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1.
Chinese Journal of Lung Cancer ; (12): 137-146, 2022.
Article in English | WPRIM | ID: wpr-928791

ABSTRACT

BACKGROUND@#The literature recommends that reduced dosage of CPT-11 should be applied in patients with UGT1A1 homozygous mutations, but the impact of UGT1A1 heterozygous mutations on the adverse reactions of CPT-11 is still not fully clear.@*METHODS@#A total of 107 patients with UGT1A1 heterozygous mutation or wild-type, who were treated with CPT-11 from January 2018 to September 2021 in Peking University Third Hospital, were retrospectively enrolled. The adverse reaction spectra of patients with UGT1A1*6 and UGT1A1*28 mutations were analyzed. Adverse reactions were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 5.0. The efficacy was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The genotypes of UGT1A1*6 and UGT1A1*28 were detected by digital fluorescence molecular hybridization.@*RESULTS@#There were 43 patients with UGT1A1*6 heterozygous mutation, 26 patients with UGT1A1*28 heterozygous mutation, 8 patients with UGT1A1*6 and UGT1A1*28 double heterozygous mutations, 61 patients with heterozygous mutation at any gene locus of UGT1A1*6 and UGT1A1*28. Logistic regression analysis showed that the presence or absence of vomiting (P=0.013) and mucositis (P=0.005) was significantly correlated with heterozygous mutation of UGT1A1*28, and the severity of vomiting (P<0.001) and neutropenia (P=0.021) were significantly correlated with heterozygous mutation of UGT1A1*6. In colorectal cancer, UGT1A1*6 was significantly correlated to diarrhea (P=0.005), and the other adverse reactions spectrum was similar to that of the whole patient cohort, and efficacy and prognosis were similar between patients with different genotypes and patients treated with reduced CPT-11 dosage or not.@*CONCLUSIONS@#In clinical use, heterozygous mutations of UGT1A1*6 and UGT1A1*28 are related to the risk and severity of vomiting, diarrhea, neutropenia and mucositis in patients with Pan-tumor and colorectal cancer post CPT-11 therpy. In colorectal cancer, UGT1A1*6 is significantly related to diarrhea post CPT-11 use, efficacy and prognosis is not affected by various genotypes or CPT-11 dosage reduction.


Subject(s)
Camptothecin/therapeutic use , Glucuronosyltransferase/genetics , Humans , Lung Neoplasms/drug therapy , Mutation , Polymorphism, Genetic , Retrospective Studies
2.
Article in Chinese | WPRIM | ID: wpr-887992

ABSTRACT

This study aims to investigate metabolic activities of psoralidin in human liver microsomes( HLM) and intestinal microsomes( HIM),and to identify cytochrome P450 enzymes( CYPs) and UDP-glucuronosyl transferases( UGTs) involved in psoralidin metabolism as well as species differences in the in vitro metabolism of psoralen. First,after incubation serial of psoralidin solutions with nicotinamide adenine dinucleotide phosphate( NADPH) or uridine 5'-diphosphate-glucuronic acid( UDPGA)-supplemented HLM or HIM,two oxidic products( M1 and M2) and two conjugated glucuronides( G1 and G2) were produced in HLM-mediated incubation system,while only M1 and G1 were detected in HIM-supplemented system. The CLintfor M1 in HLM and HIM were 104. 3,and57. 6 μL·min~(-1)·mg~(-1),respectively,while those for G1 were 543. 3,and 75. 9 μL·min~(-1)·mg~(-1),respectively. Furthermore,reaction phenotyping was performed to identify the main contributors to psoralidin metabolism after incubation of psoralidin with NADPH-supplemented twelve CYP isozymes( or UDPGA-supplemented twelve UGT enzymes),respectively. The results showed that CYP1 A1( 39. 5 μL·min~(-1)·mg~(-1)),CYP2 C8( 88. 0 μL·min~(-1)·mg~(-1)),CYP2 C19( 166. 7 μL·min~(-1)·mg~(-1)),and CYP2 D6( 9. 1 μL·min~(-1)·mg~(-1)) were identified as the main CYP isoforms for M1,whereas CYP2 C19( 42. 0 μL·min~(-1)·mg~(-1)) participated more in producing M2. In addition,UGT1 A1( 1 184. 4 μL·min~(-1)·mg~(-1)),UGT1 A7( 922. 8 μL·min~(-1)·mg~(-1)),UGT1 A8( 133. 0 μL·min~(-1)·mg~(-1)),UGT1 A9( 348. 6 μL·min~(-1)·mg~(-1)) and UGT2 B7( 118. 7 μL·min~(-1)·mg~(-1)) played important roles in the generation of G1,while UGT1 A9( 111. 3 μL·min~(-1)·mg~(-1)) was regarded as the key UGT isozyme for G2. Moreover,different concentrations of psoralidin were incubated with monkey liver microsomes( MkLM),rat liver microsomes( RLM),mice liver microsomes( MLM),dog liver microsomes( DLM) and mini-pig liver microsomes( MpLM),respectively. The obtained CLintwere used to evaluate the species differences.Phase Ⅰ metabolism and glucuronidation of psoralidinby liver microsomes showed significant species differences. In general,psoralidin underwent efficient hepatic and intestinal metabolisms. CYP1 A1,CYP2 C8,CYP2 C19,CYP2 D6 and UGT1 A1,UGT1 A7,UGT1 A8,UGT1 A9,UGT2 B7 were identified as the main contributors responsible for phase Ⅰ metabolism and glucuronidation,respectively. Rat and mini-pig were considered as the appropriate model animals to investigate phase Ⅰ metabolism and glucuronidation,respectively.


Subject(s)
Animals , Benzofurans , Coumarins , Dogs , Glucuronides , Glucuronosyltransferase/metabolism , Kinetics , Mice , Microsomes, Liver/metabolism , Phenotype , Rats , Species Specificity , Swine , Swine, Miniature/metabolism
3.
Article in Chinese | WPRIM | ID: wpr-828502

ABSTRACT

A case of Gilbert syndrome (GS) with a heterozygous mutation in the gene is reported. The patient had no symptoms except for recurrent sclera icterus since childhood. Laboratory examinations revealed an elevated unconjugated bilirubin. Biliary obstruction, hemolysis and other diseases that might cause jaundice were excluded. *28 and c.211G>A heterozygous mutations in gene were found, which may be another type of mutation causing GS in Chinese population.


Subject(s)
Asians , Bilirubin , Gilbert Disease , Genetics , Glucuronosyltransferase , Genetics , Heterozygote , Humans , Mutation
4.
Article in Chinese | WPRIM | ID: wpr-773085

ABSTRACT

To evaluate the hepatotoxicity risks of physcion on the basis of the bilirubin metabolism mediated by glucuronidation of UDP-glucuronosyltransferases 1A1(UGT1A1 enzyme). The monomers were added into the rat liver microsomes to test the hepatotoxicity by using bilirubin as UGT1A1 enzyme substrate, with apparent inhibition constant K_i as the evaluation index. Liver microsome incubation in vitro was adopted to initiate phase Ⅱ metabolic reaction and investigate the inhibitory effect of physcion. Then the phase Ⅰ and Ⅱ metabolic reactions were initiated to investigate the comprehensive inhibition of metabolites and prototype components. The results showed that when only the phase Ⅱ reaction was initiated, physcion directly acted on the UGT1A1 enzyme in a prototype form, exhibited weak inhibition and the inhibition type was mixed inhibition; When the phase Ⅰ and Ⅱ reactions were initiated simultaneously, the inhibitory effects of physcion on UGT1A1 enzyme became strong and the inhibition type was mixed inhibition, suggesting that physcion had phase Ⅰ and Ⅱ metabolic processes, and the metabolites had strong inhibitory effect on UGT1A1 enzyme. This experiment preliminarily proved that the metabolites of physcion may be the main components to induce hepatotoxicity.


Subject(s)
Animals , Chemical and Drug Induced Liver Injury , Emodin , Toxicity , Glucuronosyltransferase , Metabolism , Kinetics , Microsomes, Liver , Rats
5.
Yonsei Medical Journal ; : 30-37, 2019.
Article in English | WPRIM | ID: wpr-719690

ABSTRACT

PURPOSE: The present study aimed to investigate correlations between uridine glucuronosyltransferase 2B7 (UGT2B7) -161 single nucleotide polymorphism C to T (C>T) and the occurrence of cardiotoxicity in Chinese breast cancer (BC) patients undergoing epirubicin/cyclophosphamide-docetaxel (EC-D) adjuvant chemotherapy. MATERIALS AND METHODS: 427 BC patients who had underwent surgery were consecutively enrolled in this prospective cohort study. All patients were scheduled to receive EC-D adjuvant chemotherapy regimen, and they were divided into UGT2B7 -161 CC (n=141), UGT2B7 -161 CT (n=196), and UGT2B7 -161 TT (n=90) groups according to their genotypes. Polymerase chain reaction was performed for determination of UGT2B7 -161 genotypes. Cardiotoxicity was defined as an absolute decline in left ventricular ejection fraction (LVEF) of at least 10% points from baseline to a value less than 53%, heart failure, acute coronary artery syndrome, or fatal arrhythmia. RESULTS: LVEF values were lower at cycle (C) 4, C8, 3 months after chemotherapy (M3), M6, M9, and M12 compared to C0 (all p < 0.001), in BC patients undergoing EC-D adjuvant chemotherapy. Cardiotoxicity was recorded for 4.2% of the overall population and was lowest in the UGT2B7 -161 TT group (1.1%), compared to UGT2B7 -161 CT (3.1%) and UGT2B7 -161 CC (7.8%) group (p=0.026). Multivariate logistic regression revealed that UGT2B7 -161 T allele could independently predict a low occurrence of cardiotoxicity in BC patients undergoing EC-D adjuvant chemotherapy (p=0.004). CONCLUSION: A UGT2B7 -161 T allele serves as a potential biomarker for predicting a low occurrence of cardiotoxicity in BC patients undergoing EC-D adjuvant chemotherapy.


Subject(s)
Alleles , Arrhythmias, Cardiac , Asians , Breast Neoplasms , Breast , Cardiotoxicity , Chemotherapy, Adjuvant , Cohort Studies , Coronary Vessels , Drug Therapy , Genotype , Glucuronosyltransferase , Heart Failure , Humans , Logistic Models , Polymerase Chain Reaction , Polymorphism, Single Nucleotide , Prospective Studies , Stroke Volume , Uridine
7.
Article in English | WPRIM | ID: wpr-776924

ABSTRACT

Pharmacological activities and adverse side effects of ginkgolic acids (GAs), major components in extracts from the leaves and seed coats of Ginkgo biloba L, have been intensively studied. However, there are few reports on their hepatotoxicity. In the present study, the metabolism and hepatotoxicity of GA (17 : 1), one of the most abundant components of GAs, were investigated. Kinetic analysis indicated that human and rat liver microsomes shared similar metabolic characteristics of GA (17 : 1) in phase I and II metabolisms. The drug-metabolizing enzymes involved in GA (17 : 1) metabolism were human CYP1A2, CYP3A4, UGT1A6, UGT1A9, and UGT2B15, which were confirmed with an inhibition study of human liver microsomes and recombinant enzymes. The MTT assays indicated that the cytotoxicity of GA (17 : 1) in HepG2 cells occurred in a time- and dose-dependent manner. Further investigation showed that GA (17 : 1) had less cytotoxicity in primary rat hepatocytes than in HepG2 cells and that the toxicity was enhanced through CYP1A- and CYP3A-mediated metabolism.


Subject(s)
Animals , Cells, Cultured , Cytochrome P-450 CYP1A2 , Metabolism , Cytochrome P-450 CYP3A , Metabolism , Ginkgo biloba , Chemistry , Glucuronosyltransferase , Metabolism , Hepatocytes , Chemistry , Metabolism , Humans , Kinetics , Liver , Chemistry , Metabolism , Microsomes, Liver , Chemistry , Metabolism , Plant Extracts , Chemistry , Metabolism , Toxicity , Rats , Rats, Sprague-Dawley , Salicylates , Chemistry , Metabolism , Toxicity
8.
Article in English | WPRIM | ID: wpr-812346

ABSTRACT

Pharmacological activities and adverse side effects of ginkgolic acids (GAs), major components in extracts from the leaves and seed coats of Ginkgo biloba L, have been intensively studied. However, there are few reports on their hepatotoxicity. In the present study, the metabolism and hepatotoxicity of GA (17 : 1), one of the most abundant components of GAs, were investigated. Kinetic analysis indicated that human and rat liver microsomes shared similar metabolic characteristics of GA (17 : 1) in phase I and II metabolisms. The drug-metabolizing enzymes involved in GA (17 : 1) metabolism were human CYP1A2, CYP3A4, UGT1A6, UGT1A9, and UGT2B15, which were confirmed with an inhibition study of human liver microsomes and recombinant enzymes. The MTT assays indicated that the cytotoxicity of GA (17 : 1) in HepG2 cells occurred in a time- and dose-dependent manner. Further investigation showed that GA (17 : 1) had less cytotoxicity in primary rat hepatocytes than in HepG2 cells and that the toxicity was enhanced through CYP1A- and CYP3A-mediated metabolism.


Subject(s)
Animals , Cells, Cultured , Cytochrome P-450 CYP1A2 , Metabolism , Cytochrome P-450 CYP3A , Metabolism , Ginkgo biloba , Chemistry , Glucuronosyltransferase , Metabolism , Hepatocytes , Chemistry , Metabolism , Humans , Kinetics , Liver , Chemistry , Metabolism , Microsomes, Liver , Chemistry , Metabolism , Plant Extracts , Chemistry , Metabolism , Toxicity , Rats , Rats, Sprague-Dawley , Salicylates , Chemistry , Metabolism , Toxicity
9.
Article in English | WPRIM | ID: wpr-812095

ABSTRACT

Polygoni Multiflori Radix (PMR) has been commonly used as a tonic in China for centuries. However, PMR-associated hepatotoxicity is becoming a safety issue. In our previous in vivo study, an interaction between stilbenes and anthraquinones has been discovered and a hypothesis is proposed that the interaction between stilbene glucoside-enriching fraction and emodin may contribute to the side effects of PMR. To further support our previous in vivo results in rats, the present in vitro study was designed to evaluate the effects of 2, 3, 5, 4'-tetrahydroxystilbene-2-O-β-D-glucopyranoside (TSG) on the cellular absorption and human liver microsome metabolism of emodin. The obtained results indicated that the absorption of emodin in Caco-2 cells was enhanced and the metabolism of emodin in human liver microsomes was inhibited after TSG treatment. The effects of the transport inhibitors on the cellular emodin accumulation were also examined. Western blot assay suggested that the depressed metabolism of emodin could be attributed to the down-regulation of UDP-glucuronosyltransferases (UGTs) 1A8, 1A10, and 2B7. These findings definitively demonstrated the existence of interaction between TSG and emodin, which provide a basis for a better understanding of the underlying mechanism for PMR-induced liver injury.


Subject(s)
Caco-2 Cells , Chemical and Drug Induced Liver Injury , Emodin , Metabolism , Fallopia multiflora , Glucosides , Toxicity , Glucuronosyltransferase , Humans , Plant Roots , Stilbenes , Toxicity
10.
Article in English | WPRIM | ID: wpr-812066

ABSTRACT

Ferulic acid (FA) is an active component of herbal medicines. One of the best documented activities of FA is its antioxidant property. Moreover, FA exerts antiallergic, anti-inflammatory, and hepatoprotective effects. However, the metabolic pathways of FA in humans remain unclear. To identify whether human CYP or UGT enzymes are involved in the metabolism of FA, reaction phenotyping of FA was conducted using major CYP-selective chemical inhibitors together with individual CYP and UGT Supersomes. The CYP- and/or UGT-mediated metabolism kinetics were examined simultaneously or individually. Relative activity factor and total normalized rate approaches were used to assess the relative contributions of each major human CYPs towards the FA metabolism. Incubations of FA with human liver microsomes (HLM) displayed NADPH- and UDPGA-dependent metabolism with multiple CYP and UGT isoforms involved. CYPs and UGTs contributed equally to the metabolism of FA in HLM. Although CYP1A2 and CYP3A4 appeared to be the major contributors in the CYP-mediated clearance, their contributions to the overall clearance are still minor (< 25%). As a constitute of many food and herbs, FA poses low drug-drug interaction risk when co-administrated with other herbs or conventional medicines because multiple phase I and phase II enzymes are involved in its metabolism.


Subject(s)
Coumaric Acids , Chemistry , Metabolism , Cytochrome P-450 Enzyme System , Chemistry , Metabolism , Drugs, Chinese Herbal , Metabolism , Glucuronosyltransferase , Chemistry , Metabolism , Humans , Kinetics , Medicine, Chinese Traditional , Microsomes, Liver , Chemistry
11.
Article in Chinese | WPRIM | ID: wpr-351397

ABSTRACT

A two-year-old girl was admitted due to repeated yellowing of the skin and sclera for 2 years and had no other specific symptoms or signs. The use of phenobarbital could relieve the symptoms of jaundice. Multiple examinations showed increased indirect bilirubin levels, and the results of aminotransferases and liver imaging were normal. There was no evidence of hemolysis. The analysis of UGT1A1 gene in her family found that this child had double homozygous mutation of c.211G>A(G71R) and c.1456T>G(Y486D), which had been reported as the pathogenic mutation for Gilbert syndrome. Her parents carried double heterozygous mutation of G71R and Y486D and had no symptom of jaundice. The child was diagnosed as having Gilbert syndrome. It is concluded that as for patients with unconjugated hyperbilirubinemia which cannot be explained by liver damage and hemolysis, their family history should be investigated in detail and gene analysis should be performed as early as possible, in order to identify congenital bilirubin metabolic disorders.


Subject(s)
Child, Preschool , Female , Gilbert Disease , Diagnosis , Glucuronosyltransferase , Genetics , Humans , Mutation , Sclera , Pathology , Skin , Pathology
12.
Article in Chinese | WPRIM | ID: wpr-247680

ABSTRACT

<p><b>OBJECTIVE</b>To detect potential mutation of the UGT1A1 gene in a child affected with Crigler-Najjar syndrome type II.</p><p><b>METHODS</b>Blood samples were collected from the patient and his parents for the extraction of genomic DNA. Potential mutation of the UGT1A1 gene was detected with polymerase chain reaction (PCR) and direct sequencing. The child was followed up until the age of 3 years and 6 months.</p><p><b>RESULTS</b>The patient showed persistent unconjugated hyperbilirubinemia. Sequencing of the UGT1A1 gene has detected a rare heterozygous c.610 A>G (p.Met204Val) mutation in the exon 1, in addition with a heterozygous c.1091 C>T (p.Pro364Leu) mutation in exon 4. The two mutations were inherited from his father and mother, respectively. The patient was diagnosed with Crigler-Najjar syndrome type II and received oral phenobarbital treatment.</p><p><b>CONCLUSION</b>The compound UGT1A1 gene mutation probably accounts for the disease in the patient manifesting persistent mild unconjugated hyperbilirubinemia. Genetic counseling and prenatal diagnosis should be provided for his family.</p>


Subject(s)
Crigler-Najjar Syndrome , Genetics , Glucuronosyltransferase , Genetics , Humans , Infant , Male , Mutation , Sequence Analysis, DNA
13.
Article in English | WPRIM | ID: wpr-812593

ABSTRACT

Glycyrrhizin is a major bioactive component of liquorice, which exerts multiple biochemical and pharmacological activities and is frequently used in combination with other drugs in the clinic. Mycophenolate mofetil (MMF), an immunosuppressant widely used in transplant patients, is metabolized by UDP-glucuronyltransferases (UGTs). Although significant evidence supports that glycyrrhizin could interact with the cytochrome P450s (CYPs), few studies have addressed its effects on UGTs. The present study aimed at investigating the regulatory effects of diammonium glycyrrhizinate (GLN) on UGTs in vitro and in vivo. We found that long-term administration of GLN in rats induced overall metabolism of MMF, which might be due to the induction of UGT1A protein expression. Hepatic UGT1A activity and UGT1A mRNA and protein expression were significantly increased in GLN-treated rats. UGT1A expression levels were also increased in the intestine, contradicting with the observed decrease in intestinal UGT1A activities. This phenomenon may be attributed to different concentrations of glycyrrhetinic acid (GA) in liver and intestine and the inhibitory effects of GA on UGT1A activity. In conclusion, our study revealed that GLN had multiple effects on the expression and activities of UGT1A isoforms, providing a basis for a better understanding of interactions between GLN and other drugs.


Subject(s)
Animals , Drugs, Chinese Herbal , Chemistry , Pharmacology , Glucuronosyltransferase , Chemistry , Metabolism , Glycyrrhizic Acid , Chemistry , Pharmacology , Herb-Drug Interactions , Intestines , Chemistry , Kinetics , Liver , Chemistry , Male , Rats , Rats, Sprague-Dawley
14.
Article in English | WPRIM | ID: wpr-812566

ABSTRACT

Isochlorogenic acid A (ICQA), which has anti-inflammatory, hepatoprotective, and antiviral properties, is commonly presented in fruits, vegetables, coffee, plant-based food products, and herbal medicines. These herbal medicines are usually used in combination with other medicines in the clinic. However, little is known about the regulatory effects of ICQA on drug-metabolizing enzymes and the herb-drug interactions. In the present study, we evaluated the inhibitory potentials of ICQA on CYP1A2, CYP2C9, CYP2C19, CYP3A4, CYP2D6, and CYP2E1 in vitro based on a cocktail approach. The P450 and UGT activities in mice treated with ICQA for a prolonged period were also determined. Our results demonstrated that ICQA exhibited a weak inhibitory effect on CYP2C9 in human liver microsomes with IC being 57.25 μmol·L and Ki being 26.77 μmol·L. In addition, ICQA inhibited UGT1A6 activity by 25%, in the mice treated with ICQA (i.p.) at 30 mg·kg for 14 d, compared with the control group. Moreover, ICQA showed no mechanism-based inhibition on CYP2C9 or UGT1A6. In conclusion, our results further confirm a safe use of ICQA in clinical practice.


Subject(s)
Animals , Chlorogenic Acid , Chemistry , Cytochrome P-450 Enzyme Inhibitors , Chemistry , Cytochrome P-450 Enzyme System , Chemistry , Metabolism , Glucuronosyltransferase , Chemistry , Metabolism , Humans , Kinetics , Mice , Mice, Inbred C57BL , Microsomes, Liver , Chemistry
15.
Braz. j. med. biol. res ; 48(11): 1039-1047, Nov. 2015. tab, graf
Article in English | LILACS | ID: lil-762910

ABSTRACT

We collected a series of 136 lung/bronchial and 56 matched lung parenchyma tissue samples from patients who underwent lung/bronchial biopsies and presented invasive carcinoma after lung surgery. The lung/bronchial samples included basal cell hyperplasia, squamous metaplasia, moderate dysplasia, adenomatous hyperplasia, severe dysplasia, squamous cell carcinoma and adenocarcinoma. Matched lung parenchyma tissue samples included 25 squamous cell carcinomas and 31 adenocarcinomas. Immunohistochemistry was performed to analyze for the distribution of hyaluronidase (Hyal)-1 and −3, and hyaluronan synthases (HAS)-1, −2, and −3. Hyal-1 showed significantly higher expression in basal cell hyperplasia than in moderate dysplasia (P=0.01), atypical adenomatous hyperplasia (P=0.0001), or severe dysplasia (P=0.03). Lower expression of Hyal-3 was found in atypical adenomatous hyperplasia than in basal cell hyperplasia (P=0.01) or moderate dysplasia (P=0.02). HAS-2 was significantly higher in severe dysplasia (P=0.002) and in squamous metaplasia (P=0.04) compared with basal cell hyperplasia. HAS-3 was significantly expressed in basal cell hyperplasia compared with atypical adenomatous hyperplasia (P=0.05) and severe dysplasia (P=0.02). Lower expression of HAS-3 was found in severe dysplasia compared with squamous metaplasia (P=0.01) and moderate dysplasia (P=0.01). Epithelial Hyal-1 and −3 and HAS-1, −2, and −3 expressions were significantly higher in pre-neoplastic lesions than in neoplastic lesions. Comparative Cox multivariate analysis controlled by N stage and histologic tumor type showed that patients with high HAS-3 expression in pre-neoplastic cells obtained by lung/bronchial biopsy presented a significantly higher risk of death (HR=1.19; P=0.04). We concluded that localization of Hyal and HAS in lung/bronchial pre-neoplastic and neoplastic lesions was inversely related to malignancy, which implied that visualizing these factors could be a useful diagnostic procedure for suspected lung cancer. Finalizing this conclusion will require a wider study in a randomized and prospective trial.


Subject(s)
Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Bronchial Neoplasms/enzymology , Carcinoma, Squamous Cell/enzymology , Glucuronosyltransferase/metabolism , Hyaluronoglucosaminidase/metabolism , Lung Neoplasms/enzymology , Neoplasm Proteins/metabolism , Precancerous Conditions/enzymology , Bronchial Neoplasms/pathology , Carcinoma, Squamous Cell/pathology , Cell Adhesion Molecules/analysis , Hyaluronoglucosaminidase/analysis , Hyperplasia/enzymology , Immunohistochemistry , Kaplan-Meier Estimate , Lung Neoplasms/pathology , Multivariate Analysis , Metaplasia/enzymology , Prognosis , Precancerous Conditions/pathology , Severity of Illness Index , Statistics, Nonparametric
16.
Chinese Journal of Oncology ; (12): 29-32, 2015.
Article in Chinese | WPRIM | ID: wpr-248414

ABSTRACT

<p><b>OBJECTIVE</b>To explore the correlation between UGT1A1 (*28, *60 and * 93) polymorphism and the adverse reactions in small cell lung cancer patients after irinotecan chemotherapy.</p><p><b>METHODS</b>Clinical data of 58 small cell lung cancer patients in extensive stage treated in our hospital were retrospectively analyzed. Polymerase chain reaction was used to amplify the UTG, and direct sequencing was performed to determine the UGT polymorphism. The adverse reactions ≥ grade 3 after irinotecan chemotherapy in patients with different UGT genotype were analyzed.</p><p><b>RESULTS</b>Amongthe 58 patients with extensive stage small cell lung cancer, there were 45 (77.6%) cases of wild type UGT1A1*28, 40 (69.0%) cases of wild type UGT1A1* 93, 38 (65.5%) cases of wild type UGT1A1*60, 18 cases of mutation in UGT1A1* 93 and 20 cases of mutation in UGT1A1*60. In UGT1A1 promoter position 28, there were 8 (13.8%) cases of TA5 mutation and 5 (8.6%) cases of TA7 mutation. Among the patients with TA5 mutation, 5 cases had ≥ grade 3 diarrhea, 3 cases had ≥ grade 3 leucopenia and 3 cases had ≥ grade 3 neutropenia, while among the patients with UGT1A1 * 93 mutation, 7 cases had ≥ grade 3 diarrhea, 6 cases had ≥ grade 3 leucopenia and 4 cases had ≥ grade 3 neutropenia.</p><p><b>CONCLUSIONS</b>TA5 and UGT1A1* 93 mutation increase the risk of diarrhea and ≥ grade 3 leukopenia and neutropenia, however, wild type UGT1A1 (*28, * 93, *60) and mutant UGT1A1*60 do not increase those risks. Further prospective study in a larger number of patients is needed to clarify the association between UGT1A1*28, UGT1A1* 93 and UGT1A1*60 polymorphism and adverse reactions of irinotecan, and to help clinicians in choosing a better therapeutic modality for personalized chemotherapy to improve curative effect and reduce adverse reactions.</p>


Subject(s)
Antineoplastic Agents, Phytogenic , Camptothecin , Diarrhea , Genotype , Glucuronosyltransferase , Genetics , Metabolism , Humans , Neutropenia , Polymorphism, Genetic , Promoter Regions, Genetic , Prospective Studies , Retrospective Studies , Small Cell Lung Carcinoma , Drug Therapy , Genetics
17.
Acta Pharmaceutica Sinica ; (12): 406-412, 2015.
Article in Chinese | WPRIM | ID: wpr-251764

ABSTRACT

With the wide application of Chinese herbal medicine, herb-drug interaction (HDI) has become increasingly prominent. Metabolic enzymes and transporters are the main targets of HDI, because the changes in expression and function of enzymes and transporters can influence the disposition of drugs. Metabolic enzymes are responsible for the metabolic clearance of drugs, including cytochrome P450 (CYP), UDP-glucuronyl transferase (UGT) and sulfotransferases (SULT); transporters widely expressed in the intestine, kidney, liver and brain are involved in the oral absorption, distribution and excretion of drugs. Pueraria, ginkgo, ginseng, St. John's wort and other Chinese herbal medicine often induce a HDI because those herbal medicines combined with chemical medicine are widely used in clinic. The components of herb medicines mentioned above are prone to interact with enzymes and transporters, which often induce a HDI. This paper reviews the advances in the study of enzymes and transporters-mediated pharmacokinetic mechanism of HDI.


Subject(s)
Biological Products , Biological Transport , Cytochrome P-450 Enzyme System , Physiology , Drugs, Chinese Herbal , Ginkgo biloba , Glucuronosyltransferase , Physiology , Herb-Drug Interactions , Humans , Membrane Transport Proteins , Physiology , Oxidation-Reduction , Panax , Plants, Medicinal , Pueraria
18.
Chinese Journal of Hepatology ; (12): 13-16, 2015.
Article in Chinese | WPRIM | ID: wpr-337057

ABSTRACT

<p><b>OBJECTIVE</b>To explore the clinical features and gene mutation profiles of patients with chronic hepatitis B (CHB) and Gilbert's syndrome.</p><p><b>METHODS</b>Thirty-three patients with CHB and Gilbert's syndrome were enrolled in the study. Serum markers of liver function and histological features of disease-related liver injury were assessed by standard methods. Gene mutations were detected by PCR and direct DNA sequencing.Statistical analysis was carried out with the chi-square and t tests.</p><p><b>RESULTS</b>Sequencing of the Gilbert syndrome-associated gene, UGT 1A 1, revealed mutations in the upstream promoter phenobarbital-responsive element module (PBREM) (-3279 mutation, 23 cases), in the promoter TATA box (a TA insertion mutation, 21 cases), and in the coding region of exon 1 (a GGA-AGA Gly71Arg mutation, 18 cases); there was no statistical difference found for any of the three mutations among this patient population (x2 =1.640, P more than 0.05).</p><p><b>CONCLUSION</b>The traditional methods of diagnosis for patients with CHB and Gilbert's syndrome remain a technical challenge in the clinic, and gene detection may represent a more favorable method for diagnosing this patient population.</p>


Subject(s)
Base Sequence , Exons , Gilbert Disease , Glucuronosyltransferase , Hepatitis B, Chronic , Humans , Mutagenesis, Insertional , Mutation , Polymerase Chain Reaction , Promoter Regions, Genetic , TATA Box
19.
Article in Chinese | WPRIM | ID: wpr-357323

ABSTRACT

<p><b>OBJECTIVE</b>To analyze the 5' and 3'-untranslated region sequences of the UGT1A1 gene in Chinese Han population and to find polymorphic variants within the untranslated region.</p><p><b>METHODS</b>Genomic DNA was extracted from peripheral leukocytes in 220 healthy Han individuals. The 5' and 3'-untranslated region sequences of the UGT1A1 gene were amplified by polymerase chain reaction, and followed by DNA sequencing.</p><p><b>RESULTS</b>Two polymorphic loci were identified in the 5'-untranslated region of the UGT1A1 gene with -64(G/C) and A(TA)6TAA/A(TA)7TAA in TATAA box region among Chinese Han population. Genotype frequencies were 98.4% (G) and 1.6% (C) in -64 locus of the UGT1A1 gene among the 220 individuals. The allele frequency of A(TA)6TAA and A(TA)7TAA within the promoter region was found to be 93.4% and 6.6%, respectively. Two polymorphic loci of 1813(C/T) and 1941(C/G) were detected in the 3'-untranslated region of the UGT1A1 gene, they showed a homozygous state at two loci with cosegregation pattern at 1813 and 1941 locus. The haplotype frequencies were 73.6% (CC/1813+CC/1941) and 26.4% (TT/1813+GG/1941) for 1813 and 1941 loci in the UGT1A1 gene.</p><p><b>CONCLUTION</b>Cosegregation pattern, at 1813 and 1941 locus with homozygous state in the 3'-untranslated region of the UGT1A1 gene may be selected from the human genome among Chinese Han population. More studies should be focused on the mechanism of homozygous cosegregation.</p>


Subject(s)
Alleles , Asians , Base Sequence , DNA , Gene Frequency , Genotype , Glucuronosyltransferase , Humans , Polymerase Chain Reaction , Polymorphism, Genetic , Sequence Analysis , Untranslated Regions
20.
Article in Chinese | WPRIM | ID: wpr-747271

ABSTRACT

OBJECTIVE@#To study the expression of hyaluronan synthasel-3 (HAS1-3) in nasal polyps, and discuss their clinical significance.@*METHOD@#The expression of HA, HAS1, HAS2 and HAS3 in nasal polyps group (25 cases) and inferior turbinate group (15 cases) was detected by immunohistochemistry and semi-quantitative RT-PCR.@*RESULT@#Compared with the control, the expression of HA, HAS1 and HAS3 was higher in nasal polyps (P0. 05).@*CONCLUSION@#The increase of HASI and HAS3 expression may be the main cause of the excessive deposition of HA in nasal polyps, which may play an important role in the pathogenic process of nasal polyps, and become a potential target for therapy of nasal polyps.


Subject(s)
Glucuronosyltransferase , Metabolism , Humans , Hyaluronan Synthases , Hyaluronic Acid , Immunohistochemistry , Nasal Polyps
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