Diverse fates of ancient horizontal gene transfers in extremophilic red algae.

Horizontal genetic transfer (HGT) is a common phenomenon in eukaryotic genomes. However, the mechanisms by which HGT-derived genes persist and integrate into other pathways remain unclear. This topic is of significant interest because, over time, the stressors that initially favoured the fixation of HGT may diminish or disappear. Despite this, the foreign genes may continue to exist if they become part of a broader stress response or other pathways. The conventional model suggests that the acquisition of HGT equates to adaptation. However, this model may evolve into more complex interactions between gene products, a concept we refer to as the 'Integrated HGT Model' (IHM). To explore this concept further, we studied specialized HGT-derived genes that encode heavy metal detoxification functions. The recruitment of these genes into other pathways could provide clear examples of IHM. In our study, we exposed two anciently diverged species of polyextremophilic red algae from the Galdieria genus to arsenic and mercury stress in laboratory cultures. We then analysed the transcriptome data using differential and coexpression analysis. Our findings revealed that mercury detoxification follows a 'one gene-one function' model, resulting in an indivisible response. In contrast, the arsH gene in the arsenite response pathway demonstrated a complex pattern of duplication, divergence and potential neofunctionalization, consistent with the IHM. Our research sheds light on the fate and integration of ancient HGTs, providing a novel perspective on the ecology of extremophiles.

A transcriptional regulatory network of HNF4α and HNF1α involved in human diseases and drug metabolism.

HNF4α and HNF1α are core transcription factors involved in the development and progression of a variety of human diseases and drug metabolism. They play critical roles in maintaining the normal growth and function of multiple organs, mainly the liver, and in the metabolism of endogenous and exogenous substances. The twelve isoforms of HNF4α may exhibit different physiological functions, and HNF4α and HNF1α show varying or even opposing effects in different types of diseases, particularly cancer. Additionally, the regulation of CYP450, phase II drug-metabolizing enzymes, and drug transporters is affected by several factors. This article aims to review the role of HNF4α and HNF1α in human diseases and drug metabolism, including their structures and physiological functions, affected diseases, regulated drug metabolism genes, influencing factors, and related mechanisms. We also propose a transcriptional regulatory network of HNF4α and HNF1α that regulates the expression of target genes related to disease and drug metabolism.

Evaluations of two glutathione S-transferase epsilon genes for their contributions to metabolism of three selected insecticides in Locusta migratoria.

The insect-specific epsilon class of glutathione S-transferases (GSTEs) plays important roles in insecticide detoxification in insects. In our previous work, five GSTEs were identified in Locusta migratoria, and two recombinant GSTEs, rLmGSTE1 and rLmGSTE4, showed high catalytic activity when 1-chloro-2,4-dinitrobenzene (CDNB) was used as a substrate. In this work, we further investigated whether these two GSTEs could metabolize three insecticides including malathion, deltamethrin and DDT. Using ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC/MS) method, we found that rLmGSTE4, but not rLmGSTE1, can metabolize malathion and DDT. Malathion bioassays of L.migratoria after the expression of LmGSTE4 was suppressed by RNA interference (RNAi) showed increased insect mortality from 33.8% to 68.9%. However, no changes in mortality were observed in deltamethrin- or DDT-treated L.migratoria after the expression of LmGSTE4 was suppressed by RNAi. Our results provided direct evidences that LmGSTE4 participates in malathion detoxification in L.migratoria. These findings are important for understanding the mechanisms of insecticide resistance in L.migratoria and developing new strategies for managing the insect populations in the field.

Impact of DNA methylation on ADME gene expression, drug disposition, and efficacy.

Interindividual differences in drug response have always existed in clinical treatment. Genes involved in drug absorption, distribution, metabolism, and excretion (ADME) play an important role in the process of pharmacokinetics. The effects of genetic polymorphism and nuclear receptors on the expression of drug metabolism enzymes and transporters can only explain some individual differences in clinical treatment. Several key ADME genes have been demonstrated to be regulated by epigenetic mechanisms that can potentially affect inter-individual variability in medical treatment. Emerging studies have focused on the importance of DNA methylation for ADME gene expression and for drug response. Among them, the most studied are anti-tumor drugs, followed by anti-tuberculous and anti-platelet drugs. Therefore, we provide an epigenetics perspective on variability in drug response. The review summarizes the correlation between ADME gene expression and DNA methylation, including the exact methylation locations, and focuses on the corresponding drug disposition and effects to illuminate interindividual differences in clinical medication.

The reference liver-CYP450 and UGT enzymes in healthy donor and metastatic livers: the impact of genotype.

BACKGROUND: Hepatic enzymes involved in drug metabolism vary markedly in expression, abundance and activity, which affects individual susceptibility to drugs and toxicants. The present study aimed to compare mRNA expression and protein abundance of the most pharmacologically relevant drug-metabolizing enzymes in two main sources of the control liver samples that are used as the reference, i.e. organ donor livers and non-tumorous tissue from metastatic livers. An association analysis of the most common genetic variants with mRNA and protein levels was also performed. METHODS: The CYP450 and UGT enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, UGT1A1, UGT1A3, UGT2B7 and UGT2B15) were analyzed for mRNA (qPCR) and protein abundance (LC-MS/MS) in healthy donors (n = 11) and metastatic (n = 13) livers. Genotyping was performed by means of TaqMan assays and pyrosequencing. RESULTS: Significantly higher protein abundance in the metastatic livers was observed in case of CYP2C9, CYP2D6, and UGT2B7, and for UGT1A3 the difference was only significant at mRNA level. For all the enzymes except CYP2E1 some significant correlation between mRNA and protein content was observed, and for UGT1A1 an inverse correlation with age was noted. CYP2C19, CYP3A5 and CYP2D6 were significantly affected by genotype. CONCLUSION: The selection of a control group for the study on drug-metabolizing enzymes (e.g. in pathological states) may possibly affect its conclusions on differences in mRNA and protein content. Genotyping for common functional variants of CYP450 enzymes should be performed in all studies on drug-metabolizing enzymes.

Involvement of CYP2 and mitochondrial clan P450s of Helicoverpa armigera in xenobiotic metabolism.

Insect CYP2 and mitochondrial clan P450s are relatively conserved genes encoding enzymes generally thought to be involved in biosynthesis or metabolism of endobiotics. However, emerging evidence argues they have potential roles in chemical defense as well, but their actual detoxification functions remain largely unknown. Here, we focused on the full complement of 8 CYP2 and 10 mitochondrial P450s in the generalist herbivore, Helicoverpa armigera. Their varied spatiotemporal expression profiles were analyzed and reflected their specific functions. For functional study of the mitochondrial clan P450s, the redox partners, adrenodoxin reductase (AdR) and adrenodoxin (Adx), were identified from genomes of eight insects and an efficient in vitro electron transfer system of mitochondrial P450 was established by co-expression with Adx and AdR of H. armigera. All CYP2 clan P450s and 8 mitochondrial P450s were successfully expressed in Sf9 cells and compared functionally. In vitro metabolism assays showed that two CYP2 clan P450s (CYP305B1 and CYP18A1) and CYP333B3 (mito clan) could epoxidize aldrin to dieldrin, while CYP305B1 and CYP339A1 (mito clan) have limited but significant hydroxylation capacities to esfenvalerate. CYP303A1 of the CYP2 clan exhibits high metabolic efficiency to 2-tridecanone. Screening the xenobiotic metabolism competence of CYP2 and mitochondrial clan P450s not only provides new insights on insect chemical defense but also can give indications on their physiological functions in H. armigera and other insects.

Role of the Filifactor alocis Hypothetical Protein FA519 in Oxidative Stress Resistance.

In the periodontal pocket, there is a direct correlation between environmental conditions, the dynamic oral microbial flora, and disease. The relative abundance of several newly recognized microbial species in the oral microenvironment has raised questions on their impact on disease development. One such organism, Filifactor alocis, is significant to the pathogenic biofilm structure. Moreover, its pathogenic characteristics are highlighted by its ability to survive in the oxidative-stress microenvironment of the periodontal pocket and alter the microbial community dynamics. There is a gap in our understanding of its mechanism(s) of oxidative stress resistance and impact on pathogenicity. Several proteins, including HMPRFF0389-00519 (FA519), were observed in high abundance in F. alocis during coinfection of epithelial cells with Porphyromonas gingivalis W83. Bioinformatics analysis shows that FA519 contains a "Cys-X-X-Cys zinc ribbon domain" which could be involved in DNA binding and oxidative stress resistance. We have characterized FA519 to elucidate its roles in the oxidative stress resistance and virulence of F. alocis. Compared to the wild-type strain, the F. alocis isogenic gene deletion mutant, FLL1013 (ΔFA519::ermF), showed significantly reduced sensitivity to hydrogen peroxide and nitric oxide-induced stress. The ability to form biofilm and adhere to and invade gingival epithelial cells was also reduced in the isogenic mutant. The recombinant FA519 protein was shown to protect DNA from Fenton-mediated damage with an intrinsic ability to reduce hydrogen peroxide and disulfide bonds. Collectively, these results suggest that FA519 is involved in oxidative stress resistance and can modulate important virulence attributes in F. alocis. IMPORTANCE Filifactor alocis is an emerging member of the periodontal community and is now proposed to be a diagnostic indicator of periodontal disease. However, due to the lack of genetic tools available to study this organism, not much is known about its virulence attributes. The mechanism(s) of oxidative stress resistance in F. alocis is unknown. Therefore, identifying the adaptive mechanisms utilized by F. alocis to survive in the oxidative stress environment of the periodontal pocket would lead to understanding its virulence regulation, which could help develop novel therapeutic treatments to combat the effects of periodontal disease. This study is focused on the characterization of FA519, a hypothetical protein in F. alocis, as a multifunctional protein that plays an important role in the reactive oxygen species-detoxification pathway. Collectively, our results suggest that FA519 is involved in oxidative stress resistance and can modulate important virulence attributes in F. alocis.

Drug metabolism-related eight-gene signature can predict the prognosis of gastric adenocarcinoma.

BACKGROUND: Metabolic abnormalities in patients with gastric adenocarcinoma lead to drug resistance and poor prognosis. Therefore, this study aimed to explore biomarkers that can predict the prognostic risk of gastric adenocarcinoma by analyzing drug metabolism-related genes. METHODS: The RNA-seq and clinical information on gastric adenocarcinoma were downloaded from the UCSC and gene expression omnibus databases. Univariate and least absolute shrinkage and selection operator regression analyses were used to identify the prognostic gene signature of gastric adenocarcinoma. The relationships between gastric adenocarcinoma prognostic risk and tumor microenvironment were assessed using CIBERSORT, EPIC, QUANTISEQ, MCPCounter, xCell, and TIMER algorithms. The potential drugs that could target the gene signatures were predicted in WebGestalt, and molecular docking analysis verified their binding stabilities. RESULTS: Combined with clinical information, an eight-gene signature, including GPX3, ABCA1, NNMT, NOS3, SLCO4A1, ADH4, DHRS7, and TAP1, was identified from the drug metabolism-related gene set. Based on their expressions, risk scores were calculated, and patients were divided into high- and low-risk groups, which had significant differences in survival status and immune infiltrations. Risk group was also identified as an independent prognostic factor of gastric adenocarcinoma, and the established prognostic and nomogram models exhibited excellent capacities for predicting prognosis. Finally, miconazole and niacin were predicted as potential therapeutic drugs for gastric adenocarcinoma that bond stably with NOS3 and NNMT through hydrogen interactions. CONCLUSIONS: This study proposed a drug metabolism-related eight-gene signature as a potential biomarker to predict the gastric adenocarcinoma prognosis risks.

Pharmacogenetics of Drug-Resistant Epilepsy (Review of Literature).

Pharmacogenomic studies in epilepsy are justified by the high prevalence rate of this disease and the high cost of its treatment, frequent drug resistance, different response to the drug, the possibility of using reliable methods to assess the control of seizures and side effects of antiepileptic drugs. Candidate genes encode proteins involved in pharmacokinetic processes (drug transporters, metabolizing enzymes), pharmacodynamic processes (receptors, ion channels, enzymes, regulatory proteins, secondary messengers) and drug hypersensitivity (immune factors). This article provides an overview of the literature on the influence of genetic factors on treatment in epilepsy.

Insights into the Genetic Variations of Human Cytochrome P450 2C9: Structural Analysis, Characterization and Comparison.

Cytochromes P450 (CYP) are one of the major xenobiotic metabolizing enzymes with increasing importance in pharmacogenetics. The CYP2C9 enzyme is responsible for the metabolism of a wide range of clinical drugs. More than sixty genetic variations have been identified in CYP2C9 with many demonstrating reduced activity compared to the wild-type (WT) enzyme. The CYP2C9*8 allele is predominantly found in persons of African ancestry and results in altered clearance of several drug substrates of CYP2C9. The X-ray crystal structure of CYP2C9*8, which represents an amino acid variation from arginine to histidine at position 150 (R150H), was solved in complex with losartan. The overall conformation of the CYP2C9*8-losartan complex was similar to the previously solved complex with wild type (WT) protein, but it differs in the occupancy of losartan. One molecule of losartan was bound in the active site and another on the surface in an identical orientation to that observed in the WT complex. However, unlike the WT structure, the losartan in the access channel was not observed in the *8 complex. Furthermore, isothermal titration calorimetry studies illustrated weaker binding of losartan to *8 compared to WT. Interestingly, the CYP2C9*8 interaction with losartan was not as weak as the CYP2C9*3 variant, which showed up to three-fold weaker average dissociation constant compared to the WT. Taken together, the structural and solution characterization yields insights into the similarities and differences of losartan binding to CYP2C9 variants and provides a useful framework for probing the role of amino acid substitution and substrate dependent activity.

Evidence for the Role of CYP51A and Xenobiotic Detoxification in Differential Sensitivity to Azole Fungicides in Boxwood Blight Pathogens.

Boxwood blight, a fungal disease of ornamental plants (Buxus spp.), is caused by two sister species, Calonectria pseudonaviculata (Cps) and C. henricotiae (Che). Compared to Cps, Che is documented to display reduced sensitivity to fungicides, including the azole class of antifungals, which block synthesis of a key fungal membrane component, ergosterol. A previous study reported an ergosterol biosynthesis gene in Cps, CYP51A, to be a pseudogene, and RNA-Seq data confirm that a functional CYP51A is expressed only in Che. The lack of additional ergosterol biosynthesis genes showing significant differential expression suggests that the functional CYP51A in Che could contribute to reduced azole sensitivity when compared to Cps. RNA-Seq and bioinformatic analyses found that following azole treatment, 55 genes in Cps, belonging to diverse pathways, displayed a significant decrease in expression. Putative xenobiotic detoxification genes overexpressed in tetraconazole-treated Che encoded predicted monooxygenase and oxidoreductase enzymes. In summary, expression of a functional CYP51A gene and overexpression of predicted xenobiotic detoxification genes appear likely to contribute to differential fungicide sensitivity in these two sister taxa.

Comparative analysis of the detoxification gene inventory of four major Spodoptera pest species in response to xenobiotics.

The genus Spodoptera (Lepidoptera: Noctuidae) comprises some of the most polyphagous and destructive agricultural pests worldwide. The success of many species of this genus is due to their striking abilities to adapt to a broad range of host plants. Superfamilies of detoxification genes play a crucial role in the adaption to overcome plant defense mechanisms mediated by numerous secondary metabolites and toxins. Over the past decade, a substantial amount of expression data in Spodoptera larvae was produced for those genes in response to xenobiotics such as plant secondary metabolites, but also insecticide exposure. However, this information is scattered throughout the literature and in most cases does not allow to clearly identify candidate genes involved in host-plant adaptation and insecticide resistance. In the present review, we analyzed and compiled information on close to 600 pairs of inducers (xenobiotics) and induced genes from four main Spodoptera species: S. exigua, S. frugiperda, S. littoralis and S. litura. The cytochrome P450 monooxygenases (P450s; encoded by CYP genes) were the most upregulated detoxification genes across the literature for all four species. Most of the data was provided from studies on S. litura, followed by S. exigua, S. frugiperda and S. littoralis. We examined whether these detoxification genes were reported for larval survival under xenobiotic challenge in forward and reverse genetic studies. We further analyzed whether biochemical assays were carried out showing the ability of corresponding enzymes and transporters to breakdown and excrete xenobiotics, respectively. This revealed a clear disparity between species and the lack of genetic and biochemical information in S. frugiperda. Finally, we discussed the biological importance of detoxification genes for this genus and propose a workflow to study the involvement of these enzymes in an ecological and agricultural context.

Pregnane X Receptor (PXR) Polymorphisms and Cancer Treatment.

Pregnane X Receptor (PXR) belongs to the nuclear receptors' superfamily and mainly functions as a xenobiotic sensor activated by a variety of ligands. PXR is widely expressed in normal and malignant tissues. Drug metabolizing enzymes and transporters are also under PXR's regulation. Antineoplastic agents are of particular interest since cancer patients are characterized by significant intra-variability to treatment response and severe toxicities. Various PXR polymorphisms may alter the function of the protein and are linked with significant effects on the pharmacokinetics of chemotherapeutic agents and clinical outcome variability. The purpose of this review is to summarize the roles of PXR polymorphisms in the metabolism and pharmacokinetics of chemotherapeutic drugs. It is also expected that this review will highlight the importance of PXR polymorphisms in selection of chemotherapy, prediction of adverse effects and personalized medicine.

A novel machine learning-based approach for the computational functional assessment of pharmacogenomic variants.

BACKGROUND: The field of pharmacogenomics focuses on the way a person's genome affects his or her response to a certain dose of a specified medication. The main aim is to utilize this information to guide and personalize the treatment in a way that maximizes the clinical benefits and minimizes the risks for the patients, thus fulfilling the promises of personalized medicine. Technological advances in genome sequencing, combined with the development of improved computational methods for the efficient analysis of the huge amount of generated data, have allowed the fast and inexpensive sequencing of a patient's genome, hence rendering its incorporation into clinical routine practice a realistic possibility. METHODS: This study exploited thoroughly characterized in functional level SNVs within genes involved in drug metabolism and transport, to train a classifier that would categorize novel variants according to their expected effect on protein functionality. This categorization is based on the available in silico prediction and/or conservation scores, which are selected with the use of recursive feature elimination process. Toward this end, information regarding 190 pharmacovariants was leveraged, alongside with 4 machine learning algorithms, namely AdaBoost, XGBoost, multinomial logistic regression, and random forest, of which the performance was assessed through 5-fold cross validation. RESULTS: All models achieved similar performance toward making informed conclusions, with RF model achieving the highest accuracy (85%, 95% CI: 0.79, 0.90), as well as improved overall performance (precision 85%, sensitivity 84%, specificity 94%) and being used for subsequent analyses. When applied on real world WGS data, the selected RF model identified 2 missense variants, expected to lead to decreased function proteins and 1 to increased. As expected, a greater number of variants were highlighted when the approach was used on NGS data derived from targeted resequencing of coding regions. Specifically, 71 variants (out of 156 with sufficient annotation information) were classified as to "Decreased function," 41 variants as "No" function proteins, and 1 variant in "Increased function." CONCLUSION: Overall, the proposed RF-based classification model holds promise to lead to an extremely useful variant prioritization and act as a scoring tool with interesting clinical applications in the fields of pharmacogenomics and personalized medicine.

Transcriptome analysis and response of three important detoxifying enzymes to Serratia marcescens Bizio (SM1) in Hyphantria cunea (Drury) (Lepidoptera: Noctuidae).

Hyphantria cunea (Drury) (Lepidoptera: Noctuidae) is a main pest of forest trees. In this study, the effects of Serratia marcescens Bizio (SM1) infection on the transcriptome of H. cunea were studied. The expression of 1068 unigenes in the transcriptome of H. cunea infected by S. marcescens was markedly different from that in the control of H. cunea; 474 genes were upregulated, and 594 genes were downregulated in the former. Among them, 8 cytochrome P450s (CYPs), 5 uridine diphosphate-glycosyltransferases (UGTs) and 3 glutathione S-transferases (GSTs) were significantly differentially expressed. Pathway enrichment analysis indicated that these differentially expressed detoxification enzyme genes were mainly involved in the drug metabolism pathway, glutathione metabolism pathway and ABC transporter pathway. Interestingly, we found that five UGTs were related to oestradiol metabolism in the steroid hormone biosynthesis pathway. Furthermore, the real-time fluorescent quantitative PCR results showed that SM1 could induce the expression of CYPs and UGTs, but inhibit the expression of GSTs. This research will identify the response of important detoxification enzymes to S. marcescens, which will provide a theoretical foundation for the development of new immunosuppressants for H. cunea control. Furthermore, H. cunea was performed transcriptome sequencing to explore the key metabolic pathways, signalling pathways and genes affected by S. marcescens, which will clarify the mechanisms of S. marcescens infection of H. cunea. In addition, this study also explored the relationship between H. cunea and S. marcescens, which will provide a theoretical basis for the biological control of H. cunea by using S. marcescens.

Seed dressing with mefenpyr-diethyl as a safener for mesosulfuron-methyl application in wheat: The evaluation and mechanisms.

Mesosulfuron-methyl is always applied by foliar spraying in combination with the safener mefenpyr-diethyl to avoid phytotoxicity on wheat (Triticum aestivum L.) cultivars. However, it was observed that the tolerance of Tausch's goatgrass (Aegilops tauschii Coss.) to mesosulfuron-methyl significantly increased in the presence of mefenpyr-diethyl by performing bioassay. This confirmed phenomenon may lead to overuse of mesosulfuron-methyl and weed resistance evolution in field conditions. Therefore, we tested the effect of wheat seed dressing with mefenpyr-diethyl as a possible alternative and disclosed the underlying mechanisms by herbicide dissipation study, enzymatic analysis and transcriptome profiling. The results suggest that increase of ALS activity, enhancement of metabolic processes, and other stress responses are crucial for the regulation of herbicide detoxification induced by mefenpyr-diethyl. Additionally, transcription factors such as AP2/ERF-ERF, bHLH, NAC, and MYB, and protein kinase such as RLK-Pelle_DLSV might play vital regulatory roles. The current study has important implications for mesosulfuron-methyl application in wheat field to control Tausch's goatgrass and provides a comprehensive understanding of the protective effect of mefenpyr-diethyl.

How to Integrate CYP2D6 Phenoconversion Into Clinical Pharmacogenetics: A Tutorial.

CYP2D6 genotype is increasingly being integrated into practice to guide prescribing of certain medications. The CYP2D6 drug metabolizing enzyme is susceptible to inhibition by concomitant drugs, which can lead to a clinical phenotype that is different from the genotype-based phenotype, a process referred to as phenoconversion. Phenoconversion is highly prevalent but not widely integrated into practice because of either limited experience on how to integrate or lack of knowledge that it has occurred. We built a calculator tool to help clinicians integrate a standardized method of assessing CYP2D6 phenoconversion into practice. During tool-building, we identified several clinical factors that need to be considered when implementing CYP2D6 phenoconversion into clinical practice. This tutorial shares the steps that the University of Florida Health Precision Medicine Program took to build the calculator tool and identified clinical factors to consider when implementing CYP2D6 phenoconversion in clinical practice.

Host-specific gene expression as a tool for introduction success in Naupactus parthenogenetic weevils.

Food resource access can mediate establishment success in invasive species, and generalist herbivorous insects are thought to rely on mechanisms of transcriptional plasticity to respond to dietary variation. While asexually reproducing invasives typically have low genetic variation, the twofold reproductive capacity of asexual organisms is a marked advantage for colonization. We studied host-related transcriptional acclimation in parthenogenetic, invasive, and polyphagous weevils: Naupactus cervinus and N. leucoloma. We analyzed patterns of gene expression in three gene categories that can mediate weevil-host plant interactions through identification of suitable host plants, short-term acclimation to host plant defenses, and long-term adaptation to host plant defenses and their pathogens. This approach employed comparative transcriptomic methods to investigate differentially expressed host detection, detoxification, immune defense genes, and pathway-level gene set enrichment. Our results show that weevil gene expression responses can be host plant-specific, and that elements of that response can be maintained in the offspring. Some host plant groups, such as legumes, appear to be more taxing as they elicit a complex gene expression response which is both strong in intensity and specific in identity. However, the weevil response to taxing host plants shares many differentially expressed genes with other stressful situations, such as host plant cultivation conditions and transition to novel host, suggesting that there is an evolutionarily favorable shared gene expression regime for responding to different types of stressful situations. Modulating gene expression in the absence of other avenues for phenotypic adaptation may be an important mechanism of successful colonization for these introduced insects.

Acute and chronic toxicity of microcystin-LR and phenanthrene alone or in combination to the cladoceran (Daphnia magna).

Hazardous substances, such as microcystin-LR (MC-LR) and phenanthrene (Phe) are ubiquitous co-contaminants in eutrophic freshwaters, which cause harms to aquatic organisms. However, the risks associated with the co-exposure of aquatic biota to these two chemicals in the environment have received little attention. In this study, the single and mixture toxic effects of MC-LR and Phe mixtures were investigated in Daphnia magna after acute and chronic exposure. Acute tests showed that the median effective concentrations (48 h) for MC-LR, Phe and their mixtures were 13.46, 0.57 and 8.84 mg/L, respectively. Mixture toxicity prediction results indicated that the independent action model was more applicable than the concentration addition model. Moreover, combination index method suggested that the mixture toxicity was concentration dependent. Synergism was elicited at low concentrations of MC-LR and Phe exposure (≤4.04 + 0.17 mg/L), whereas antagonistic or additive effects were induced at higher concentrations. The involved mechanism of antagonism was presumably attributable to the protective effects of detoxification genes activated by high concentrations of MC-LR in mixtures. Additionally, chronic results also showed that exposure to a MC-LR and Phe mixture at low concentrations (≤50 +2 µg/L) resulted in greater toxic effects on D. magna life history than either chemical acting alone. The significant inhibition on detoxification genes and increased accumulation of MC-LR could be accounted for their synergistic toxic effects on D. magna. Our findings revealed the exacerbated ecological hazard of MC-LR and Phe at environmental concentrations (≤50 +2 µg/L), and provided new insights to the potential toxic mechanisms of MC-LR and Phe in aquatic animals.