Metabolic Diversity Research Articles

Toward an Efficient Differentiation of Two Diaporthe Strains Through Mass Spectrometry for Fungal Biotyping

Considering that fungi display a great morphological, ecological, metabolic, and phylogenetic diversity, their taxonomic identification is extremely important because it helps us establish important information about each species and its possible biochemical and ecological roles. Traditionally, the identification of fungi at the species level has been carried out with molecular tools such as DNA sequencing, but it still represents a huge challenge today due to the heterogeneity of the fungal kingdom, making the task of identification a complex and difficult process. Biotyping, a type of chemotaxonomy, has been developed in the field of the identification/differentiation and classification of micro-fungi through tools such as mass spectrometry (MS). Here, two endophytic strains isolated from two different hosts were cultivated and studied regarding their morphology and molecular biology. Morphology analysis determined the strains as Diaporthe, and the molecular analysis results grouped them as D. melongenae. We sought a faster and less complex way of differentiating these fungal strains of interest through an MS chemical profile and MS/MS data using a low-resolution mass spectrometer. Additionally, we linked this information with the structure of compounds previously isolated in the genus Diaporthe. Studies conducted using this technique allowed us to propose the structure of distinctive molecules that are unique to each strain and share compounds common to this genus (13 compounds in total). In addition, this is the first report of secondary metabolites in D. melongenae. The dataset demonstrates that the two strains under investigation can be distinguished via mass spectrometry, suggesting host affinity; both exhibits pronounced differences in their chemical profiles across all culture media and incubation periods with the parameters described herein.

Immunometabolic alterations in type 2 diabetes mellitus revealed by single-cell RNA sequencing: insights into subtypes and therapeutic targets

BackgroundType 2 Diabetes Mellitus (T2DM) represents a major global health challenge, marked by chronic hyperglycemia, insulin resistance, and immune system dysfunction. Immune cells, including T cells and monocytes, play a pivotal role in driving systemic inflammation in T2DM; however, the underlying single-cell mechanisms remain inadequately defined.MethodsSingle-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from 37 patients with T2DM and 11 healthy controls (HC) was conducted. Immune cell types were identified through clustering analysis, followed by differential expression and pathway analysis. Metabolic heterogeneity within T cell subpopulations was evaluated using Gene Set Variation Analysis (GSVA). Machine learning models were constructed to classify T2DM subtypes based on metabolic signatures, and T-cell-monocyte interactions were explored to assess immune crosstalk. Transcription factor (TF) activity was analyzed, and drug enrichment analysis was performed to identify potential therapeutic targets.ResultsIn patients with T2DM, a marked increase in monocytes and a decrease in CD4+ T cells were observed, indicating immune dysregulation. Significant metabolic diversity within T cell subpopulations led to the classification of patients with T2DM into three distinct subtypes (A-C), with HC grouped as D. Enhanced intercellular communication, particularly through the MHC-I pathway, was evident in T2DM subtypes. Machine learning models effectively classified T2DM subtypes based on metabolic signatures, achieving an AUC > 0.84. Analysis of TF activity identified pivotal regulators, including NF-kB, STAT3, and FOXO1, associated with immune and metabolic disturbances in T2DM. Drug enrichment analysis highlighted potential therapeutic agents targeting these TFs and related pathways, including Suloctidil, Chlorpropamide, and other compounds modulating inflammatory and metabolic pathways.ConclusionThis study underscores significant immunometabolic dysfunction in T2DM, characterized by alterations in immune cell composition, metabolic pathways, and intercellular communication. The identification of critical TFs and the development of drug enrichment profiles highlight the potential for personalized therapeutic strategies, emphasizing the need for integrated immunological and metabolic approaches in T2DM management.

Presence of polyketide synthases and nonribosomal peptide synthetase in culturable bacteria associated with Aplysina fulva and Aplysina caissara (Porifera).

Culture-dependent and -independent studies have provided access to symbiont genes and the functions they play for host sponges. Thus, this work investigates the diversity, presence of genes of pharmacological interest, biological activities and metabolome of the bacteria isolated from the sponges Aplysina caissara and Aplysina fulva collected on the southwestern Atlantic Coast. The genes for Polyketide Synthases types I and II and Nonribosomal Peptide Synthetases were screened in more than 200 bacterial strains obtained, from which around 40% were putatively novel. Twenty-two were positive for at least one of the genes screened. Among them, 12 exhibited antimicrobial activities and one inhibited the proliferation of cancer cells. The metabolic profiles of the 22 strains were analyzed by liquid chromatography with tandem mass spectrometry and molecular network. The Global Natural Products Social Molecular Networking MolNetEnhancer workflow provided a more comprehensive understanding of the metabolic profiles. The results revealed the existence of a wide range of metabolites, however more than half of the compounds could not be identified. It was further observed that the metabolic diversity among the strains varied primarily due to the cultivation medium used. Together the results obtained here revealed the pharmacological potential of the bacteria isolated from Aplysina species.

Genome-resolved analysis of Serratia marcescens SMTT infers niche specialization as a hydrocarbon-degrader.

Bacteria that are chronically exposed to high levels of pollutants demonstrate genomic and corresponding metabolic diversity that complement their strategies for adaptation to hydrocarbon-rich environments. Whole genome sequencing was carried out to infer functional traits of Serratia marcescens SMTT recovered from soil contaminated with crude oil. The genome size (Mb) was 5,013,981 with a total gene count of 4,842. Comparative analyses with carefully selected S. marcescens strains, two of which are associated with contaminated soil, show conservation of central metabolic pathways in addition to intra-specific genetic diversity and metabolic flexibility. Genome comparisons also indicated an enrichment of genes associated with multidrug resistance and efflux pumps for SMTT. The SMTT genome contained genes that enable the catabolism of aromatic compounds via the protocatechuate para-degradation pathway, in addition to meta-cleavage of catechol (meta-cleavage pathway II); gene enrichment for aromatic compound degradation was markedly higher for SMTT compared to the other S. marcescens strains analyzed. Our data presents a valuable genetic inventory for future studies on strains of S. marcescens and provides insights into those genomic features of SMTT with industrial potential.

Genetic heterogeneity and metabolic reprogramming in breast cancer

Breast cancer is the most prevalent cancer and the leading cause of cancer-related mortality among women. Recent breakthroughs in breast cancer therapeutics have significantly enhanced outcomes for hormone receptor-positive and HER2-negative subtypes. However, the emergence of drug resistance, particularly in triple-negative breast cancer, presents a formidable challenge. The intricate interplay of genetic and metabolic diversity within breast cancer cells is pivotal to its development. By reprogramming metabolic pathways, cancer cells can adapt and thrive, meeting the demands of survival, growth, and invasion. These metabolic shifts also play a key role in the development of resistance to conventional therapies. This review explores the genetic and metabolic complexities of breast cancer, emphasizing the diverse subtypes and their unique profiles. We examine how genetic variations and metabolic alterations contribute to breast cancer development and progression, influencing both treatment efficacy and resistance. By integrating insights into the genetic background and metabolic reprogramming of breast cancer subtypes, this review aims to highlight the genetic variations and metabolic alterations that contribute to the pathogenesis of breast cancer, with a vision of advancing more precise and effective targeted therapies as well as discovering of novel diagnostic and prognostic markers.

Role of horizontal gene transfer and cooperation in rhizosphere microbiome assembly.

Microbes employ a variety of mechanisms, encompassing chemical signaling (e.g., quorum-sensing molecules) and genetic processes like horizontal gene transfer (HGT), to engage in interactions. HGT, in particular, holds a pivotal role as it facilitates the generation of metabolic diversity, thus directly or indirectly influencing microorganisms' interactions and functioning within their habitat. In this study, we investigate the correlations between enhanced metabolic diversity through HGT and cooperative behavior in the rhizosphere. Despite the potential drawbacks of cooperative behavior, which renders it susceptible to exploitation by cheaters based on evolutionary theory, HGT emerges as a mitigating factor. It serves as a valuable and adaptive tool for survival in competitive environments, notably the rhizosphere. By initiating a comprehensive discussion on these processes combined, we anticipate achieving a profound understanding of the rhizosphere microbiome, ultimately enhancing soil microbiology management and the exploitation of this ecological niche.

Unlocking the Heterogeneity in Acute Leukaemia: Dissection of Clonal Architecture and Metabolic Properties for Clinical Interventions.

Genetic studies of haematological cancers have pointed out the heterogeneity of leukaemia in its different subpopulations, with distinct mutations and characteristics, impacting the treatment response. Next-generation sequencing (NGS) and genome-wide analyses, as well as single-cell technologies, have offered unprecedented insights into the clonal heterogeneity within the same tumour. A key component of this heterogeneity that remains unexplored is the intracellular metabolome, a dynamic network that determines cell functions, signalling, epigenome regulation, immunity and inflammation. Understanding the metabolic diversities among cancer cells and their surrounding environments is therefore essential in unravelling the complexities of leukaemia and improving therapeutic strategies. Here, we describe the currently available methodologies and approaches to addressing the dynamic heterogeneity of leukaemia progression. In the second section, we focus on metabolic leukaemic vulnerabilities in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL). Lastly, we provide a comprehensive overview of the most interesting clinical trials designed to target these metabolic dependencies, highlighting their potential to advance therapeutic strategies in leukaemia treatment. The integration of multi-omics data for cancer identification with the metabolic states of tumour cells will enable a comprehensive "micro-to-macro" approach for the refinement of clinical practices and delivery of personalised therapies.

Electron transfer in multicentre redox proteins: from fundamentals to extracellular electron transfer.

Multicentre redox proteins participate in diverse metabolic processes, such as redox shuttling, multielectron catalysis, or long-distance electron conduction. The detail in which these processes can be analysed depends on the capacity of experimental methods to discriminate the multiple microstates that can be populated while the protein changes from the fully reduced to the fully oxidized state. The population of each state depends on the redox potential of the individual centres and on the magnitude of the interactions between the individual redox centres with their neighbours. It also depends on the interactions with binding sites for other ligands such as protons giving origin to the redox-Bohr effect. Modelling strategies that match the capacity of experimental methods to discriminate the contributions of individual centres are presented. These models provide thermodynamic and kinetic characterization of multicentre redox proteins. The current state of the art in the characterization of multicentre redox proteins is illustrated using the case of multiheme cytochromes involved in the process of extracellular electron transfer. In this new frontier of biological electron transfer, which can extend for distances that exceed the size of the individual multicentre redox proteins by orders of magnitude, current experimental data is still unable, in most cases, to provide discrimination between incoherent conduction by heme orbitals from coherent band conduction.

Impact of Different Land-Use Types on Soil Microbial Carbon Metabolism Function in Arid Region of Alpine Grassland.

There are discrepancies that exist in the effects of different land uses on soil organic carbon (SOC) and soil microbial carbon metabolism functions. However, the impact of land-use type changes on soil microbial carbon metabolism in alpine grassland arid areas is not well understood, hindering our understanding of the carbon cycling processes in these ecosystems. Therefore, we chose three types of land use (continuous reclamation of grassland (RG), abandoned grassland (AG), and natural grazing grassland (GG)) to study the microbial carbon metabolism and its driving factors by the Biolog-ECO method. The results showed that the soil organic carbon content decreased by 16.02% in the RG and by 32.1% in the AG compared to the GG in the 0-20 cm soil layer (p < 0.05). Additionally, microorganisms have the highest utilization efficiency of carbohydrate carbon sources, the average values of average well color development (AWCD) were RG (0.26), AG (0.35), and GG (0.26). In the 0-20 cm soil layer, the Shannon-Wiener and the Simpson indices were 3% and 1% higher in the AG compared to the GG, respectively. The soil TOC/TN and soil available phosphorus (AP) were key factors that affected the diversity of soil microbial and carbon metabolism. They were closely related to land-use types. This study holds that abandoning grasslands accelerates the carbon metabolism of microorganisms, leading to the loss of SOC content.

Metabolomic Diversity and Defensive Phenolic Compounds in Cloud Forest Ferns.

The few current metabolomic studies on ferns are mostly restricted to a single species or focused on specific compounds. We performed an untargeted metabolomic study on six of the most common fern species from the cloud forest, followed by a targeted analysis of 64 phenolic compounds, many of which have been associated with herbivore defense. The untargeted analysis revealed a total of 232 putatively identified metabolites from 463 to 1427 signals per fern species, each with its proper chemical signature but not necessarily correlated to their phylogenetic relationship. The flavonoid, flavone, and flavonol biosynthesis were the most expressed pathways in all species except for Marattia laxa. Fern species also differed strongly in the concentrations of the 10 detected phenolic compounds. Our results show that ferns, including the most ancestral species, such as M. laxa, display a high metabolomic diversity comparable to seed plants. Each fern species held a different combination of defensive phenolic compounds. Further research is needed to explore the metabolic diversity, to identify the biochemical defenses of ferns, and, in particular, to detect the chemical compounds that act against their specific herbivorous insects in the cloud forest ecosystem.

Experimental evidence on the impact of climate-induced hydrological and thermal variations on glacier-fed stream biofilms.

Climate change is predicted to alter the hydrological and thermal regimes of high-mountain streams, particularly glacier-fed streams. However, relatively little is known about how these environmental changes impact the microbial communities in glacier-fed streams. Here, we operated streamside flume mesocosms in the Swiss Alps, where benthic biofilms were grown under treatments simulating climate change. Treatments comprised four flow (natural, intermittent, stochastic, and constant) and two temperature (ambient streamwater and warming of +2 °C) regimes. We monitored microbial biomass, diversity, community composition, and metabolic diversity in biofilms over three months. We found that community composition was largely influenced by successional dynamics independent of the treatments. While stochastic and constant flow regimes did not significantly affect community composition, droughts altered their composition in the intermittent regime, favouring drought-adapted bacteria and decreasing algal biomass. Concomitantly, warming decreased algal biomass and the abundance of some typical glacier-fed stream bacteria and eukaryotes, and stimulated heterotrophic metabolism overall. Our study provides experimental evidence toward potential and hitherto poorly considered impacts of climate change on benthic biofilms in glacier-fed streams.

Genome-wide association study of metabolic traits in the giant duckweed Spirodela polyrhiza.

The exceptionally high growth rate and high flavonoid content make the giant duckweed Spirodela polyrhiza (L.) Schleid. (Arales: Lemnaceae Martinov) an ideal organism for food production and metabolic engineering. To facilitate this, identification of the genetic basis underlying growth and metabolic traits is essential. Here, we analysed growth and content of 42 metabolites in 137 S. polyrhiza genotypes and characterized the genetics underpinning these traits using a genome-wide association (GWA) approach. We found that biomass positively correlated with the content of many free amino acids, including L-glutamine, L-tryptophan, and L-serine, but negatively correlated with specialized metabolites, such as flavonoids. GWA analysis showed that several candidate genes involved in processes such as photosynthesis, protein degradation, and organ development were jointly associated with multiple metabolic traits. The results suggest the above genes are suitable targets for simultaneous optimization of duckweed growth and metabolite levels. This study provides insights into the metabolic diversity of S. polyrhiza and its underlying genetic architecture, paving the way for industrial applications of this plant via targeted breeding or genetic engineering.

Integrating genomic evidence for an updated taxonomy of the bacterial genus Spiribacter

The genus Spiribacter encompasses halophilic bacteria widely distributed in hypersaline environments worldwide. Despite their ecological significance, initially isolating Spiribacter species under laboratory settings was challenging due to the lack of knowledge of their growth and cultivation requirements. However, with improved understanding of their ecological niche and metabolic pathways, additional species of Spiribacter have been successfully isolated and identified from diverse locations around the globe. Enriched media with sodium pyruvate as carbon source facilitated the isolation of twelve new strains closely related to the genus Spiribacter from hypersaline environments in Spain. Genome sequencing and analysis of these new strains and previously described Spiribacter species provided insights into their genomic features and phylogenomic relationships, supporting the delineation of three distinct new species within this genus, designated as Spiribacter insolitus sp. nov., Spiribacter onubensis sp. nov., and Spiribacter pallidus sp. nov. In Spiribacter species, streamlined genomes enhance survival in hypersaline environments by reducing non-essential genes and optimizing resource utilization. Key genes involved in osmoprotectant mechanisms, including those for the metabolism of myo-inositol, hydroxyproline, and L-proline, were identified and numerous transporters were noted, ensuring efficient nutrient acquisition and osmotic balance. Notably, these new species, along with other Spiribacter strains, exhibit metabolic diversity in utilizing inorganic sulfur compounds, including thiosulfate and tetrathionate, for energy production and adaptation to hypersaline environments. The presence of thiosulfate dehydrogenase (TsdA) genes suggests their capability to oxidize thiosulfate to tetrathionate, potentially influencing both aerobic and anaerobic respiration. Furthermore, the prevalence of the sqr gene indicates a role for sulfide oxidation in Spiribacter metabolism, underlining their metabolic versatility in saline habitats. These adaptations allow Spiribacter to thrive in nutrient-limited, high-salinity habitats. Moreover, genome mining analysis and physiological disparities observed in the already described species Spiribacter halobius raise significant challenges to its classification within the genus Spiribacter.

The functional dominance and metabolic diversity of comammox Nitrospira in recirculating aquaculture systems.

As a newly discovered group of ammonia-oxidizing microorganisms, complete ammonia oxidizing (comammox) Nitrospira has been widely found in various oligotrophic ecosystems. However, their activity and ecological niche is still unclear in recirculating aquaculture systems (RAS). This study aimed to compare the abundance and activity of comammox Nitrospira, ammonia-oxidizing bacteria (AOB) and ammonia-oxidizing archaea (AOA), and elucidate metabolic versatility of comammox Nitrospira in RAS. Quantitative PCR (qPCR) results showed that either comammox Nitrospira or AOB numerically predominated, while comammox Nitrospira and AOA shared similar low ammonia niches. Specifically, DNA-based stable isotope probing in conjunction with high-throughput 16S rRNA gene amplicon sequencing revealed that comammox Nitrospira accounted for 79.1 %, 97.5 %, 91.9 % and 97.6 % in the active ammonia-oxidizing community in four selected typical samples representing high abundance of comammox, AOA, and AOB, respectively. Phylogenetic analysis of heavy fraction DNA further identified novel comammox species from Nitrospira nitrificans cluster and clade A.2 acting as active species in different freshwater aquariums. Moreover, metagenome-assembled genome analysis revealed them as novel species with stress resistance and metabolic diversity compared with known comammox Nitrospira. This study underscores the dominant role of comammox Nitrospira as active ammonia-oxidizers in RAS and presents two novel comammox MAGs with metabolic flexibility, enriching our understanding of the nitrification process in oligotrophic artificial ecosystems.

Multi-omics analysis reveals the role of UGT72 family genes in arbutin biosynthesis in Pyrus and evolution driven by whole genome duplication.

The UGT72 gene family encodes proteins that glycosylate phenylpropanoids, and thus contribute to the synthesis of various phenolic substances. However, their functional role and evolutionary history in Pyrus spp. remains poorly understood. Here we explored the evolution, amplification, coding region structural variation, and functional divergence of the UGT72 gene family and its subfamilies. Further, we identified functional genes involved in arbutin synthesis and functionally validated the key genes. 15 UGT72 genes were identified in the complete genome sequence and classified into two subfamilies of Pyrus betulifolia. Significant expansion of the UGT72 gene family occurred after genome duplication in P. betulifolia. 53.33 % of all UGT72 family genes were found to have undergone expansion via WGD/segmental duplication. A noteworthy discovery was that the amplification of functional genes such as PbUGT72B1714 during polyploidization, combined with the loss of vital motifs and variations at important sites within these genes, significantly impacted the diversification of arbutin metabolism. These findings offer novel insights into how gene gains and losses caused by WGDs have contributed to metabolic diversification and evolutionary adaptation in Pyrus, as well as a groundwork for more detailed investigations into the mechanisms of arbutin metabolism.

Generation of a PDK-1 knockout human embryonic stem cell line by CRISPR/(WAe009-A-2K) Cas9 editing.

Pyruvate Dehydrogenase Kinase1 (PDK1) belongs to the family of kinases, regulates diverse metabolic processes. PDK1 is a susceptibility locus for heart failure via thinning of ventricle walls, and enlarged atria and ventricles. We successfully developed a PDK1 knockout (PDK1-/-) human embryonic stem cell (hESC) line using an episomal vector-based CRISPR/Cas9 system explore the role of PDK in human heart development. This PDK1-KO hESC line-maintained stem cell-like morphology, pluripotency, and normal karyotype and can differentiate into all three germ layers in vivo. This cell line will be a valuable tool for future research on the role of PDK1 in heart development.

Insights into functional divergence, catalytic versatility and specificity of small molecule glycosyltransferases.

Glycosylation is one of the most fundamental biochemical processes in cells. It plays crucial roles in diversifying plant natural products for structures, bioavailability and bioactivity, and thus, renders the glycosylated compounds valuable as food additives, nutraceuticals and pharmaceuticals. Moreover, glycosylated compounds impact plant growth, development and stress response. Therefore, understanding the biochemical function of the glycosyltransferases (GTs) is crucial to the elucidation of natural product biosynthetic pathways, improving plant traits and development of processes for industrially-important compounds. UDP-dependent glycosyltransferases (UGTs) that belong to the glycosyltransferase family-1 (GT1) and catalyze the transfer of glycosyl moieties from UDP-sugars to various small molecules, are the key players in natural product glycosylation. Recent studies also found the involvement of non-canonical cellulose synthase-like (CesAs) and glycosyl hydrolase (GH) family enzymes in the glycosylation of plant specialized metabolites. Decades of research on GTs provided critical insights into catalytic mechanism, substrate/product specificity and catalytic promiscuity, but biochemical function and physiological roles of GTs in majority of the natural product biosynthetic pathways remain to be understood. It is also important to redefine high-throughput strategies of GT mining to uncover novel biochemical function, considering that GTs are the large superfamily members in plants and other organisms. This review underscores the roles of GTs in small molecule glycosylation, plant development and stress responses, highlighting the catalytic versatility and substrate/product specificity of GTs in shaping plant metabolic diversity, and discusses the emerging strategies for mining of uncharacterized GTs to unravel biochemical and physiological functions and to elucidate natural product biosynthetic pathways.

Uneven distribution of prokaryote-derived horizontal gene transfer in fungi: a lifestyle-dependent phenomenon.

This study sheds new light on the role of horizontal gene transfer (HGT) in fungi, an area that has remained relatively unexplored compared to its well-established prevalence in bacteria. By analyzing 829 fungal genomes, we identified over 20,000 genes that fungi acquired from prokaryotes, revealing the significant impact of HGT on fungal evolution. Our findings highlight that fungal lifestyle traits, such as being parasitic or saprotrophic, play a key role in determining the extent of HGT, with parasites showing the highest gene acquisition rates. We also uncovered unique patterns of HGT occurrence based on fungal morphology and reproduction. Importantly, genes with introns, which are more highly expressed, appear to play a crucial role in fungal adaptation. This research deepens our understanding of how HGT contributes to the metabolic diversity and ecological success of fungi, and it underscores the broader significance of gene transfer in shaping fungal evolution.

Transcriptional and functional characterization in the terpenoid precursor pathway of the early land plant Physcomitrium patens.

Isoprenoids comprise the largest group of plant specialized metabolites. 1-deoxy-D-xylulose-5-phosphate synthase (DXS) is one of the major rate-limiting enzymes in their biosynthesis. The DXS family expanded structurally and functionally during evolution and is believed to have significantly contributed to metabolic complexity and diversity in plants. This family has not yet been studied in Physcomitrium patens or other bryophytes. Here, we assessed the degree of evolutionary expansion in the DXS family in bryophytes and, more specifically, in P. patens using phylogenetic analysis. Transcriptome profiling was applied to investigate tissue-specific, developmental, and environmental responses, such as salt stress, in the DXS family. Moreover, the effect of salt stress on terpenoid biosynthesis was monitored through metabolomics. The phylogenetic analysis of DXS revealed that a structural expansion occurred in bryophytes, but not in P. patens. Functional complementation assay revealed functional activity in all four copies. Comparative transcriptomics showed tissue- and condition-specific divergence in the expression profiles of DXS copies and demonstrated specific stress responses for PpDXS1D, particularly to salt stress. These findings coincide with increased flux in the pathway towards downstream metabolites under salt stress. Additionally, co-expression network analysis revealed significant differences between the co-expressed genes of the DXS copies and illustrated enrichment of stress-responsive genes in the PpDXS1D network. These results suggest that the DXS family in P. patens is conserved but undergoes differential transcriptional regulation, which might allow P. patens to fine-tune DXS levels under different conditions, such as abiotic stress.

Human Cytochrome P450 Cancer-Related Metabolic Activities and Gene Polymorphisms: A Review.

Cytochromes P450 (CYPs) are heme-containing oxidoreductase enzymes with mono-oxygenase activity. Human CYPs catalyze the oxidation of a great variety of chemicals, including xenobiotics, steroid hormones, vitamins, bile acids, procarcinogens, and drugs. In our review article, we discuss recent data evidencing that the same CYP isoform can be involved in both bioactivation and detoxification reactions and convert the same substrate to different products. Conversely, different CYP isoforms can convert the same substrate, xenobiotic or procarcinogen, into either a more or less toxic product. These phenomena depend on the type of catalyzed reaction, substrate, tissue type, and biological species. Since the CYPs involved in bioactivation (CYP3A4, CYP1A1, CYP2D6, and CYP2C8) are primarily expressed in the liver, their metabolites can induce hepatotoxicity and hepatocarcinogenesis. Additionally, we discuss the role of drugs as CYP substrates, inducers, and inhibitors as well as the implication of nuclear receptors, efflux transporters, and drug-drug interactions in anticancer drug resistance. We highlight the molecular mechanisms underlying the development of hormone-sensitive cancers, including breast, ovarian, endometrial, and prostate cancers. Key players in these mechanisms are the 2,3- and 3,4-catechols of estrogens, which are formed by CYP1A1, CYP1A2, and CYP1B1. The catechols can also produce quinones, leading to the formation of toxic protein and DNA adducts that contribute to cancer progression. However, 2-hydroxy- and 4-hydroxy-estrogens and their O-methylated derivatives along with conjugated metabolites play cancer-protective roles. CYP17A1 and CYP11A1, which are involved in the biosynthesis of testosterone precursors, contribute to prostate cancer, whereas conversion of testosterone to 5α-dihydrotestosterone as well as sustained activation and mutation of the androgen receptor are implicated in metastatic castration-resistant prostate cancer (CRPC). CYP enzymatic activities are influenced by CYP gene polymorphisms, although a significant portion of them have no effects. However, CYP polymorphisms can determine poor, intermediate, rapid, and ultrarapid metabolizer genotypes, which can affect cancer and drug susceptibility. Despite limited statistically significant data, associations between CYP polymorphisms and cancer risk, tumor size, and metastatic status among various populations have been demonstrated. The metabolic diversity and dual character of biological effects of CYPs underlie their implications in, preliminarily, hormone-sensitive cancers. Variations in CYP activities and CYP gene polymorphisms are implicated in the interindividual variability in cancer and drug susceptibility. The development of CYP inhibitors provides options for personalized anticancer therapy.