The flavin-containing monooxygenase 3 (FMO3) is an important hepatic microsomal enzyme. Numerous mutations of FMO3 gene have been reported, and polymorphic varients of the gene have been identified. Several studies indicated that variability in the expression of FMO3 involved in some nitrogen, or sulfur-containing durg metabolism. This review summarizes the genetic polymorphism of FMO3 and its role in drug metabolism and toxicity.
Drug-Related Side Effects and Adverse Reactions ; Humans ; Oxygenases ; genetics ; Polymorphism, Genetic

The human leukocyte antigen (HLA) molecules encoded within the human major histocompatibility complex are a group of highly conserved cell surface proteins, which are related to antigen recognition. HLA genes display a high degree of genetic polymorphism, which is the basis of individual differences in immunity. Specific HLA genotypes have been highly associated with typical adverse drug reactions. HLA-A*31:01 and HLA-B*15:02 are associated with carbamazepine-induced severe cutaneous adverse reactions, HLA-B*57:01 is related to abacavir-induced drug-induced hypersensitivity syndrome and flucloxacillin/pazopanib-induced drug-induced liver injury, while HLA-B*35:01 is a potential biomarker for predicting polygonum multiflorum-induced liver injury. It is not clear how small drug molecules to interact with HLA molecules and T cell receptors (TCR). There are four mechanistic hypotheses, including the hapten/prohapten theory, the pharmacological interaction concept, the altered peptide repertoire model, and the altered TCR repertoire model.
Drug-Related Side Effects and Adverse Reactions/genetics* ; Genotype ; HLA Antigens/genetics* ; Humans ; Polymorphism, Genetic

The effects of androgen on lipid and the cardiovascular system are very important. The relationship between androgen and lipoprotein is rather complicated and influenced by many factors. The effects of endogenous androgen on the metabolism of lipoprotein vary with age, environment, nutrition and gender, while the effects of exogenous androgen on lipoprotein vary with different androgen preparations, administration methods and diseases to be treated. Androgen can impact the metabolism of lipoprotein, vascular endothelium, macrophage, vascular smooth muscle, angiotasis, blood coagulation, platelet and so on. The effects of polymorphism of the androgen receptor gene CAG on the cardiovascular system are important and yet somehow controversial and have to be further investigated.
Androgens ; pharmacology ; physiology ; Cardiovascular System ; drug effects ; Female ; Humans ; Lipoproteins ; metabolism ; Male ; Polymorphism, Genetic ; Receptors, Androgen ; genetics ; physiology

Anemia ; chemically induced ; Hepatitis C, Chronic ; drug therapy ; genetics ; Humans ; Polymorphism, Genetic ; Pyrophosphatases ; genetics ; Ribavirin ; adverse effects ; therapeutic use

The BubR1 mitotic-checkpoint protein monitors proper attachment of microtubules to kinetochores, and links regulation of chromosome-spindle attachment to mitotic-checkpoint signaling. Thus, disruption of BubR1 activity results in a loss of checkpoint control, chromosomal instability caused by a premature anaphase, and/or the early onset of tumorigenesis. The mechanisms by which deregulation and/or abnormalities of BubR1 expression operate, however, remain to be elucidated. In this study, we demonstrate that levels of BubR1 expression are significantly increased by demethylation. Bisulfite sequencing analysis revealed that the methylation status of two CpG sites in the essential BubR1 promoter appear to be associated with BubR1 expression levels. Associations of MBD2 and HDAC1 with the BubR1 promoter were significantly relieved by addition of 5-aza-2'-deoxycytidine, an irreversible DNA methyltransferase inhibitor. However, genomic DNA isolated from 31 patients with colorectal carcinomas exhibited a +84A/G polymorphic change in approximately 60% of patients, but this polymorphism had no effect on promoter activity. Our findings indicate that differential regulation of BubR1 expression is associated with changes in BubR1 promoter hypermethylation patterns, but not with promoter polymorphisms, thus providing a novel insight into the molecular regulation of BubR1 expression in human cancer cells.
Azacitidine/pharmacology ; Base Sequence ; Cell Line, Tumor ; *DNA Methylation/drug effects ; DNA Mutational Analysis ; DNA-Binding Proteins/metabolism ; *Gene Expression Regulation, Neoplastic/drug effects ; Hela Cells ; Histone Deacetylases/metabolism ; Humans ; Jurkat Cells ; Molecular Sequence Data ; Neoplasms/*genetics/*pathology ; Polymorphism, Genetic/drug effects ; Promoter Regions, Genetic/drug effects/*genetics ; Protein Binding/drug effects ; Protein Kinases/*genetics ; Protein-Serine-Threonine Kinases ; Transcription, Genetic/drug effects

Adolescent ; Adult ; Antitubercular Agents ; adverse effects ; Arylamine N-Acetyltransferase ; genetics ; Chemical and Drug Induced Liver Injury ; Female ; Humans ; Isoniazid ; adverse effects ; Male ; Middle Aged ; Polymorphism, Genetic ; Young Adult

OBJECTIVETo investigate the influence of thymidylate synthase (TS) gene polymorphisms on high-dose methotrexate (HD-MTX)-related toxicities in childhood acute lymphoblastic leukemia (ALL).

METHODSA total of 73 children who were diagnosed with ALL between March 2011 and March 2013 were included into this study. Genomic DNAs were extracted from their peripheral blood. And then the genotypes of TS 5'-UTR were determined by direct DNA sequencing after PCR. The toxicity response of 73 patients receiving HD-MTX chemotherapy were observed and recorded, and plasma MTX concentrations at 42-48 hours after chemotherapy were measured.

RESULTSThe main HD-MTX-related toxicities of 73 patients receiving HD-MTX chemotherapy were neutropenia, decreased hemoglobin level, thrombocytopenia, liver toxicity, mucosal damage, and gastrointestinal reactions. There were no significant differences in the incidence rate of HD-MTX-related toxicities between children with different TS 5'-UTR genotypes after chemotherapy (P>0.05). TS 5'-UTR genotype was not significantly correlated with plasma MTX concentrations at 42-48 hours after chemotherapy (P>0.05).

CONCLUSIONSTS gene polymorphisms have no influence on the incidence of HD-MTX-related toxicities in childhood ALL.

Antimetabolites, Antineoplastic ; adverse effects ; Child ; Child, Preschool ; Female ; Genotype ; Humans ; Infant ; Male ; Methotrexate ; adverse effects ; Polymorphism, Genetic ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; genetics ; Thymidylate Synthase ; genetics

PURPOSE: Adverse cutaneous reactions to antituberculous drugs (ATD), such as maculopapular eruption (MPE), are the most common causes of discontinuation of scheduled treatment of tuberculosis. We previously reported that tumor necrosis factor (TNF)-alpha genetic polymorphism -308G/A is significantly associated with ATD-induced hepatitis. This study aimed to investigate associations between TNF-alpha -308G/A and ATD-induced MPE. METHODS: Patients with ATD-induced MPE and controls without any adverse reactions to ATD were recruited from the database of the Adverse Drug Reaction Pharmacogenomic Research Group database of Korea. We compared the genotype frequency of TNF-alpha-308G/A between patients with ATD-induced MPE and ATD-tolerant controls. RESULTS: A total of 69 patients with ATD-induced MPE and 229 control subjects were enrolled for this study. There were no significant differences in genotype frequency between the patients and the controls, suggesting lack of associations between TNF-alpha-308G/A and ATD-induced MPE. CONCLUSION: The TNF-alpha genetic polymorphism -308G/A may not be related to the development of ATD-induced MPE, in contrast to ATD-induced hepatitis. These findings suggest that associations between TNF-alpha-308G/A and ATD-induced adverse reactions can be phenotype-specific.
Antitubercular Agents ; Drug Eruptions ; Drug-Related Side Effects and Adverse Reactions ; Genotype ; Hepatitis ; Humans ; Korea ; Polymorphism, Genetic* ; Tuberculosis ; Tumor Necrosis Factor-alpha*

OBJECTIVEMacrolide susceptibility and drug resistance mechanisms of clinical non-tuberculous mycobacteria (NTM) isolates were preliminarily investigated for more accurate diagnosis and treatment of the infection in China.

METHODSFour macrolides, including clarithromycin (CLAR), azithromycin (AZM), roxithromycin (ROX), and erythromycin (ERY), were used to test the drug susceptibility of 310 clinical NTM isolates from six provinces of China with the broth microdilution method. Two resistance mechanisms, 23S rRNA and erm, were analyzed with nucleotide sequence analysis.

RESULTSVaried effectiveness of macrolides and species-specific resistance patterns were observed. Most Mycobacterium abscessus subsp. massiliense were susceptible and all M. fortuitum were highly resistant to macrolides. All the drugs, except for erythromycin, exhibited excellent activities against slow-growing mycobacteria, and drug resistance rates were below 22.2%. Only four highly resistant strains harbored 2,058/2,059 substitutions on rrl and none of other mutations were related to macrolide resistance. G2191A and T2221C on rrl were specific for the M. abscessus complex (MABC). Seven sites, G2140A, G2210C, C2217G, T2238C, T2322C, T2404C, and A2406G, were specifically carried by M. avium and M. intracellulare. Three sites, A2192G, T2358G, and A2636G, were observed only in M. fortuitum and one site G2152A was specific for M. gordonae. The genes erm(39) and erm(41) were detected in M. fortuitum and M. abscessus and inducible resistance was observed in relevant sequevar.

CONCLUSIONThe susceptibility profile of macrolides against NTM was demonstrated. The well-known macrolide resistance mechanisms, 23S rRNA and erm, failed to account for all resistant NTM isolates, and further studies are warranted to investigate macrolide resistance mechanisms in various NTM species.

Anti-Bacterial Agents ; pharmacology ; Bacterial Proteins ; genetics ; metabolism ; China ; Drug Resistance, Bacterial ; Gene Expression Regulation, Bacterial ; Humans ; Macrolides ; pharmacology ; Mycobacterium ; drug effects ; genetics ; Polymorphism, Genetic

The multidrug resistance protein 2 (MRP2, ABCC2) gene may determine individual susceptibility to adverse drug reactions (ADRs) in the central nervous system (CNS) by limiting brain access of antiepileptic drugs, especially valproic acid (VPA). Our objective was to investigate the effect of ABCC2 polymorphisms on ADRs caused by VPA in Korean epileptic patients. We examined the association of ABCC2 single-nucleotide polymorphisms and haplotype frequencies with VPA related to adverse reactions. In addition, the association of the polymorphisms with the risk of VPA related to adverse reactions was estimated by logistic regression analysis. A total of 41 (24.4%) patients had shown VPA-related adverse reactions in CNS, and the most frequent symptom was tremor (78.0%). The patients with CNS ADRs were more likely to have the G allele (79.3% vs. 62.7%, p = 0.0057) and the GG genotype (61.0% vs. 39.7%, p = 0.019) at the g.-1774delG locus. The frequency of the haplotype containing g.-1774Gdel was significantly lower in the patients with CNS ADRs than without CNS ADRs (15.8% vs. 32.3%, p = 0.0039). Lastly, in the multivariate logistic regression analysis, the presence of the GG genotype at the g.-1774delG locus was identified as a stronger risk factor for VPA related to ADRs (odds ratio, 8.53; 95% confidence interval, 1.04 to 70.17). We demonstrated that ABCC2 polymorphisms may influence VPA-related ADRs. The results above suggest the possible usefulness of ABCC2 gene polymorphisms as a marker for predicting response to VPA-related ADRs.
Alleles ; Anticonvulsants ; Brain ; Central Nervous System ; Drug Resistance, Multiple ; Drug Toxicity* ; Drug-Related Side Effects and Adverse Reactions ; Epilepsy ; Genetic Variation* ; Genotype ; Haplotypes ; Humans ; Logistic Models ; Polymorphism, Genetic ; Risk Factors ; Tremor ; Valproic Acid*