UGT2B17 as a disease accelerator in CLL

Zhong, Yun‐Shi; Byrd, John C.

doi:10.1182/blood-2012-12-469965

Cited by 2 publications

(4 citation statements)

References 7 publications

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“…Previous reports identified UGT2B17 as a prognostic marker and a potential therapeutic target. 17 , 20 , 21 , 38 A potential impact of UGT2B17 expression on clinical outcome in treated patients emerges with observations of poor response in fludarabine-treated patients expressing high UGT2B17 levels whereas drug treatment further induces the UGT2B17-associated metabolic capacity of lymphoid cells according to our findings. Our observations further support a significant impact of the UGT metabolic pathway on the inactivation of most anti-cancer agents used in CLL, including commonly used treatments fludarabine, ibrutinib, bendamustine, chlorambucil and emerging targeted therapies idelalisib, venetoclax, acalabrutinib, cerdulatinib and duvelisib.…”

Section: Discussionsupporting

confidence: 63%

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UGT2B17 modifies drug response in chronic lymphocytic leukaemia

et al. 2020

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Background High UGT2B17 is associated with poor prognosis in untreated chronic lymphocytic leukaemia (CLL) patients and its expression is induced in non-responders to fludarabine-containing regimens. We examined whether UGT2B17, the predominant lymphoid glucuronosyltransferase, affects leukaemic drug response and is involved in the metabolic inactivation of anti-leukaemic agents. Methods Functional enzymatic assays and patients’ plasma samples were analysed by mass-spectrometry to evaluate drug inactivation by UGT2B17. Cytotoxicity assays and RNA sequencing were used to assess drug response and transcriptome changes associated with high UGT2B17 levels. Results High UGT2B17 in B-cell models led to reduced sensitivity to fludarabine, ibrutinib and idelalisib. UGT2B17 expression in leukaemic cells involved a non-canonical promoter and was induced by short-term treatment with these anti-leukaemics. Glucuronides of both fludarabine and ibrutinib were detected in CLL patients on respective treatment, however UGT2B17 conjugated fludarabine but not ibrutinib. AMP-activated protein kinase emerges as a pathway associated with high UGT2B17 in fludarabine-treated patients and drug-treated cell models. The expression changes linked to UGT2B17 exposed nuclear factor kappa B as a key regulatory hub. Conclusions Data imply that UGT2B17 represents a mechanism altering drug response in CLL through direct inactivation but would also involve additional mechanisms for drugs not inactivated by UGT2B17.

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Section: Discussionsupporting

confidence: 63%

“…Previous reports identified UGT2B17 as a prognostic marker and a potential therapeutic target. 17,20,21,38 Idelalisib-G (pmol/min/mg protein) UGT2B17 modifies drug response in chronic lymphocytic leukaemia EP Allain et al…”

Section: Discussionmentioning

confidence: 99%

UGT2B17 modifies drug response in chronic lymphocytic leukaemia

et al. 2020

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“… Structures of testosterone (1) and selected inhibitors: epicatechin (2), quercetin (3), and epigallocatechin gallate (4) .…”

Section: Pharmaceutical Inhibitors Of Ugt Steroid Glucuronidationmentioning

confidence: 99%

“…As a major route for excretion of exogenous and endogenous compounds, there is considerable interest in the roles of the UDP-glucuronosyltransferase (UGT) family, which has led to widespread investigations of their potential effects in health and disease (1–4). In particular, genetic and chemical modification of UGT activity relating to steroid metabolism has ramifications for a range of pathologies such as prostate cancer, medication contra-indications, disruption to the endocrine system, and potential confounding effects on doping tests in sport.…”

Section: Introductionmentioning

confidence: 99%

Effects of Dietary Components on Testosterone Metabolism via UDP-Glucuronosyltransferase

Jenkinson¹,

Petróczi²,

Naughton³

2013

Front. Endocrinol.

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The potential interference in testosterone metabolism through ingested substances has ramifications for: (i) a range of pathologies such as prostate cancer, (ii) medication contra-indications, (iii) disruption to the endocrine system, and (iv) potential confounding effects on doping tests. Conjugation of anabolic steroids during phase II metabolism, mainly driven by UDP-glucuronosyltransferase (UGT) 2B7, 2B15, and 2B17, has been shown to be impaired in vitro by a range of compounds including xenobiotics and pharmaceuticals. Following early reports on the effects of a range of xenobiotics on UGT activity in vitro, the work was extended to reveal similar effects with common non-steroidal anti-inflammatory drugs. Notably, recent studies have evidenced inhibitory effects of the common foodstuffs green tea and red wine, along with their constituent flavonoids and catechins. This review amalgamates the existing evidence for the inhibitory effects of various pharmaceutical and dietary substances on the rate of UGT glucuronidation of testosterone; and evaluates the potential consequences for health linked to steroid levels, interaction with treatment drugs metabolized by the UGT enzyme and steroid abuse in sport.

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UGT2B17 as a disease accelerator in CLL

Cited by 2 publications

References 7 publications

UGT2B17 modifies drug response in chronic lymphocytic leukaemia

UGT2B17 modifies drug response in chronic lymphocytic leukaemia

Effects of Dietary Components on Testosterone Metabolism via UDP-Glucuronosyltransferase

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