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 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

MicroRNAs (miRNAs) are a new class of endogenous, single-strand, noncoding small RNAs. MiRNAs play an important regulatory role in a variety of pathological and physiological process, such as cell proliferation and apoptosis, organ development and differentiation and tumorigenesis and so on. It has been found that circulating miRNAs are also stably and specially expressed in serum or plasma and other body fluids. Circulating miRNAs could be taken as noninvasive and new biomarkers for evaluating the drug-induced target organ injury, which may play a vital role in monitoring the drug toxicity at the early stage.
Animals ; Biomarkers ; metabolism ; Diagnosis ; Disease ; genetics ; Drug Monitoring ; instrumentation ; methods ; Drug-Related Side Effects and Adverse Reactions ; Humans ; MicroRNAs ; genetics ; metabolism

China is the country possessing the largest amount of trade and consumption of medicinal plants in the world. Research and application of gene engineering on medicinal plants are the one of the most promising ways to increase the productivity and quality of medicinal plants, reduce the resource stress, and enhance the competitive power and sustainable development ability of the medicinal plants industry. In spite of the great progress in research and application of plant gene engineering worldwide, the research of gene transformation has mostly been conducted on some model plants, and the application of transgenic plant has been limited to a few staple and important crop species. For medicinal plants, recently the researches of gene transformation has emerged, however, compared with other crop and economic plants, it is still a very limited amount. On the basis of a general introduction of application of transgenic plants, this paper focuses on the present situation of the research and application of gene engineering on medicinal plants, to put forward the problems in this field, and give a prospect for its development.
Breeding ; Drug-Related Side Effects and Adverse Reactions ; Drugs, Chinese Herbal ; Genetic Engineering ; methods ; Humans ; Plants, Genetically Modified ; Plants, Medicinal ; genetics

OBJECTIVETo study the possibly transferable properties of multi-biological toxicities caused by aluminium exposure from exposed animals to their progeny.

METHODSMulti-biological toxicities in aluminium (2.5 micromol/L, 75 micromol/L, and 200 micromol/L) exposed animals and their progeny were analyzed by using model organism Caenorhabditis elegans. Endpoints of lifespan, development, reproduction, locomotion behavior and behavioral plasticity were selected for the assay of multiple toxicities and their transfer properties. Four groups of experiments were performed for each endpoint assay. Twenty animals were used for assay of lifespan, development, reproduction and locomotion behaviors, and 100 animals were used for assay of behavioral plasticity in each group experiment. The data were performed for statistical analysis using SPSS 13.0 software.

RESULTSOur data suggest that the aluminium exposure could result in multi-biological defects of phenotypes and behaviors. As compared to those average survival days, 24 d, body size, (1.30 +/- 0.05) mm; brood size, (278 +/- 20); generation time (64.0 +/- 1.2) h; body bend, (45.8 +/- 3.0) times, head thrash, (109.33 +/- 7.30) times, behavioral plasticity (3 +/- 4)% in 0 micromol/L aluminum exposed animals, the low-concentration (2.5 micromol/L) aluminium exposure caused severe defects of average survival days (20 d), body size [(1.12 +/- 0.02 ) mm, t = 14.55, P<0.01], brood size [(145 +/- 23), t = 30.62, P< 0.01], body bend [(29.8 +/- 3.0), t = 20.31, P<0.01], and head thrash, (95.8 +/- 6.2), t = 16.43, P < 0.01]. High-concentration aluminium exposure could further result in severe defects of generation time [75 micromol/L, (67.0 +/- 1.7 ) h, t = 8.92, P<0.01; 200 micromol/L, (70.7 +/- 1.5) h, t =15.13, P<0.01] and behavioral plasticity [75 micromol/L, (16.5 +/- 3.0)%, t = 27.11, P<0.05; 200 micromol/L, (23.5 +/- 4.0)%, t = 16.43, P<0.01]. Moreover, most of these toxicities caused by high-concentration aluminium exposure could be transferred from exposed animals to their progeny. In progeny animals, the phenotypic and behavioral defects might be only partially (such as body size, brood size, and locomotion behaviors) or very slightly (such as the lifespan defects induced by high concentrations of aluminium exposure) rescued. Especially, the generation time defects induced by aluminium exposure would become more severe in progeny animals than in their parents.

CONCLUSIONThe multi-biological defects caused by aluminium exposure might be largely transferred from exposed animals to their progeny in Caenorhabditis elegans.

Aluminum ; toxicity ; Animals ; Caenorhabditis elegans ; drug effects ; genetics ; growth & development ; Drug-Related Side Effects and Adverse Reactions ; genetics ; Environmental Exposure ; Environmental Pollutants ; toxicity ; Genes, Helminth

Drug-induced liver injury (DILI) risk prediction, diagnosis establishment, clinical management, and all other aspects are facing great challenges. Although the current understanding of its pathogenesis is still incomplete, research over the past 20 years has shown that genetic susceptibility may play an important role in the occurrence and development of DILI. In recent years, pharmacogenomics studies have further revealed the association between human leukocyte antigen (HLA) genes, some non-HLA genes, and hepatotoxicity from certain drugs. However, due to the lack of well-designed, prospective, large-sample cohort validation and low positive predictive values, there may still be some way to go before the current results can be truly translated into clinical practice for precise prediction and prevention of DILI risk.
Humans ; Genetic Predisposition to Disease ; Prospective Studies ; Risk Factors ; Chemical and Drug Induced Liver Injury/genetics* ; Drug-Related Side Effects and Adverse Reactions ; Liver

Anaplastic lymphoma kinase (ALK) fusions represent the second most common oncogenic driver mutation in non-small cell lung cancer (NSCLC). As the new class of 3rd generation of ALK tyrosine kinase inhibitor (TKI), lorlatinib has shown robust potency and brain-penetrant clinical activity against a wide spectrum of multiple resistance mutations within the ALK domain detected during crizotinib and 2nd generation ALK TKI treatment. Lorlatinib is generally well-tolerated with unique adverse drug reaction/adverse event, including hyperlipidemia and central nervous system effects, which are mostly mild to moderate severity and manageable through dosage modifications and/or standard medical intervention. For advanced NSCLC with ALK positivity, patients should be evaluated for baseline characteristics and pre-existing medication, informed of the potential toxicities, and periodically monitored to balance benefits and risks. Moreover, a multidisciplinary group of experts is essential to establish a comprehensive diagnostic and therapeutic strategy.
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Aminopyridines ; Carcinoma, Non-Small-Cell Lung/pathology* ; China ; Consensus ; Drug Resistance, Neoplasm/genetics* ; Drug-Related Side Effects and Adverse Reactions/drug therapy* ; Humans ; Lactams ; Lactams, Macrocyclic/adverse effects* ; Lung Neoplasms/pathology* ; Protein Kinase Inhibitors/adverse effects* ; Protein-Tyrosine Kinases/genetics* ; Pyrazoles

OBJECTIVE: To establish a new digital polymerase chain reaction (dPCR) system for the detection of BCR-ABL fusion gene in patients with chronic myeloid leukemia (CML), and explore its analytical performance and clinical applicability in the detection of BCR-ABL^p190/210/230. METHODS: A new dPCR system for detecting BCR-ABL^p190/210/230 was successfully developed, and its sensitivity difference with qPCR and improvement of drug side effects in patients with CML during drug reduction or withdrawal were compared. RESULTS: Among 176 samples, qPCR and dPCR showed high consistency in the sensitivity of detecting BCR-ABL (82.39%), and the positive rate of dPCR was about 5 times higher that of qPCR (20.45% vs 3.98%). During follow-up, blood routine (25% vs 10%), kidney/liver/stomach (25% vs 20%) and cardiac function (10% vs 0) were significantly improved after drug reduction or withdrawal in patients with initial dPCR negative compared with before drug reduction or withdrawal. CONCLUSIONS This new dPCR detection system can be applied to the detection of BCR-ABL^p190/210/230. It has better consistency and higher positive detection rate than qPCR. Drug withdrawal or dose reduction guided by dPCR has a certain effect on improving drug side effects.
Humans ; Fusion Proteins, bcr-abl/genetics* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis* ; Polymerase Chain Reaction ; Drug-Related Side Effects and Adverse Reactions ; Reverse Transcriptase Polymerase Chain Reaction

MET gene is a proto-oncogene, which encodes MET protein with tyrosine kinase activity. After binding to its ligand, hepatocyte growth factor, MET protein can induce MET dimerization and activate downstream signaling pathways, which plays a crucial role in tumor formation and metastasis. Savolitinib, as a specific tyrosine kinase inhibitor (TKI) targeting MET, selectively inhibits the phosphorylation of MET kinase with a significant inhibitory effect on tumors with MET abnormalities. Based on its significant efficacy shown in the registration studies, savolitinib was approved for marketing in China on June 22, 2021 for the treatment of advanced non-small cell lung cancer with MET 14 exon skipping mutations. In addition, many studies have shown that MET TKIs are equally effective in patients with advanced solid tumors with MET gene amplification or MET protein overexpression, and relevant registration clinical studies are ongoing. The most common adverse reactions during treatment with savolitinib include nausea, vomiting, peripheral edema, pyrexia, and hepatotoxicity. Based on two rounds of extensive nationwide investigations to guide clinicians, the consensus is compiled to use savolitinib rationally, prevent and treat various adverse reactions scientifically, and improve the clinical benefits and quality of life of patients. This consensus was prepared under the guidance of multidisciplinary experts, especially including the whole-process participation and valuable suggestions of experts in Traditional Chinese Medicine, thus reflecting the clinical treatment concept of integrated Chinese and western medicines.
Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; Lung Neoplasms/pathology* ; Consensus ; Quality of Life ; Proto-Oncogene Proteins c-met/genetics* ; Protein Kinase Inhibitors/adverse effects* ; Drug-Related Side Effects and Adverse Reactions ; Mutation

With the advent of Twenty-First century, more and more genome-wide association studies (GWAS) showed that idiosyncratic adverse drug reactions (ADRs) were closely related with human leukocyte antigen (HLA) alleles, such as the associations of abacavir-HLA-B*5701, allopurinol-HLA-B*5801, and carbamazepine-HLA-B*1502, etc. To explore the mechanisms of these idiosyncratic drug reactions, hapten hypothesis, danger signal hypothesis, pharmacological interaction (P-I) concept and autoimmune mechanism are proposed. In this paper, recent GWAS studies on the HLA-mediated adverse drug reactions and underlying mechanism are reviewed in detail.
Alleles ; Allopurinol ; adverse effects ; Anti-HIV Agents ; adverse effects ; Anticonvulsants ; adverse effects ; Carbamazepine ; adverse effects ; Dideoxynucleosides ; adverse effects ; Drug Hypersensitivity Syndrome ; etiology ; immunology ; Drug-Related Side Effects and Adverse Reactions ; genetics ; immunology ; Enzyme Inhibitors ; adverse effects ; Genome-Wide Association Study ; HLA Antigens ; genetics ; HLA-B Antigens ; immunology ; HLA-B15 Antigen ; immunology ; Humans ; Stevens-Johnson Syndrome ; etiology ; immunology