The importance of the UGT1A1 variants in the development of osteopenia and osteoporosis in postmenopausal women

Bogacz, Anna; Kamiński, Adam; Łochyńska, Małgorzata; Uzar, Izabela; Gorący, Jarosław; Kotrych, Daniel; Seremak‐Mrozikiewicz, Agnieszka; Czerny, Bogusław

doi:10.1038/s41598-021-96429-x

Cited by 3 publications

(4 citation statements)

References 36 publications

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“…For example, the drug irinotecan, used to treat small cell lung cancer, has serious drug toxicity. It is converted to the active metabolite SN-38 via carboxylesterase, and UGT1A1 mediates the conversion of SN-38 to an inactive compound by binding to SN-38G, facilitating its excretion from the body ( 61 ). An evaluation and analysis of a large body of literature revealed a high occurrence of severe irinotecan-induced toxicity in pure carriers of the UGT1A1 mutant UGT1A1*28 or UGT1A1*6; hence, these UGT1A1 mutations were predictive of irinotecan-related toxicity ( 62 ).…”

Section: Roles Of Ugts In the Regulation Of Tumor Metabolismmentioning

confidence: 99%

“…UGT1A1 plays an important role in estrogen metabolism. It is highly expressed in the uterus and is involved in the elimination of estrogen ( 61 ). After menopause, women gain weight and fat content, with a subsequent increase in estrogen sources, which leads to a decrease in bone transformation and an increase in bone loss ( 61 ).…”

Section: Roles Of Ugts In the Regulation Of Tumor Metabolismmentioning

confidence: 99%

“…It is highly expressed in the uterus and is involved in the elimination of estrogen ( 61 ). After menopause, women gain weight and fat content, with a subsequent increase in estrogen sources, which leads to a decrease in bone transformation and an increase in bone loss ( 61 ). Analysis of postmenopausal women with osteoporosis revealed that UGT1A1*28 can be used as a marker of bone loss for the timely assessment of bone tissue changes, and that pureton mutations in UGT1A1*28 can reduce the risk of bone loss and osteoporosis in postmenopausal women ( 25 , 61 ).…”

Section: Roles Of Ugts In the Regulation Of Tumor Metabolismmentioning

confidence: 99%

“…After menopause, women gain weight and fat content, with a subsequent increase in estrogen sources, which leads to a decrease in bone transformation and an increase in bone loss ( 61 ). Analysis of postmenopausal women with osteoporosis revealed that UGT1A1*28 can be used as a marker of bone loss for the timely assessment of bone tissue changes, and that pureton mutations in UGT1A1*28 can reduce the risk of bone loss and osteoporosis in postmenopausal women ( 25 , 61 ). Excessive accumulation of estrogen and its toxic metabolites can stimulate abnormal proliferation of breast cells, which causes breast cancer, while UGT can react with estrogen, which promotes the metabolism of estrogen and play a certain detoxifying effect ( 86 ).…”

Section: Roles Of Ugts In the Regulation Of Tumor Metabolismmentioning

confidence: 99%

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The Uridine diphosphate (UDP)-glycosyltransferases (UGTs) superfamily: the role in tumor cell metabolism

Liu

Zhao

et al. 2023

Front. Oncol.

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UDP-glycosyltransferases (UGTs), important enzymes in biotransformation, control the levels and distribution of numerous endogenous signaling molecules and the metabolism of a wide range of endogenous and exogenous chemicals. The UGT superfamily in mammals consists of the UGT1, UGT2, UGT3, and UGT8 families. UGTs are rate-limiting enzymes in the glucuronate pathway, and in tumors, they are either overexpressed or underexpressed. Alterations in their metabolism can affect gluconeogenesis and lipid metabolism pathways, leading to alterations in tumor cell metabolism, which affect cancer development and prognosis. Glucuronidation is the most common mammalian conjugation pathway. Most of its reactions are mainly catalyzed by UGT1A, UGT2A and UGT2B. The body excretes UGT-bound small lipophilic molecules through the bile, urine, or feces. UGTs conjugate a variety of tiny lipophilic molecules to sugars, such as galactose, xylose, acetylglucosamine, glucuronic acid, and glucose, thereby inactivating and making water-soluble substrates, such as carcinogens, medicines, steroids, lipids, fatty acids, and bile acids. This review summarizes the roles of members of the four UGT enzyme families in tumor function, metabolism, and multiple regulatory mechanisms, and its Inhibitors and inducers. The function of UGTs in lipid metabolism, drug metabolism, and hormone metabolism in tumor cells are among the most important topics covered.

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Section: Roles Of Ugts In the Regulation Of Tumor Metabolismmentioning

confidence: 99%

Section: Roles Of Ugts In the Regulation Of Tumor Metabolismmentioning

confidence: 99%

Section: Roles Of Ugts In the Regulation Of Tumor Metabolismmentioning

confidence: 99%

Section: Roles Of Ugts In the Regulation Of Tumor Metabolismmentioning

confidence: 99%

See 2 more Smart Citations

The Uridine diphosphate (UDP)-glycosyltransferases (UGTs) superfamily: the role in tumor cell metabolism

Liu

Zhao

et al. 2023

Front. Oncol.

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Determining the targets of of licorice against postmenopausal osteoporosis: A drug target mendelian randomization study followed network pharmacology analysis

Shan,

Chen,

Zhang

2023

Preprint

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Background We aimed to examine the main active components and mechanism of action of licorice against postmenopausal osteoporosis (PMOP) using a network pharmacology approach.And we also use the drug target mendelian Randomization (MR) to estimated the association between protein targets and PMOP, osteoporosis. Methods The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform was searched for active ingredients and potential targets of licorice. Cytoscape 3.7.2 software was used to build a network between the active components of licorice and its targets. A protein–protein interaction network of the prospective targets of licorice for PMOP treatment was constructed. Enrichment studies using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were performed on the primary targets. Instrument variables obtained from eQTLGen stroage, the outcome data get from the FinnGEN and Bionbank Japan Project. Primary causal effect was estimated by inverse variance weighted. Leave-one-out analyses and co-localization were uesd to vertifited the driven effect of single nucleotide polymorphism. Results We identified 88 potent active compounds from licorice and the corresponding 226 targets of action and retrieved 2,271 osteoporosis-related genes. The main active components were quercetin, kaempferol, naringenin, formononetin, and 7-methoxy-2-methyl isoflavone; the relevant protein targets were RXRA, AKT1, PPARA, TNF, CYP1A1, F2, and STAT3. MR analyses suggested STAT3 has a positive association both with PMOP of European population (odds radio [OR] 1.27, 95% confidence interval [CI] 1.01–1.60) and osteoporosis of East Asian (OR 1.29, 95% CI 1.18–1.41). Conclusions The pharmacodynamic effects of licorice for PMOP are the result of multi-component, -target, and -pathway interactions. Licorice may affect the development of PMOP throughSTAT3 gene,tumor, lipid, and arteriosclerosis pathways; chemical carcinogenicity activation; and advanced glycation end products–receptor (AGE–RAGE) pathways, thus providing a scientific basis for using licorice against PMOP.

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Influence of polymorphism of enzymes of the UDP family-glucuronyl transferases on the biotransformation of tamoxifen in the therapy of luminal forms of breast cancer

Yurchenko,

Shkarupa,

Kachula

et al. 2023

Rep. of Vinnytsia Nation. Med. Univ.

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Annotation. Tamoxifen (TAM) (1-[4-(2-dimethylaminoethoxy)-phenyl]-1,2-diphenylbut-1(Z)-ene) is a non-steroidal selective estrogen receptor modulator (SERM), which is recognized as the "gold standard" of hormone therapy for estrogen-dependent breast cancer (BC). It is known that adjuvant treatment with TAM increases recurrence-free survival and overall survival in patients with hormone-receptor-positive breast cancer. Also, tamoxifen manifests itself as a partial estrogen agonist, which can be associated with the development of complications such as endometrial cancer, venous thromboembolism, etc. The presence of resistance and relapses during TAM therapy, which reach up to 30%, remains an actual problem. Therefore, studying the mechanisms underlying the individualization of both therapeutic effect and toxicity associated with TAM remains an important challenge. In the detoxification of both TAM and its active metabolites, glucuronidation processes, which belong to the second phase of biotransformation of xenobiotics and actively take place in the liver as well as in the mammary gland, play an important role, and therefore the study of this process can contribute to the understanding of the interindividual variability of the therapeutic effect and toxicity of TAM. The aim – to analyze the data of the scientific literature on the study of the influence of glucuronyltransferase (UGT) enzymes and their polymorphic forms on the biotransformation of TAM and its active metabolites in the treatment of hormone-receptor-positive breast cancer. A retrospective analysis of the literature of scientific databases Scopus, Web of Science, PubMed., MedLines for 2013-2023 was carried out. It is possible to draw the following conclusions that UGT isozymes are responsible for the conjugation and detoxification of tamoxifen and its metabolites in the form of glucuronides 4-OH-tamoxifen-N-glucuronide, 4-OH-tamoxifen-O-glucuronide and endoxifen-O-glucuronide. UGT1A8, UGT1A10, UGT2B7, UGT2B15 and UGT2B17 isoforms played the greatest role in glucuronidation of tamoxifen and its active metabolites, but UGT1A4 was recognized as the main one. Depending on the content of active TAM metabolites and their glucuronides in the blood plasma, it can be stated that carriers of the UGT2B15 Lys523Thr and UGT2B17del alleles demonstrated increased enzyme activity, and individuals with one variant UGT2B15 523Thr allele can even be considered superactive metabolizers of 4-OH-tamoxifen-O- glucuronide and endoxifen-glucuronide. Also, high levels of 4-OH-tamoxifen-N-glucuronide were observed in carriers of the allele of the UGT2B17del genotype. Carriers of the above alleles have high activity of glucuronidation processes and low levels of active metabolites of TAM, which calls into question the rationality of prescribing TAM as hormone therapy. In contrast, patients with UGT1A4 48Val, UGT2B7 268Tyr alleles, or with wild-type genotypes for UGT2B17 nodel and UGT2B15 523Lys, will have high levels of active metabolites and are the group of choice for tamoxifen therapy in estrogen-receptor-positive breast cancer because they will have a low rate of glucuronidation and detoxification. However, in order to create a system of clinical algorithms for the formation of tamoxifen-sensitive groups of patients, further detailed study of other possibilities of the biotransformation system in the metabolism of tamoxifen is required.

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The importance of the UGT1A1 variants in the development of osteopenia and osteoporosis in postmenopausal women

Cited by 3 publications

References 36 publications

The Uridine diphosphate (UDP)-glycosyltransferases (UGTs) superfamily: the role in tumor cell metabolism

The Uridine diphosphate (UDP)-glycosyltransferases (UGTs) superfamily: the role in tumor cell metabolism

Determining the targets of of licorice against postmenopausal osteoporosis: A drug target mendelian randomization study followed network pharmacology analysis

Influence of polymorphism of enzymes of the UDP family-glucuronyl transferases on the biotransformation of tamoxifen in the therapy of luminal forms of breast cancer

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