Arsenic trioxide (ATO) is both a life-saving therapy for acute promyelocytic leukemia and a systemic toxicant whose hepatic effects remain incompletely defined. This study examined how a single clinically relevant ATO dose (8 mg/kg, i.p.) acutely remodels hepatic xenobiotic-metabolizing enzymes, arsenic transporters, and pro-inflammatory mediators in male and female C57Bl/6 mice. Mice were treated with ATO or saline and livers were collected at 6 and 24 h for integrated mRNA and protein profiling of major Cytochrome P450 (CYP) families, aquaglyceroporins (Aqp3/7/9), ATP-binding cassette (Abcb1, Abcc1-6) transporters, and cytokines (Tnf-α, Il-1β, Il-6). ATO induced highly sex-, time-, and isoform-specific reprogramming. Females exhibited a wider and earlier decline in several female-predominant CYP2, CYP3, and CYP4 isoforms, including a more pronounced reduction in hepatic CYP3A, CYP4A, and CYP4F protein abundance. In contrast, males showed mainly transcriptional induction of specific genes (Cyp1a1, Cyp2a, Cyp3a13, and Cyp4a), accompanied by comparatively modest decreases in overall CYP protein levels. Aqp and Abc transporters were differentially modulated, with males displaying early, relatively monotonic upregulation of Abcb1/Abcc efflux systems, while females exhibited higher basal Abc expression but more complex, biphasic regulation of both influx (Aqp7/9) and efflux pathways. These transcriptional changes paralleled a transient inflammatory response, including early Tnf-α induction and female-specific Il-6 elevation. Collectively, these findings highlight sex-dependent modulation of hepatic ATO handling and drug metabolizing capacity, with important implications for risk assessment and individualized ATO containing regimens.

The expression and activity of cytochrome P450 (CYP) enzymes are influenced by sex differences, and their arachidonic acid (AA)-mediated metabolites play crucial roles in physiological and pathological conditions. Isoproterenol (ISO) can induce kidney injury mediated by the activation of the renin–angiotensin–aldosterone system and may progress to end-stage renal disease. Our study aims to investigate the sex-related differences in CYP enzymes following ISO-induced kidney injury. Male and female rats were injected with ISO (1 mg/kg, i.p.) for 7 days. Kidney tissues were analyzed for injury markers, and the gene and protein expression of CYP enzymes were measured using real-time PCR and Western blot, respectively. Kidney microsomes were incubated with AA, and the formation rate of the metabolites was analyzed. The level of microsomal epoxide hydrolase (mEH) was evaluated. Our results indicated that ISO-treated female rats exhibited an increase in the kidney injury markers. Gene expression of CYP1A1, CYP4A1, CYP4F1, and CYP2B was significantly elevated in ISO-treated female kidneys. In treated males, CYP4F6 increased markedly while CYP2C11 decreased significantly. The protein levels of CYP4A and CYP2E1 increased in both sexes, while CYP1B1 increased only in male treated rats. The formation rate of 14S(15R) and 5S(6R) epoxyeicosatrienoic acids significantly decreased in treated females, likely due to having higher levels of mEH. Our findings revealed significant sex differences in kidney injury severity and CYP expression, with female rats experiencing more pronounced renal injury. These results highlight the potential relationship between kidney injury progression and CYP enzyme levels and activity, which may have implications for sex-specific therapeutic strategies.

The cytochrome P450 (CYP) 1A subfamily, regulated by the aryl hydrocarbon receptor (AhR), is central to the bioactivation or deactivation of xenobiotics, endogenous substrates, and carcinogens. Music can alter hormonal and neurotransmitter concentrations, which are partly regulated by CYP-dependent pathways. This study investigated whether defined musical elements modulate hepatic CYP1A in male and female Sprague-Dawley rats. Animals were exposed for 24 h to music containing variations of rhythm, tempo, and harmony. Of all conditions tested, fast-tempo, irregular-rhythm, and atonal-harmony (FT-IR-AH) produced the greatest increases in hepatic CYP1A1 (7-ethoxyresorufin O-deethylase) and CYP1A2 (7-methoxyresorufin O-demethylase) activities. In the combined-sex cohort, FT-IR-AH music increased CYP1A1 maximum velocity (Vmax) and intrinsic clearance (CLint) by 3.2- and 3.1-fold, respectively, and increased CYP1A2 Vmax and CLint by 1.9- and 1.8-fold, respectively, without altering enzyme affinities. FT-IR-AH also increased CYP1A1 protein expression by 1.9-fold in females and 2.6-fold in males, and CYP1A2 by 1.6-fold and 1.7-fold, respectively, with concordant elevations in mRNA levels. Replication of the same music elements across different music composers yielded consistent findings, with variations in effects potentially attributed to percentages of gaps (i.e., staccato) and frequency patterns. Selective induction of AhR-regulated genes in the absence of nuclear factor erythroid 2-related factor 2-dependent antioxidant gene activation suggests that FT-IR-AH music selectively engages AhR signaling without a generalized oxidative stress response. These data identify specific music features as an external stimulus capable of modulating CYP1A expression and function, with potential implications for therapeutic responses, toxicological effects, and drug interactions.

Metabolites of arachidonic acid (AA) generated by cytochrome P450 (CYP) enzymes play significant roles in cardiac pathophysiology. Epoxyeicosatrienoic acids (EETs) exert vasodilatory, anti-inflammatory, and cardioprotective effects, but their rapid degradation limits therapeutic use. A metabolically stable analog, EET-A, was developed to mimic native 14,15-EET. The role of EET-A in cardiac hypertrophy and its interaction with CYP pathways remains unclear. This study investigated whether EET-A modulates cardiac hypertrophy, CYP enzyme expression, and AA metabolite formation in an isoproterenol (ISO)-induced model. Male Sprague-Dawley rats were administered ISO (1 mg/kg/day, i.p.) for 7 consecutive days to induce cardiac hypertrophy, with EET-A (10 mg/kg, i.p.) administered in parallel. Cardiac hypertrophy induction was confirmed, and the gene and protein levels of expression of cardiac CYP enzymes were assessed. Hydroxyeicosatetraenoic acids (HETEs) and EETs formation rates were measured using liquid chromatography-mass spectrometric analysis after incubating heart microsomes with AA. Concurrent administration of EET-A with ISO attenuated cardiac hypertrophy, as evidenced by reduced heart weight/body weight, heart weight/tibial length ratio and the gene expression of β-myosin heavy chain compared with ISO alone. ISO significantly increased cardiac hypertrophic markers and altered CYP-mediated AA metabolism, including increased CYP1B1 expression, elevated mid-chain HETEs, and reduced EET formation rates. EET-A partially prevented these changes by suppressing CYP1B1 protein induction, decreasing 11-HETE formation, and restoring 8,9-EET levels. These findings indicate that EET-A attenuates ISO-induced cardiac hypertrophy and partially modulates CYP-dependent AA metabolism, conferring partial protection against β-adrenergic receptor agonist-induced cardiac remodeling.

Menopause is associated with a marked increase in cardiac hypertrophy and progression to heart failure with preserved ejection fraction (HFpEF), a condition that disproportionately affects women and lacks effective targeted therapies. Although estrogen deficiency has long been implicated in postmenopausal cardiac remodeling, emerging evidence highlights a critical role for cytochrome P450 (CYP)-derived arachidonic acid metabolites as central regulators of myocardial structure and function. In a healthy premenopausal heart, a balance between cardioprotective epoxyeicosatrienoic acids (EETs), produced by the CYP2J2 and CYP2C enzymes, and the pro-hypertrophic metabolite 20-hydroxyeicosatetraenoic acid (20-HETE), produced by the CYP4A and CYP4F isoforms, supports adaptive remodeling and diastolic function. Menopause disrupts this equilibrium by estrogen-mediated reprogramming of CYP expression and activity, leading to diminished EET bioavailability, heightened 20-HETE signaling, and accelerated EETs breakdown by soluble epoxide hydrolase (sEH). This metabolic shift induces oxidative stress, calcium imbalance, fibroblast activation, extracellular matrix buildup, and cardiomyocyte enlargement, which together lead to ventricular stiffness and diastolic failure. This review aims to consolidate contemporary experimental and translational evidence linking CYP-derived eicosanoids to menopause-related cardiac hypertrophy and to assess novel non-hormonal therapeutic approaches, including sEH inhibitors, stable EET analogs, and CYP4A/20-HETE inhibitors, that target these molecular pathways. Targeting CYP-derived metabolites represents a promising mechanism-based approach to prevent or reverse postmenopausal cardiac hypertrophy and to modify the natural history of HFpEF. Importantly, these non-hormonal strategies may offer a safer therapeutic alternative to hormone replacement therapy by avoiding the systemic risks associated with exogenous estrogen exposure while directly targeting disease-specific molecular pathways.

Background/Objectives: Oleosomes, plant-derived lipid nanostructures comprising a triacylglycerol core surrounded by a phospholipid monolayer and interfacial proteins, provide sustainable alternatives to synthetic lipid vesicles. This study compares solvent-free aqueous extractions of oleosomes from five nuts (almond, macadamia, walnut, hazelnut, pine) and five seeds (flaxseed, sunflower, hemp, sesame, canola/rapeseed) to understand how botanical origin influences composition and physicochemical behavior. Methods: Oleosomes were isolated using solvent-free aqueous extraction. Extraction yield, lipid content, protein content, particle size, polydispersity, and zeta potential were determined using standard analytical assays and dynamic light scattering techniques. SDS–PAGE was performed to evaluate interfacial protein profiles and oleosin abundance. Results: Extraction yields ranged from 8.4% (flaxseed) to 59.5% (walnut). Oleosome diameters spanned 424 nm to 3.9 µm, and all oleosome dispersions exhibited negative zeta potentials (–26 to –57 mV). SDS–PAGE revealed abundant 15–25 kDa oleosins in seed oleosomes but relatively sparse proteins in nut oleosomes. Seed oleosomes were smaller and exhibited stronger electrostatic stabilization, while nut oleosomes formed larger droplets stabilized primarily through steric interactions due to lower oleosin content. Conclusions: Variation in oleosin abundance and interfacial composition leads to distinct stabilization mechanisms in nut and seed oleosomes. These findings establish a predictive basis for tailoring oleosome size, stability, and functionality, and highlight their potential as natural nanocarriers for food, cosmetic, and pharmaceutical formulations.

Pressure overload induced cardiac hypertrophy is a major contributor to heart failure, and the arachidonic acid (AA) metabolism through cytochrome P450 enzymes is one of the metabolic pathways implicated in the hypertrophic response. The aryl hydrocarbon receptor (AhR) regulates CYP1A1 and CYP1B1 that generate protective 19-hydroxyeicosatetraenoic (HETE) and hypertrophic midchain-HETEs eicosanoids, respectively. The endogenous AhR ligand 6-formylindolo[3,2-b]carbazole (FICZ) is a potent and selective inducer of CYP1A1, but its role in pressure overload induced cardiac hypertrophy has not been examined. This study investigated whether daily AhR activation by FICZ alters AA metabolites and attenuates cardiac hypertrophy in the abdominal aortic constriction (AAC) model. Male Sprague-Dawley rats underwent AAC or sham surgery and received FICZ (0.2 mg/kg per day) for 5 weeks. Echocardiography was performed at baseline and 5 weeks post-AAC, and gene, protein, and midchain-HETEs levels were assessed by real-time polymerase chain reaction, western blot, and liquid chromatography-tandem mass spectrometry, respectively. FICZ significantly reduced AAC-induced increases in left ventricular mass, ventricular wall thickness, heart weight-to-tibial length ratio, and hypertrophic gene expression. FICZ produced selective induction of CYP1A1 and significant rise in cardiac 19(S)-HETE. AAC significantly increased CYP1B1 and 12-LOX protein expressions and midchain-HETEs, whereas FICZ significantly attenuated 12-LOX and midchain-HETE. AAC also upregulated G protein coupled receptor 31, and FICZ reduced this increase at both mRNA and protein levels. This study provides the first evidence that endogenously generated 19(S)-HETE is cardioprotective in a pressure overload model and identifies FICZ as a modulator of the CYP1A1/19(S)-HETE that suppresses midchain-HETEs/G protein coupled receptor 31 pathways. SIGNIFICANT STATEMENT: This study demonstrates that 6-formylindolo[3,2-b]carbazole protect against cardiac hypertrophy induced by abdominal aortic constriction in rats. The significance of this research lies in its novel discovery, which elucidates for the first time the involvement of G protein coupled receptor 31 and the induction of CYP1A1 and 19-hydroxyeicosatetraenoic acid and suppressing midchain-hydroxyeicosatetraenoic acid/G protein coupled receptor 31 pathways by 6-formylindolo[3,2-b]carbazole in the protection against pressure overload cardiac hypertrophy in rats.

Pressure overload induced cardiac hypertrophy is a major contributor to heart failure, and the arachidonic acid (AA) metabolism through cytochrome P450 (CYP) enzymes is one of the metabolic pathways implicated in the hypertrophic response. The aryl hydrocarbon receptor (AhR) regulates CYP1A1 and CYP1B1 that generate protective 19-hydroxyeicosatetraenoic (HETE) and hypertrophic midchain-HETEs eicosanoids, respectively. The endogenous AhR ligand 6-formylindolo[3,2-b]carbazole (FICZ) is a potent and selective inducer of CYP1A1, but its role in pressure overload induced cardiac hypertrophy has not been examined. This study investigated whether daily AhR activation by FICZ alters AA metabolites and attenuates cardiac hypertrophy in the abdominal aortic constriction (AAC) model. Male Sprague-Dawley rats underwent AAC or sham surgery and received FICZ (0.2 mg/kg/day) for five weeks. Echocardiography was performed at baseline and 5 weeks post-AAC, and gene, protein, and midchain-HETEs levels were assessed by real-time PCR, Western blot, and liquid chromatography-tandem mass spectrometry, respectively. FICZ significantly reduced AAC-induced increases in LV mass, ventricular wall thickness, HW/TL ratio and hypertrophic gene expression. FICZ produced selective induction of CYP1A1 and significant rise in cardiac 19(S)-HETE. AAC significantly increased CYP1B1 and 12-LOX protein expressions and midchain-HETEs, whereas FICZ significantly attenuated 12-LOX and midchain-HETE. AAC also upregulated G protein coupled receptor 31 (GPR31), and FICZ reduced this increase at both mRNA and protein levels. This study provides the first evidence that endogenously generated 19(S)-HETE is cardioprotective in a pressure overload model and identify FICZ as a modulator of the CYP1A1/19(S)-HETE that suppresses midchain-HETEs/GPR31 pathways.

Dimethylmonothioarsinic acid (DMMTAV), a potent toxic metabolite of arsenic, exhibits higher cytotoxicity than other arsenicals. This study investigates its influence on NAD(P)H:quinone oxidoreductase (NQO1) regulation in C57BL/6 mice and Hepa-1c1c7 cells. Mice were administered DMMTAV (6 mg/kg, IP) with or without TCDD (15 µg/kg, IP), and hepatic and extrahepatic tissues were analyzed for NQO1 expression. In vitro, Hepa-1c1c7 cells were treated with 0-2 µM DMMTAV in the presence and absence of TCDD (1 nM), and NQO1 levels were assessed over time. Western blot, real-time PCR, and ARE-luciferase assays determined protein and transcriptional regulation. DMMTAV upregulated NQO1 in liver tissues and induced a time-dependent increase in vitro, peaking at 12 h. It enhanced TCDD-induced NQO1 expression and increased nuclear NRF2 and AHR levels, with peak accumulation at two hours. ARE-luciferase activity confirmed transcriptional activation. These findings reveal DMMTAV enhances NQO1 primarily via NRF2/AHR pathway activation, providing insight into cellular responses to thioarsenicals.

Cardiac hypertrophy is a risk factor for heart failure and is usually less common in young women than in men. Cytochrome P450 (CYP) enzymes in the heart metabolize arachidonic acid into hydroxyeicosatetraenoic acids (HETEs), which generally have hypertrophic effects, and epoxyeicosatrienoic acids, which have cardioprotective effects. In this study, we aimed to investigate sex-specific differences in cardiac hypertrophy and cardiac CYP, HETE, and epoxyeicosatrienoic acid levels in response to pressure overload. Adult male and female Sprague-Dawley rats were subject to sham or abdominal aortic constriction (AAC) surgeries. Five weeks postsurgery, cardiac function was assessed by echocardiography. The mRNA and protein levels of hypertrophic markers and CYP enzymes were measured by real-time polymerase chain reaction and Western blot. Heart tissue HETE levels and microsomal formation of HETEs and epoxyeicosatrienoic acids were measured by liquid chromatography-tandem mass spectrometry. Our results show significant sex-specific differences in AAC-induced cardiac hypertrophy. Echocardiography and ventricular wall measurements showed more hypertrophy in male rats. Some hypertrophic markers were significantly upregulated only in male AAC rats and were significantly higher in the hearts of male rats compared to female AAC rats. Different CYP hydroxylases such as CYP1B1, CYP4A, and CYP4F and epoxygenases such as CYP2C and CYP2J10 were significantly upregulated in the hearts of male AAC rats only. The heart level of 12(R)-HETE and the microsomal formation of several HETEs were also significantly increased only in male rats. In conclusion, male rats developed stronger AAC-induced cardiac hypertrophy compared to female rats, which was accompanied by a significant increase in cardiac CYP enzymes and HETEs. SIGNIFICANCE STATEMENT: Previous studies demonstrated that male rats experience more severe cardiac hypertrophy compared to female rats. To our knowledge, this research is the first to investigate and compare the expression of cytochrome P450 enzymes and arachidonic acid metabolites in male and female rat hearts following pressure overload-induced hypertrophy. This study highlights significant sex-specific differences in cytochrome P450-mediated metabolism during hypertrophy, providing valuable insights into the molecular mechanisms underlying these responses and identifying potential targets for sex-specific therapies in cardiac diseases.

We previously showed that male rats develop more severe cardiac hypertrophy than female rats following abdominal aortic constriction (AAC) and highlighted corresponding changes in cardiac cytochrome P450 (CYP) enzymes and their arachidonic acid (AA) metabolites. In this study, we report sex-specific changes in renal CYP enzymes and AA metabolites after AAC. Kidneys were isolated from adult male and female Sprague-Dawley rats 5 weeks after sham or AAC surgeries. Renal CYP, lipoxygenase, and epoxide hydrolase enzyme levels were measured by PCR and Western blot, and renal microsomal formation of hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatrienoic acids (EETs) was measured by liquid chromatography-tandem mass spectrometry. Protein levels of CYP2E1 and CYP4F were significantly elevated post-AAC only in female rats, paralleled by a significant increase in their respective metabolites, 19(R)-HETE and 20-HETE. On the other hand, CYP2C23 mRNA levels were significantly decreased only in male rats, with no significant decrease in EETs. Our findings indicate that renal CYP-mediated AA metabolism undergoes sex-specific reprogramming in response to cardiac pressure overload, which may contribute to the observed divergent cardiac remodeling. This research highlights the importance of the kidney-heart axis and supports the potential for sex-specific metabolic targets in the treatment of cardiovascular diseases.

Distinct differences between sexes exist in various cardiovascular diseases. Moreover, there is a significant correlation between the pathogenesis of cardiac hypertrophy (CH) and the metabolites of arachidonic acid (AA) mediated by cytochrome P450 (CYP) enzymes. The potential link between these sex differences, the levels and the activity of CYP enzymes, and their AA-mediated metabolites remains to be elucidated. Male and female Sprague Dawley rats were injected with 1 mg/kg isoproterenol for 7 days to induce CH. Echocardiography was performed before and after the induction of CH. The hypertrophic markers and CYP enzyme levels were analyzed at the gene and protein levels using real-time polymerase chain reaction and Western blot, respectively. Heart microsomal proteins were incubated with AA, and the resulting metabolites were quantified using liquid chromatography-tandem mass spectrometry. Both sexes showed a significant degree of CH, albeit to varying extents, as the echocardiograph, heart weight/tibial length, and left ventricular parameters proved. In addition, the β/α-myosin heavy chain was 2-fold higher in male compared with female rats. Albeit the 20-hydroxyeicosatetraenoic acid (20-HETE) metabolite formation showed no increase in both sexes, the mid-chain HETEs (5- and 15-HETE) were higher in male rats, which paralleled the increase in the gene and protein levels of CYP1B1. The formation rate of the epoxyeicosatrienoic acids was almost unchanged in female-treated rats, while it was significantly decreased in male-treated rats. Our results suggest sexual dimorphism in the isoproterenol-induced CH in rats, specifically on the level of CYP enzymes and their AA-mediated metabolites. SIGNIFICANCE STATEMENT: Sexual dimorphism was observed in rats following isoproterenol-induced cardiac hypertrophy, with males showing a stronger hypertrophic response. This was linked to higher CYP1B1 gene and protein expression in males, along with sex-related differences in many cytochrome P450 enzyme activities and their mediated arachidonic acid metabolites. These findings emphasized the need for targeted, sex-specific therapeutic strategies for the management and treatment of cardiac hypertrophy and other cardiovascular disorders.

Arsenic, a widespread environmental contaminant, threatens millions globally through contaminated water, soil, and food. While arsenic compounds are used to treat acute promyelocytic leukemia, their toxic legacy includes cancers, cardiovascular disease, diabetes, and neurodegeneration, primarily driven by oxidative stress, mitochondrial dysfunction, and epigenetic instability. Sirtuins, a family of NAD⁺-dependent enzymes, are central to cellular defense, orchestrating metabolism, stress resistance, DNA repair, and longevity. Arsenic disrupts sirtuin function, particularly SIRT1, SIRT2, and SIRT3, via microRNA-mediated silencing and post-translational modifications, impairing antioxidant defenses, disturbing energy metabolism, and accelerating cellular injury across organ systems. However, activating sirtuins with agents like resveratrol, metformin, or berberine, as well as through lifestyle interventions, can counteract arsenic toxicity, restore cellular resilience, and provide new therapeutic strategies. This review synthesizes current knowledge on the interplay between arsenic exposure and sirtuin biology, examining how arsenic alters sirtuin expression and activity, the downstream consequences for cellular signaling and organ health, and emerging interventions targeting sirtuin pathways. By bridging molecular insights with translational potential, we highlight the promise of sirtuins as therapeutic targets in combating arsenic toxicity and guide future research directions.

Arachidonic acid (AA) is a polyunsaturated essential fatty acid and a precursor for eicosanoids. It is metabolized by cyclooxygenases, lipoxygenases, and cytochrome P450 (P450) enzymes, which convert AA into hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatrienoic acids (EETs), chiral eicosanoids with distinct biological activities. Although racemic HETEs and EETs have been studied in cardiovascular diseases, the enantiospecific roles of their enantiomers and the enantioselectivity of P450 enzymes remain largely unexplored. This study aimed to investigate the enantioselective metabolism of AA by human recombinant P450 enzymes, focusing on the formation of R/S-HETEs and (R, S)/(S,R)-EETs. Metabolites were analyzed using liquid chromatography electrospray ionization mass spectrometry. CYP1A2 exhibited the highest activity in forming R-midchain HETEs, followed by CYP3A4. CYP2C19 was the most active enzyme in producing R-subterminal HETEs, with CYP1A2 and CYP1A1, CYP4F3B, and CYP2E1 ranking second. Similarly, CYP2C19 showed the highest activity in generating S-midchain and S-subterminal HETEs, with CYP3A4, CYP2C8, CYP1A1, and CYP1A2 contributing to varying degrees. For EETs, CYP2C19 and CYP1A2 primarily catalyzed the formation of both (R, S)/(S, R)-EETs. These findings emphasize the significant roles of CYP2C19 and CYP1A2 in the regio- and stereoselective metabolism of HETEs and EETs, highlighting their contributions to lipid signaling and potential physiological implications. SIGNIFICANT STATEMENT: This work highlights the importance of profiling P450 with respect to their enantioselectivity in arachidonic acid metabolism. The findings indicate that major P450 differ in the magnitude of their hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acid formation rates, which is a significant for studying diseases that is known to be influenced by alterations in these pathways. Altered enantioselectivity could have implications in diseases such as hypertension, cancer, inflammation, and cardiovascular disorders.

The success of arsenic trioxide (ATO) in acute promyelocytic leukemia has driven a plethora studies to investigate its efficacy in other malignancies. However, the inherent toxicity of ATO limits the expansion of its clinical applications. Such toxicity may be linked to ATO-induced metabolic derangements of endogenous substrates. Therefore, the primary objective of this study was to investigate the effect of ATO on the hepatic formation of arachidonic acid (AA) metabolites, hydroxyeicosatetraenoic acids (HETEs), as well as their most notable producing machinery, cytochrome P450 (CYP) enzymes. For this purpose, C57BL/6 mice were intraperitoneally injected with 8 mg/kg ATO for 6 and 24 h. Total RNA was extracted from harvested liver tissues for qPCR analysis of target genes. Hepatic microsomal proteins underwent incubation with AA, followed by identification/quantification of the produced HETEs. ATO downregulated Cyp2e1, while induced Cyp2j9 and most of Cyp4a and Cyp4f, and this has resulted in a significant increase in 17(S)-HETE and 18(R)-HETE, while significantly decreased 18(S)-HETE. Additionally, ATO induced Cyp4a10, Cyp4a14, Cyp4f13, Cyp4f16, and Cyp4f18, resulting in a significant elevation in 20-HETE formation. In conclusion, ATO altered hepatic AA metabolites formation through modulating the underlying network of CYP enzymes. Modifying the homeostatic production of bioactive AA metabolites, such as HETEs, may entail toxic events that can, at least partly, explain ATO-induced hepatotoxicity. Such modification can also compromise the overall body tolerability to ATO treatment in cancer patients.