The cytochrome P450 enzyme family plays a vital role in the metabolism of various drugs. In humans, this family includes 57 functional genes and 58 pseudogenes. Approximately twelve enzymes primarily from the CYP1, CYP2, and CYP3 families predominantly play a predominant role in metabolizing most xenobiotics, including 70%–80% of all pharmaceuticals currently in clinical use. Highly expressed hepatic isoforms include CYP3A4, CYP2C9, CYP2C8, CYP2E1, and CYP1A2, while CYP2A6, CYP2D6, CYP2B6, CYP2C19, and CYP3A5 show moderate expression, and CYP2J2, CYP1A1, and CYP1B1 are largely extrahepatic. Expression and activity are modulated by genetic polymorphisms, xenobiotics, cytokines, hormones, sex, age, and disease states (Zanger and Schwab, 2013; Zhao et al., 2021). Evolutionary processes such as gene duplication and loss have also shaped CYP gene diversity across species, leading to variations in gene number and subfamily composition (Nelson et al., 2013).

Genes encoding CYPs are significantly varied genetically, and various CYP variants are important clinical biomarkers for enhancing drug selection and dosing (Zhou and Lauschke, 2022). Drug metabolism rates differ among individuals due to genetic polymorphisms and differences in the expression of CYP450 enzymes. Xenobiotic metabolism, developmental processes, and treatment responses vary in every individual due to epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNA regulation, as they play a substantial role in influencing CYP450 enzyme activity (Jin and Zhong, 2023). Based on allele combinations, individuals can be classified as poor, intermediate, extensive, or ultra-rapid metabolizers, which profoundly affects drug efficacy and safety (Riaz et al., 2019). Notably, CYP2D6 shows extensive polymorphism, where 63 alleles are reported, impacting the metabolism of nearly half of its substrate (Kaptsis et al., 2024).

CYP expression is further modulated by ligand-activated receptors such as the aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR), which control a hepatoprotective gene network in the liver and intestine (Rakateli et al., 2023). Through these receptors, environmental exposures including industrial and agricultural pollutants like phenols, polyphenols, substituted polyphenols, polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), flame retardants, and azoles, induce or suppress CYP enzymes such as CYP1A1, CYP1A2, CYP1B1, CYP2B6, and CYP3A4 (Burkina et al., 2017; Smutny et al., 2013; Wuputra et al., 2025). Hormonal ligands (vitamin D, glucocorticoids, cholesterol derivatives) also regulate CYP activity via PXR, CAR, vitamin D receptor (VDR), and glucocorticoid receptor (GR), influencing both phase I metabolism and transcription of CYP3A5 (Rezen et al., 2011; Noh et al., 2022; Oladimeji et al., 2016).

This receptor-mediated transcriptional regulation represents a primary mechanism by which the exposome dynamically modulates CYP450 enzyme activity, thereby profoundly impacting drug metabolism and response.

The exposome concept, introduced by Christopher Wild in 2005 as “life-course environmental exposures from the prenatal period onwards” (Miller and Jones, 2014; Wild, 2012). This concept includes all exposures, including chemical, physical, biological, psychological, social, and behavioral factors that shape human health (Barouki et al., 2021). Later, Miller and Jones expanded this framework to include cumulative biological responses to environmental, dietary, behavioral, and internal processes throughout the lifespan. Together, the exposome and the genome help explain variability in both physiological and pathological conditions (Barouki et al., 2021; Miller and Jones, 2014). This concept is particularly relevant to toxicology because it links complex environmental exposures with mechanistic responses. The liver, as the main site of xenobiotic metabolism, expresses a large repertoire of detoxification genes—cytochrome P450s, phase II enzymes, transporters, and xenobiotic receptors—positioning it as a central interface between the exposome and human health (Barouki et al., 2021). The following subsections summarize major categories of external exposome factors and their documented impacts on CYP450 enzymes and drug metabolism.

The exposome can lead to induction or inhibition of drug-metabolizing enzymes which in turn affect the drug metabolism. Enzyme induction occurs when the exposome increases the expression of these enzymes, mainly through the activation of nuclear receptors or transcription factors that promote gene transcription (Hakkola et al., 2020). These alterations result in an increase in the capacity of the body to metabolize drugs, which is linked to lower in their plasma levels and, ultimately, a decrease in the therapeutic efficacy of the medication (Pristner and Warth, 2020; Robertson et al., 2012).

For instance, polycyclic aromatic hydrocarbons (PAHs), which are a common exposome seen in cigarette smoke, can bind and activate the aryl hydrocarbon receptor (AhR), which is a cytoplasmic receptor. Upon activation, the receptor moves into the nucleus and forms a heterodimer with the aryl hydrocarbon receptor nuclear translocator (ARNT). This complex can increase the expression of genes that encode for drug-metabolizing enzymes including CYP1 enzymes like CYP1A1 and CYP1B1 in phase I and glutathione S-transferases (GSTs) in phase II through binding to xenobiotic response elements (XREs) within gene promoter regions (Hammond et al., 2022). This leads to increase in the enzymatic activity and accelerates drug metabolism which may lower plasma drug concentrations and reduce therapeutic efficacy especially in drugs that have limited therapeutic windows (Pristner and Warth, 2020). While enzyme inhibition refers to a reduction in enzymatic activity upon exposure to exposomes, which in turn leads to lower drug metabolism. This can happen through direct competitive or non-competitive inhibition or through mechanism-based inactivation (MBI) that is also known as “suicide inhibition”, in which the enzyme is altered irreversibly (Alsanosi et al., 2014). In Figure 2, it summarizes how this mechanistic work ultimately affects drug metabolism. Competitive inhibition happens when exposome components mimic the substrate and compete with the drug for the enzyme’s active site which results in reversible inhibition in which the inhibitor can be replaced by increasing the concentration of drug (Spaggiari et al., 2016). For example, grapefruit medications can act as competitive inhibitors for cytochrome P450 3A4 enzyme (CYP3A4), resulting in reduction of drug metabolism such as simvastatin and increased toxicity in plasma levels (Bailey et al., 2013; Lee et al., 2016). Non-competitive inhibition happens when exposome components bind to an allosteric site which leads to changing in conformation of enzyme and thereby blocking the drug from binding to it which eventually leads to impairment of drug regardless of its concentration (Delaune and Alsayouri, 2022). For instance, it has been demonstrated that flavonoids like 6-hydroxyflavone can act as a non-competitive inhibitor for cytochrome P450 (P450) which affects eventually drug metabolism and leads to drug interactions (Si et al., 2009). Moreover, MBI or suicide inhibition occurs when an enzyme metabolizes a substance and converts it into a reactive intermediate where it forms a covalent bond and binds to the enzyme causing inactivation of it. This leads to permanent loss of enzyme activity until new enzymes are produced (Zhou et al., 2022).

Epigenetics describes the heritable changes that affect gene expression without altering the underlying DNA sequences. These changes include DNA methylation, Histone modifications, and regulatory non-coding RNAs. The exposomes can induce epigenetic modifications which can alter the expression of genes that are involved in drug-metabolized enzymes, ultimately affecting drug metabolism and its response (Shamsi et al., 2017). This mechanism is summarized in Figure 3.

Non-Coding RNAs are RNA molecules that do not code for proteins, but they are involved in gene regulation at transcriptional and post-transcriptional levels. Among them, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs), in which they play an important role in modulation of the expression of drug-metabolizing enzymes such as CYP450. MiRNAs are short nucleotides RNAs in which they bind to the 3′untranslated regions (3′UTRs) of target mRNAs, leading to their degradation or translational repression. While lncRNAs can regulate gene expression through various mechanisms, such as chromatin remodeling and transcriptional interference. The exposome can significantly alter the expression and activity of those non-coding RNAs. For instance, a study by Liu et al. (2020), has shown that the exposure of BPA can alter miRNA, specifically miR-27b-3p which in turn has an effect on drug metabolism. The results have shown that BPA causes a downregulation of miR-27b-3p which leads to an increase in the expression of CYP1B1 and subsequently promotes oxidative stress and apoptosis in spleen lymphocytes. Similarly, a study by Chuturgoon et al. (2014) investigates how exposure of Fumonisin B1 (FB1) alters drug metabolism through the regulation of miRNA in human liver cells.

Researchers have demonstrated that FB1 exposure leads to the downregulation of miR-27b that leads to an increase in CYP1B1 expression. This upregulation of CYP1B1 has an influence on drug metabolism and increases production of ROS, which contributes to toxicity. Moreover, lncRNAs have been involved in regulating gene expression of drug metabolizing enzymes. However, studies on how lncRNAs affect drug metabolism are very limited. One of the studies shows how benzo[a]pyrene (B[a]P) influences lncRNAs through activation of the aryl hydrocarbon receptor (AhR) in human lung epithelial cells. The results have shown that exposure to B[a]P causes an activation of AhR receptor through different lncRNAs including SATB1-AS1, MIR4290HG, AC008969.1, LINC01533, and VIPR1-AS1. Some of these lncRNAs are known for their ability to regulate CYP1A1 and CYP1B1. These findings suggest that exposure to environmental toxins like B[a]P can induce AhR activation through alteration of lncRNAs expression, which in turn has an influence on drug-metabolizing enzymes and affect drug responsiveness and toxicity.

Current research on external exposome effects on CYP450-mediated drug metabolism reveals critical knowledge gaps. First, while individual exposures (e.g., air pollutants, dietary phytochemicals) are well-characterized, synergistic effects of mixed exposures remain understudies (Barouki et al., 2021; Tomkiewicz et al., 2024). Secondly, non-chemical stressors (e.g., socioeconomic factors, circadian disruption) are rarely integrated as factors in the research studies even though they modulate CYP activity through inflammatory pathways like IL-6-mediated CYP1A2 suppression (Wang et al., 2022). Additionally, more studies should focus on population-specific vulnerabilities as they are inadequately described, particularly in groups with combined genetic polymorphisms (e.g., CYP2C19 poor metabolizers) and high occupational toxicant exposure (Chen et al., 2012). Finally, the mechanistic links between environmental exposures and epigenetic CYP regulation (e.g., DNA methylation by heavy metals) require deeper exploration and understanding so we would be able to predict individual metabolic variability (Chen et al., 2012).

One of the internal exposome that affect drug metabolism is the gut microbiome. The gut microbiome is a highly complex and diverse biological ecosystem, comprising 5 million genes and 100 trillion cells. While it includes multiple dominant phyla such as Verrucomicrobia, Fusobacteria, Proteobacteria, Bacteroidetes, Actinobacteria, and Fusobacteria, the two phyla Firmicutes and Bacteroidetes dominate its composition (Dikeocha et al., 2022). It is known that the Microbiome can only be affected by xenobiotics; however, we aim to explore the complete opposite and the culmination of both counterparts affecting each other endlessly, paving the way to the internal exposome, wide effects, and interactions with drug molecules inside the human body. That said, and as the gut microbiome influences drug metabolizing enzymes, particularly CYP450, we recognize it as an “internal exposome”.

For instance, in a recent research study the authors collected fecal samples from cholesterol gallstone patients and conducted gut microbiome analyses in which they found a higher abundance of Desulfovibrionales bacteria. Moreover, subsequent implantation of Desulfovibrionales in mice was performed, and the gene expression of cholesterol 7α-hydroxylase (CYP7A1) was measured. The inhibition of CYP7A1 was attributed to Desulfovibrionales metabolites. Desulfovibrionales have genes for sulfate reduction that reduce sulfate to hydrogen sulfide, which results in enhancing farnesoid X receptor (FXR) in HepG2 cells and followed by CYP7A1 inhibition (Hu et al., 2022). Importantly, CYP7A1 is the metabolizing enzyme of atorvastatin, which is an effective drug for cholesterol lowering in cardiovascular disease (Fu et al., 2014). However, it has been found that statins themselves alter gut microbiomes, as evidenced by Akkermansia muciniphila disruption in mice (Cheng et al., 2022).

Further evidence linking drug metabolism and gut microbiome is research investigating how tacrolimus (TAC) pharmacokinetics were affected by gut microbiome using in vivo mice models. Mainly, CYP3A11 and CYP3A13 metabolize TAC, along with an ATP-dependent drug efflux pump (ABCB1) that facilitates its excretion from the gut to the liver for further metabolism. Here, the ABCB1 gene was affected by gut microbiota in mice. In this study, it was reported that the gut microbiome in the intestines reduced the activity of CYP3A11 in the antibiotic mice group, whereas CYP3A13 remained unaffected. Strikingly, ABCB1 expression in distal, median, and proximal segments of the small intestine was significantly correlated with TAC area-under-the-curve (AUC) values, paralleling shifts in microbial taxa (e.g., high abundance of Akkermansia and Alistipes and low abundance of Oscillibacter and Ruminococcus) under the administration of TAC (Degraeve et al., 2023). Given that CYP3A11 is responsible for 75% of drug metabolism in mice, regulation is critical. Follow-up studies revealed that the regulation of CYP3A11 is modulated by both the production of interleukin-22 produced by innate lymphocyte cell 3 (ILC3) in small intestine epithelium, and the presence of the segmented filamentous bacteria (SFB) which collectively affect the expression of CYP3A11, highlighting the mechanistic link between microbial communities and drug metabolism through in vivo models. Cardiac research reported that aspirin alters the gut microbiome and is responsible for the impact of Trimethylamine N-oxide (TMAO), a byproduct of carnitine and betaine, on platelets (Brown and Pereira, 2018). Therefore, more focus should be made on microbiota-immunity crosstalk and its effect on drug metabolism and toxicity (Flannigan et al., 2020).

Inflammation markedly affects drug metabolism by downregulating CYP450 enzymes, a process often termed phenoconversion. Its extent depends on factors such as the type and severity of inflammation, genetic variability, and drug metabolic pathways (de Jong et al., 2020). Among inflammatory markers, Interleukin-6 (IL-6) is the most extensively studied, showing strong suppression of CYP2C9, CYP2C19, and especially CYP3A4 in primary human hepatocytes (PHHS). IL-6 acts primarily through three pathways: JAK/STAT3, MAPK/ERK, and PI3K/AKT, with MAPK/ERK and PI3K/AKT being the most significant regulators of CYP downregulation (Reeh et al., 2019; Keller et al., 2016).

Other cytokines also modulate CYP expression. Interleukin-1β (IL-1β) reduces CYP3A4 mRNA levels by ∼95% via NF-κB activation but has minimal effects on CYP2C9 and CYP2C19 (Zhou et al., 2016). Tumor Necrosis Factor α (TNF-α) downregulates CYP3A4 mRNA selectively through NF-κB and MAPK/ERK pathways, although without altering protein levels (Shi and Sun, 2018).

The endocrine system secretes hormones to coordinate and regulate the human body’s internal metabolism, including drug metabolism, growth, development, and response to injury, stress, or environmental stressors. The glands (e.g., thyroid, parathyroid, pituitary, adrenal) secrete many hormones. Additionally, the female hormones (e.g., estrogen and progesterone) are mainly secreted from the ovaries.

Importantly, pregnancy-induced hormonal fluctuations significantly modulate CYP450 activity. Notably, CYP3A4, responsible for metabolizing 50% of clinically used drugs, shows elevated activity during the pregnancy period, as observed in the enhanced clearance of antihypertensive drug nifedipine. Similarly, CYP2D6 activity rises during the second and third trimesters, whereas CYP1A2 and CYP2C19 activity decline during pregnancy. This suppression of CYP1A2 is relevant, as it metabolizes asthmatic and psychotic drugs, potentially increasing the risk of drug toxicity (Betcher and George, 2020). These adaptations are attributed to the pregnancy-associated hormones, though the underlying mechanisms by which endogenous sex hormones regulate CYP activity remain poorly understood.

For instance, Mongolian gerbil studies have reported that quinestrol, an exogenous estrogen, modifies metabolizing enzymes. Quinestrol binds to nuclear receptors, which then interact with specific response elements in the promoter region of CYP genes. Specifically, CYP4A1 transcription was enhanced, leading to alterations in drug metabolism. It also influences the stability of mRNA transcripts. Notably, progesterone influenced CYP activity, whereas testosterone had little effect. Further studies are required to investigate the underlying mechanisms (Su et al., 2017).

Further evidence investigating the impact of quinestrol on male mice stated that CYP450 content per gram of liver was higher than the control group. While the combined treatment (quinestrol + Clarithromycin) resulted in lower CYP450 content than the quinestrol group. This could be justified by the fact that Clarithromycin’s inhibition of CYP3A4 might lower the turnover rate of the enzyme in the liver, leading to reduced CYP450 content per liver gram (Ji et al., 2024).

Disease states significantly influence CYP450-mediated drug metabolism. Liver diseases, particularly cirrhosis, suppress CYP activity due to parenchymal changes, reduced blood flow, and loss of functional hepatocytes, leading to impaired drug metabolism and detoxification (Hirano et al., 2015).

Type 2 Diabetes (T2D) alters CYP activities in an isoform-dependent manner: CYP2C19, CYP2B6, and CYP3A4 activities are reduced by 1.5–2-fold, whereas other isoforms may be unaffected or slightly increased (Gravel et al., 2019). Given that CYP3A4 metabolizes nearly 40% of therapeutic agents, reduced activity in T2D patients, shown by a 1.6-fold decrease in hepatic CYP3A4 levels and substrate metabolism, underscores the importance of caution with polypharmacy, as disease–drug–drug interactions may occur (Coutant and Hall, 2018).

The brain also expresses resident CYP enzymes at the tissue level, the blood-brain barrier, and the cerebrospinal fluid barrier, with roles in xenobiotic metabolism, homeostasis, and disease modulation (Fanni et al., 2021). In glioma, for example, CYP1A1 is upregulated, generating reactive intermediates that may contribute to carcinogenesis (Wang and Zuo, 2018). Brain CYP distribution is extensive—across the cortex, basal ganglia, hippocampus, substantia nigra, and other regions—with several isoforms (CYP1, CYP2, CYP3, and the brain-specific CYP46A1) expressed in astrocytes, neurons, and endothelial cells (Sjöstedt et al., 2020). Consequently, neuropathologies may alter CYP expression locally, further linking disease states and CYP-mediated metabolism (Durairaj and Liu, 2025).

The interconnectedness in the internal exposomic factors is not yet posited; however, one can postulate the intricate connections between bodily response, and reactions, accumulating into grandiose, singular severe effect on the CYP450 enzymes all over the body, augmenting endogenous and exogenous substance metabolism, especially drug metabolism and breakdown. Among many systems inside our body, two were previously touched deeply, CNS and Liver, as such we came across multiple other factors in other systems and intersystem drivers for a polyexposomic interference with drug metabolism by CYP450 interactions. CYP-led reactions in the CNS can conclude an orchestra of different ROS products which disrupt by default the neuroprotective mesh of the brain and the CNS, leading to initial neurotoxicity that eventually led to neurodegeneration and disease progression (Miller et al., 2017).

Inflammation and ROS production from varying reasons such as oxidative stress and damage, activation of microglia and astrocytes, chemokine-mediated and cytokine-mediated inflammatory reactions, all can affect the expression of CYP450, consequently, mediating drug efficacy and toxicity mechanisms (Mast et al., 2021). Liver functions vary which explains its close proximity to being one of most important organs that hosts most of the phase 2 enzymes involved in drug metabolism. Intriguingly, the “pancreas-liver” axis answers many metabolic questions as well as many GITS chronic diseases with the full assistance of “gut-liver” axis, and finally the gut microbiota, this is the full orchestral crosstalk that initiate many consequences on the metabolism of different substances. A possible mechanism is lipid homeostasis disruption, with AhR, PXR, and CAR, all of these actors of the nuclear metabolic receptor superfamily are involved in developing liver steatosis that has further serious implications, leading to structural and biochemical damage of the liver parenchyma; hence, dysregulated drug metabolism as a result of dysfunctional CYP450 enzymes (Bourganou et al., 2025).

An altered microbiome will cause a dysfunctional gut barrier which will affect the first responder to xenobiotics; the liver, causing a metabolic disruption in the liver. The increased permeation of the gut barrier will allow substances such as bioactive lipids, and short-chain fatty acids, to induce inflammatory reactions in the liver exemplified in IL-1β, IL-6, and TNF-α (Barouki et al., 2021). Gao et al. investigated the core components of both internal and external exposomes, in what they called inter-omics analysis between episome, microbiome, proteome, and metabolome, as a result, they deciphered some of the mysteries underlying external-internal exposome interactions (Gao et al., 2022).

They postulated that air quality index correlates with personal creatinine, aminotransferase, cysteinyl proline, monoglyceride, adiponectin, and immunoglobulin lambda. Unexpectedly, fungi came out as the most prominent biological component in the external exposome-proteome and external exposome-metabolome interactions, but no clear human health clues. A major outcome of these analyses is finding that multiple systems such as the immune system, kidney, and the liver play significant roles in the exposomic interactions, as they’re well-known in dealing with both phases; internal and external exposures. Complement C3, IL-1 receptor, and Immunoglobulin proteins were the most highly annotated components from the external exposome-proteome analysis. L-arginine, uracil, and other amino acids were the highest degree metabolites detected in the external exposome-metabolome array. Alanine aspartate, glutamate metabolism, protein absorption and digestion, and beta-alanine metabolism are the highest degree immune-related pathways which were also involved in external exposome-metabolome analysis (Gao et al., 2022).

Moreover, we previously highlighted that Eggerthella members were likely contributing to diseases like liver disease, ulcerative colitis, and systemic bacteremia. Parasutterella was also involved in bile acid metabolism and regulation. Roseburia, Alistipes, Eggerthella, Odoribacter, Parasutterella were all involved in proinflammatory activities that promote chemical stressors, leading to systemic inflammation and increased susceptibility to disrupted systems, causing various diseases, and affecting drug metabolism (Parker et al., 2020).

In essence, the various multifactorial interactions between different Internal Omes showcases the complexity of this myriads of components that autonomously interact with each other causing disruption in biological processes, full spectrum inflammation, and consequently, dysregulated drug metabolism (Parker et al., 2020). To correlate a plethora of chemical and biological components under the umbrella of unlocking internal and external exposome, Figure 5 explains how factors such as the gut microbiome, disease states, hormonal fluctuations, inflammation, and oxidative stress (ROS) affect phenotypes and biochemical pathways in different systems inside the body. Additionally, these factors shift the therapeutic index and affect both treatment efficacy and cytotoxicity through influencing cytochrome P450 activity, which converges on drug metabolism. That mentioned, isolating these proceedings and associating them with drug metabolism, more importantly, health outcomes is the main challenge.

Environmental factors can interact with the genetic polymorphisms in CYP450 enzymes causing alteration in drug metabolism. For example, CYP2C19 ultra-rapid metabolizers when exposed to smoking exhibit a much greater clopidogrel activation, increasing bleeding risk due to enhanced prodrug conversion (Cheng et al., 2023). Similarly, for CYP1A2 slow metabolizers when they consume charred meat face an almost 5 times increase in esophageal cancer risk, as PAHs in charred foods are inadequately detoxified in their bodies (Gastelum et al., 2020; Wang et al., 2012). Also, gene-environmental epistasis further modulates detoxification pathways. GSTP1 variants reduce glutathione conjugation efficiency, impairing CYP1A1-mediated PAH detoxification and thus, increasing cancer susceptibility in smokers (Xu et al., 2013). Concurrently, UGT1A128 polymorphisms exacerbate irinotecan toxicity in urban populations exposed to PM, which induces CYP3A4-mediated bioactivation of the drug (Wang et al., 2022; Xu et al., 2013).

Advanced phenotyping methods, such as S-mephenytoin/CYP2C19 activity ratios can reveal enzyme inhibition in pesticide-exposed agricultural workers, which can be used to guide dose adjustments in those individuals (Wang et al., 2022). Omics-based approaches, such as metabolomic profiling of PAH-CYP1A1 DNA adducts, provide quantitative exposure biomarkers that can link environmental PAH levels to metabolic dysfunction (Samer et al., 2020).

Dynamic Monitoring Systems Wearable sensors that track real-time ozone exposure in correlation with CYP2E1 induction, facilitates dynamic dosing adjustments for drugs metabolized by this enzyme (Wang et al., 2022). Geo-tagged electronic health records can map urban air pollution and identify exposed populations who would have suppressed CYP1A2 activity, thus requiring therapeutic modifications and dose adjustments (Samer et al., 2020).

Recent advances in precision environmental health monitoring have demonstrated the power of integrating longitudinal exposome profiling with multi-omics analyses to capture the individualized nature of environmental exposures and their biological consequences (Gao et al., 2022). Researchers measure thousands of chemical and biological components in a single individual’s personal exposome and correlate these with internal biomolecular changes, including proteomics, metabolomics, and clinical markers. This revealed that even individuals living in the same geographic area can have highly distinct and fluctuating exposure profiles, with agrochemicals and fungi frequently dominating the external exposome. They also found strong correlations between specific environmental exposures and changes in molecular pathways related to the immune system, kidney, and liver, which necessitate the need for personalized exposure monitoring (Gao et al., 2022).

Genetic information and exposure profiles are combined in customized risk frameworks. For instance, CYP1A1 and CYP1B1 enzyme activity may be altered in urban commuters who are frequently exposed to high amounts of PM2.5 and traffic-related nitrogen oxides, which may necessitate a reduction in tamoxifen dosing to maintain therapeutic efficacy and safety in those patients (Wang et al., 2022). Furthermore, CYP2E1 and CYP3A4 are jointly induced in chronic alcohol users who are also exposed to aflatoxin B1, increasing their risk of hepatotoxicity and necessitating improved screening procedures to identify liver damage early (Chen and Wei, 2015).

Therapeutic Optimization through exposure-Aware can be seen in several cases. For instance, Prescribing Proton pump inhibitor (PPI) selection accounts for CYP2C19 genotype and indole-3-carbinol intake from cruciferous vegetables, which induce competing metabolic pathways. Also, warfarin dose adjustments should take into account vitamin K dietary fluctuations with CYP4F2 status, thus stabilizing anticoagulation response (Gaikwad et al., 2018). Together, these examples demonstrate how taking into account exposure and genetic factors allows for a more reliable and effective prescription, which is a step toward truly holistic precision medicine.