai-hua Qian-hu and have been reported to exert multiple biochemical and pharmacological activities. The present study aims to determine the inhibition of PA and PB on the activity of important phase II drug-metabolizing enzymes uridine 5'-diphospho-glucuronosyltransferase (UGTs) isoforms. In vitro UGT incubation system was used to determine the inhibition potential of PA and PB on the activity of various UGT isoforms. In silico docking was performed to explain the inhibition difference between PA and PB towards the activity of UGT1A6. Inhibition behaviour was determined, and in vitro-in vivo extrapolation was performed by using the combination of in vitro inhibition kinetic parameter (K ) and in vivo exposure level of PA. Praeruptorin A (100 μM) exhibited the strongest inhibition on the activity of UGT1A6 and UGT2B7, with 97.8% and 90.1% activity inhibited by 100 μM of PA, respectively. In silico docking study indicates the significant contribution of hydrogen bond interaction towards the stronger inhibition of PA than PB towards UGT1A6. Praeruptorin A noncompetitively inhibited the activity of UGT1A6 and competitively inhibited the activity of UGT2B7. The inhibition kinetic parameter (K ) of PA towards UGT1A6 and UGT2B7 was calculated to be 1.2 and 3.3 μM, respectively. The [I]/K value was calculated to be 15.8 and 5.8 for the inhibition of PA on UGT1A6 and UGT2B7, indicating high inhibition potential of PA towards these two UGT isoforms in vivo. Therefore, closely monitoring the interaction between PA and drugs mainly undergoing UGT1A6 or UGT2B7-catalyzed metabolism is very necessary. Copyright © 2016 John Wiley & Sons, Ltd.

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Section: Introductionsupporting

confidence: 72%

The Inhibition of UDP‐Glucuronosyltransferase (UGT) Isoforms by Praeruptorin A and B

Liu

Chen

et al. 2016

Phytotherapy Research

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“…Correlation of UGT1A1*6 and UGT1A1*28 also showed the same results in this study. In Thai patients, the UGT1A1*28 mutation frequency was nearly the same with Chinese patients (22.8% vs. 24.2%), while the UGT1A1*6 mutation frequency was lower than in Chinese patients (15.9% vs. 34.8%) [23]. The difference of polymorphism frequencies induced by ethnicity might explain the differences in the results of the two studies.…”

Section: Discussionmentioning

confidence: 99%

Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis

Liú

Gao

et al. 2017

BMC Cancer

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BackgroundTo evaluate a new UGT1A and DPYD polymorphism panel to better predict irinotecan-induced toxicity and the clinical response in Chinese patients with metastatic colorectal cancer (mCRC).MethodsThe genotypes of UGT1A (UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A7*2, UGT1A7*3, UGT1A7*4 and UGT1A9*22) and DPYD (DPYD*5, DPYD c.1896 T > C, and DPYD*2A) were examined by direct sequencing in 661 mCRC patients receiving irinotecan-based chemotherapy. The influences of UGT1A and DPYD polymorphisms on severe irinotecan-induced toxicities and clinical outcomes were assessed.ResultsIn the cohort studied here, the incidence of UGT1A1*6, UGT1A1*28, UGT1A7*2, UGT1A7*3, UGT1A9*22, DPYD*5, and DPYD c.1896 T > C variants were 34.8%, 24.2%, 34.3%, 39.4%, 81.8%, 48.4% and 20.4%, respectively. UGT1A1*27 and DPYD*2A had low frequencies and UGT1A7*4 was not found. A total of 59 patients (8.9%) suffered severe diarrhea and 136 patients (20.6%) suffered severe neutropenia. UGT1A1*28 heterozygotes (OR = 2.263, 95%CI 1.395–3.670), UGT1A1*28 homozygotes (OR = 5.910, 95%CI 1.138–30.672) and UGT1A1*6 homozygotes (OR = 4.737, 95%CI 1.946–11.533) were independent risk factors for severe neutropenia. UGT1A polymorphisms were not found to relate to severe diarrhea. DPYD*5 was determined to be an independent risk factor for severe diarrhea (OR = 2.143, 95%CI 1.136–4.041). Neither DPYD*5 nor DPYD c.1896 T > C was found to relate to severe neutropenia. In the first-line irinotecan-based treatment, UGT1A1*28 and DPYD*5 contributed to higher response rates (P = 0.043 and P = 0.019, respectively), while DPYD*5 was found to associate with better progression-free survival (P = 0.015). UGT1A1*27 contributed to worse overall survival (P < 0.001).ConclusionResults still showed UGT1A1*6 and UGT1A1*28 to be partially associated with irinotecan-induced toxicity and clinical response. An examination of more UGT1A loci, except for UGT1A1*6 and UGT1A1*28, was not helpful to improve the predictive value of irinotecan-based toxicity and efficacy. An examination of DPYD*5 assisted in the prediction of severe diarrhea.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3406-2) contains supplementary material, which is available to authorized users.

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“…Therefore, we considered the UGT1A1*6 polymorphism in Asian populations. Previously, studies have shown that UGT1A1*6/*28 gene polymorphisms can be used to assess the risk of neutropenia; Chinese people are more likely to suffer delayed diarrhea than Japanese and Thai people 12–16…”

Section: Introductionmentioning

confidence: 99%

Relationship between <em>UGT1A16/28</em> gene polymorphisms and the efficacy and toxicity of irinotecan-based chemotherapy

Bai

et al. 2017

OTT

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PurposeA retrospective study was performed to analyze the relationship between uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) *6/*28 gene polymorphisms and adverse reactions associated with irinotecan (CPT-11)-based chemotherapy. The correlation between UGT1A1 polymorphisms and the clinical efficacy of CPT-11 was also analyzed, along with the influence of age and tumor type.Patients and methodsPatients administered a CPT-11-based regimen in the Beijing Cancer Hospital from April 2015 to September 2016 were included in our study (n=81). Blood samples for detecting UGT1A1 were collected from each patient after various administration regimens.ResultsColorectal cancer patients with the UGT1A1*6 mutant genotype had a significantly higher risk of severe delayed diarrhea than that of wild-type individuals when administered a CPT-11 dose ≥130 mg/m2 (P=0.042); the same phenomenon was observed when the UGT1A1*6 and UGT1A1*28 mutant genotypes were considered together (P=0.028). However, in lung cancer patients administered a low dose of CPT-11, UGT1A1*6/*28 variants were not significantly associated with severe neutropenia or delayed diarrhea. Furthermore, adult patients with the UGT1A1*6 mutation were more likely to develop severe delayed diarrhea than did wild-type adults (P=0.013); however, the difference was not significant in elderly patients. No significant differences in tumor response were found among the different genotypes (P>0.05).ConclusionThus, age and tumor type influence our ability to predict adverse reactions based on UGT1A1 gene polymorphisms in cancer patients. Further, UGT1A1 gene polymorphisms are not correlated with the efficacy of CPT-11-based regimens.

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Correlation of UGT1A1 * 28 and * 6 polymorphisms with irinotecan-induced neutropenia in Thai colorectal cancer patients

Cited by 28 publications

References 24 publications

The Inhibition of UDP‐Glucuronosyltransferase (UGT) Isoforms by Praeruptorin A and B

The Inhibition of UDP‐Glucuronosyltransferase (UGT) Isoforms by Praeruptorin A and B

Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis

Relationship between <em>UGT1A16/28</em> gene polymorphisms and the efficacy and toxicity of irinotecan-based chemotherapy

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Correlation of UGT1A1 * 28 and * 6 polymorphisms with irinotecan-induced neutropenia in Thai colorectal cancer patients

Cited by 28 publications

References 24 publications

The Inhibition of UDP‐Glucuronosyltransferase (UGT) Isoforms by Praeruptorin A and B

The Inhibition of UDP‐Glucuronosyltransferase (UGT) Isoforms by Praeruptorin A and B

Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis

Relationship between <em>UGT1A1*6/*28</em> gene polymorphisms and the efficacy and toxicity of irinotecan-based chemotherapy

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Relationship between <em>UGT1A16/28</em> gene polymorphisms and the efficacy and toxicity of irinotecan-based chemotherapy