Cytochrome P450 Profile Research Articles

Garcinia mangostana and α-Mangostin Revive Ulcerative Colitis-Modified Hepatic Cytochrome P450 Profiles in Mice.

<b>Background and Objective:</b> Ulcerative colitis (UC) is inflammation of the large intestine with ulceration but can also cause extraintestinal manifestations (EIM) by damaging surrounding organs such as the liver. <i>Garcinia mangostana</i> (GM) pericarp and α-mangostin (MGS) have been reported to have anti-inflammatory activity. This study evaluated the effects of GM pericarp extract and MGS on the expression of hepatic cytochrome P450 (CYP) enzymes as an EIM of UC. <b>Materials and Methods:</b> Male ICR mice were orally administered GM pericarp extract (40, 200 and 1000 mg/kg/day), MGS (30 mg/kg/day) or sulfasalazine (SUL) (100 mg/kg/day) daily for 7 days. On days 4-7, UC was induced by dextran sulfate sodium (DSS 40 kDa, 6 g/kg/day). Profiles of CYP mRNA expression were determined by RT/qPCR. Alkoxyresorufin <i>O</i>-dealkylation (including ethoxy-, methoxy-, pentoxy- and benzyloxy-resorufin), aniline hydroxylation and erythromycin <i>N</i>-demethylation CYP responsive activities were also examined. <b>Results:</b> The DSS-induced UC mice showed suppressed expression<i> </i>of <i>Cyp1a1</i>, <i>Cyp1a2</i>, <i>Cyp2b9/10</i>, <i>Cyp2e1</i>, <i>Cyp2c29</i>, <i>Cyp2d9</i>, <i>Cyp3a11</i> and <i>Cyp3a13</i> mRNAs. The GM pericarp extract and MGS restored expression of all investigated CYPs and their responsive enzyme activities in DSS-induced UC mice to levels comparable to the control and parallel to the effects of the anti-inflammatory control SUL. <b>Conclusion:</b> The GM is a promising therapy to restore UC-modified hepatic CYP profiles.

Alteration of murine cytochrome P450 profiles in fatty liver disease by hesperidin and myricetin

Background: Hesperidin and myricetin are anti-inflammatory and anti-oxidant flavonoids that have beneficial effects in fatty liver disease (FLD), but information regarding their effects on cytochrome P450 (CYP450) enzymes in FLD is limited. Objectives: This study determined the impacts of hesperidin and myricetin on CYP450 profiles in FLD mice. Materials and Methods: Adult female mice were fed a high fat diet (HFD, 60 kcal % fat of total food) with daily intragastrically administered ethanol (0.5 g/kg/day) in combination with either fenofibrate (40 mg/kg/day), hesperidin (50 and 200 mg/kg/day), or myricetin (50 and 200 mg/kg/day) for 60 consecutive days. Liver histomorphology was examined by oil red O staining. Hepatic enzyme activity and mRNA expression of CYP1A2, CYP2E1, CYP3A11, CYP3A13, and CYP4A11 were assessed. Results: HFD-induced hepatocellular damage was prevented by low dose hesperidin and myricetin. Expression of Cyp1a2, Cyp2e1, and Cyp4a11 mRNAs as well as CYP2E1 and CYP3A activities was significantly induced by HFD plus ethanol (HE) while Cyp3a13 expression was slightly increased. Fenofibrate and low dose hesperidin prevented HE-induced Cyp1a2 and Cyp2e1 expression while HE-induced Cyp4a11 expression was prevented by all treatments. The expression of Cyp3a13 was extensively suppressed by high-dose hesperidin and myricetin, and CYP2E1 and CYP3A activities were significantly decreased by all treatments. Conclusion: Alteration of CYP450 profiles by high doses of hesperidin and myricetin could lead to drug interactions. Nevertheless, low dose hesperidin prevented dysregulation of CYP450 expression in FLD and is a promising candidate for FLD treatment.

1,2,4]Triazolo[1,5-a]pyrimidine Phosphodiesterase 2A Inhibitors: Structure and Free-Energy Perturbation-Guided Exploration.

We describe the hit-to-lead exploration of a [1,2,4]triazolo[1,5-a]pyrimidine phosphodiesterase 2A (PDE2A) inhibitor arising from high-throughput screening. X-ray crystallography enabled structure-guided design, leading to the identification of preferred substructural components. Further rounds of optimization used relative binding free-energy calculations to prioritize different substituents from the large accessible chemical space. The free-energy perturbation (FEP) calculations were performed for 265 putative PDE2A inhibitors, and 100 compounds were synthesized representing a relatively large prospective application providing unexpectedly active molecules with IC50's from 2340 to 0.89 nM. Lead compound 46 originating from the FEP calculations showed PDE2A inhibition IC50 of 1.3 ± 0.39 nM, ∼100-fold selectivity versus other PDE enzymes, clean cytochrome P450 profile, in vivo target occupancy, and promise for further lead optimization.

Schisandrin B and Schisandrol B induce mouse CYP2b10 associated with CAR not PXR

Schisandrin B (SinB) and Schisandrol B (SolB) are two abundant compounds with similar structures in Schisandra sphenanthera widely used for hepatic diseases in Asian countries. They are also pharmacologically active components in many other traditional Chinese medicines. However, induction features of cytochrome P450 (CYP) by SinB and SolB were not well established. The present study aimed to investigate the CYP profile induced by SinB and SolB, and the role of nuclear factors pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Wild-type (WT) and Pxr-null (KO) mice were administered SinB and SolB respectively for 5 days. CYP induction analysis was carried out and underlying mechanism was explored. CYP2b was sharply induced by SinB and SolB in WT and KO mice. CYP3a was moderately induced in WT mice, but not in KO mice. No significant induction of CYP2c or UDP glucuronosyltransferases was observed. Edema related with slight hepatomegaly was found in both WT and KO mice, which was found reversible and non-inflammatory. These data suggest SinB and SolB induced CYP3a moderately in a PXR-dependent way. In contrast, they both sharply induced CYP2b, which was supposed to be associated with nuclear factor CAR not PXR. Non-inflammatory and reversible edema contributed to hepatomegaly induced by SinB and SolB. The complicated CYP induction of SinB and SolB might cause drug-drug interactions in the clinic.

Continuous Consumption of Reused Palm Oil Induced Hepatic Injury, Depletion of Glutathione Stores, and Modulation of Cytochrome P450 Profiles in Mice

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Altered cytochrome P450 profiles by Plumbago indica Linn. and plumbagin after oral administration in mice

Background: Plumbago indica Linn. and its active constituent, plumbagin, are conventionally used in Thai alternative medicines, but information regarding their effects on cytochrome P450 (CYP450) enzymes is limited. Objective: To establish the effects of P. indica Linn. and plumbagin on CYP450 profiles. Materials and Methods: Adult male mice were orally administered P. indica extract (20, 200, and 1000 mg/kg/day) or plumbagin (1, 5, and 15 mg/kg/day) for 14 days. The levels of hepatic CYP450 mRNA and protein were assessed using reverse transcription/real-time polymerase chain reaction and immunoblotting, respectively, and specific enzyme reactions were performed to determine the enzyme activities. Results: Expression of Cyp1a2 was induced by both P. indica and plumbagin, while P. indica, but not plumbagin, slightly suppressed Cyp2c29 expression. Expression of Cyp2d9 was suppressed by both P. indica and plumbagin. Expression of Cyp2e1 was unchanged, but P. indica at the lowest dose increased Cyp2e1 activity. P. indica and plumbagin dose-dependently suppressed the expression of Cyp3a11/13 and its activity. Conclusions: Modulation of CYP450 profiles by P. indica and plumbagin is a concern as there are risks of drug–herb interaction. Abbreviations used: CYP450: Cytochrome P450; BSA: Bovine serum albumin; GAPDH; Glyceraldehyde 3-phosphate dehydrogenase.

Metabolism and Disposition of Hepatitis C Polymerase Inhibitor Dasabuvir in Humans.

Dasabuvir [also known as ABT-333 or N-(6-(3-(tert-butyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide] is a potent non-nucleoside NS protein 5B polymerase inhibitor of the hepatitis C virus (HCV) and is being developed in combination with paritaprevir/ritonavir and ombitasvir in an oral regimen with three direct-acting antivirals for the treatment of patients infected with HCV genotype 1. This article describes the mass balance, metabolism, and disposition of dasabuvir in humans. After administration of a single oral dose of 400-mg [(14)C]dasabuvir (without coadministration of paritaprevir/ritonavir and ombitasvir) to four healthy male volunteers, the mean total percentage of the administered radioactive dose recovered was 96.6%. The recovery from the individual subjects ranged from 90.8% to 103%. Dasabuvir and corresponding metabolites were predominantly eliminated in feces (94.4% of the dose) and minimally through renal excretion (2.2% of the dose). The biotransformation of dasabuvir primarily involves hydroxylation of the tert-butyl group to form active metabolite M1 [N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide], followed by glucuronidation and sulfation of M1 and subsequent secondary oxidation. Dasabuvir was the major circulating component (58% of total radioactivity) in plasma, followed by metabolite M1 (21%). Other minor metabolites represented < 10% each of total circulating radioactivity. Dasabuvir was cleared mainly through cytochrome P450-mediated oxidation metabolism to M1. M1 and its glucuronide and sulfate conjugates were primarily eliminated in feces. Subsequent oxidation of M1 to the tert-butyl acid, followed by formation of the corresponding glucuronide conjugate, plays a secondary role in elimination. Cytochrome P450 profiling indicated that dasabuvir was mainly metabolized by CYP2C8, followed by CYP3A4. In summary, the biotransformation pathway and clearance routes of dasabuvir were characterized, and the structures of metabolites in circulation and excreta were elucidated.

The discovery of novel 5,6,5- and 5,5,6-tricyclic pyrrolidines as potent and selective DPP-4 inhibitors

Novel potent and selective 5,6,5- and 5,5,6-tricyclic pyrrolidine dipeptidyl peptidase IV (DPP-4) inhibitors were identified. Structure–activity relationship (SAR) efforts focused on improving the intrinsic DPP-4 inhibition potency, increasing protease selectivity, and demonstrating clean ion channel and cytochrome P450 profiles while trying to achieve a pharmacokinetic profile suitable for once weekly dosing in humans.

Effect of tetrahydrocurcumin on the profiles of drug-metabolizing enzymes induced by a high fat and high fructose diet in mice

Cytochrome P450 (CYP), a superfamily of hepatic monooxygenase enzymes, catalyzes biotransformation of endogenous compounds and xenobiotics. Modification of CYPs associated with metabolic diseases and continuous consumption of diet with excessive energy levels.Tetrahydrocurcumin (THC) exhibited beneficial effects in metabolic syndromes such as diabetic mellitus and dyslipidemia. The present study aimed to investigate the effects of THC and vitamin E (vitE) on the expression profiles of CYPs in the livers of mice fed with the high fat and high fructose diet. In addition to ad libitum access to commercial regular diet, the high fat and high fructose diet (HFD) group of adult male ICR mice was administered a HFD, which consisted of intragastric administration of hydrogenated soybean oil (1mL/day) and the addition of 20% fructose to the drinking water for 8weeks. During the induction period, subgroups of mice (n=5) were daily intragastrically administered with THC (100 or 200mg/kg/day) or vitE (100mg/kg/day). The expressions of CYP mRNA and protein were quantified using real-time PCR and the levels of these proteins were quantified using immunoblotting. Continuous consuming of high fat and high fructose for 8weeks significantly increased the expressions of Cyp1a1, Cyp1a2, Cyp1b1, Cyp2c29, and Cyp3a11 while THC ultimately normalized these CYPs profiles. In the control mice, most of the investigated CYPs was unchanged by THC, with the exception that the Cyp1a1, Cyp2b9, and Cyp3a11 proteins were elevated. These findings provided additional important information on the effects of THC on diet induced-metabolic dysfunctions. However, drug interactions due to the use of THC as an alternative supplement are of concern, particularly in the combinations that include a drug that is a substrate of Cyp1a1, Cyp2b9, and Cyp3a11.

Precursors for cytochrome P450 profiling breath tests from an in silico screening approach

The family of cytochrome P450 enzymes (CYPs) is a major player in the metabolism of drugs and xenobiotics. Genetic polymorphisms and transcriptional regulation give a complex patient-individual CYP activity profile for each human being. Therefore, personalized medicine demands easy and non-invasive measurement of the CYP phenotype. Breath tests detect volatile organic compounds (VOCs) in the patients’ exhaled air after administration of a precursor molecule. CYP breath tests established for individual CYP isoforms are based on the detection of 13CO2 or 14CO2 originating from CYP-catalyzed oxidative degradation reactions of isotopically labeled precursors.We present an in silico work-flow aiming at the identification of novel precursor molecules, likely to result in VOCs other than CO2 upon oxidative degradation as we aim at label-free precursor molecules. The ligand-based work-flow comprises five parts: (1) CYP profiling was encoded as a decision tree based on 2D molecular descriptors derived from established models in the literature and validated against publicly available data extracted from the DrugBank. (2) Likely sites of metabolism were identified by reactivity and accessibility estimation for abstractable hydrogen radical. (3) Oxidative degradation reactions (O- and N-dealkylations) were found to be most promising in the release of VOCs. Thus, the CYP-catalyzed oxidative degradation reaction was encoded as SMIRKS (a programming language style to implement reactions based on the SMARTS description) to enumerate possible reaction products. (4) A quantitative structure property relation (QSPR) model aiming to predict the Henry constant H was derived from data for 488 organic compounds and identifies potentially VOCs amongst CYP reaction products. (5) A blacklist of naturally occurring breath components was implemented to identify marker molecules allowing straightforward detection within the exhaled air.Evident oxidative degradation reactions served as test case for the screening approach. Comparisons to metabolism data from literature support the results’ plausibility. Thus, a large scale screening for potential novel breath test precursor using the presented five stage work-flow is promising.

Expression Pattern of Entire Cytochrome P450 Genes and Response of Defensomes in the Benzo[a]pyrene-Exposed Monogonont Rotifer Brachionus koreanus

Cytochrome P450 (CYP) proteins are involved in the first line of detoxification mechanism against diverse polycyclic aromatic hydrocarbons (PAHs) including benzo[a]pyrene (B[a]P). In aquatic invertebrates, there is still a lack of knowledge on the CYP genes involved in the molecular response to B[a]P exposure due to limited gene information. In this study, we cloned the entire 25 CYP genes in the monogonont rotifer Brachionus koreanus with the aid of next generation sequencing (NGS) technologies and analyzed their transcript profiles with a real-time RT-PCR array to better understand B[a]P-triggered molecular response over different time courses. As a result, B[a]P exposure induced CYP2/3-involved detoxification mechanisms and defensome, including phase II detoxification and antioxidant systems with a modulation of the chaperone heat shock protein (hsp) expression but did not change expression of other CYP clans in B. koreanus . Therefore, we found that B[a]P induced a strong detoxification mechanism to overcome detrimental effects of B[a]P associated with B[a]P-induced growth retardation as a trade-off in fitness costs. Also, this approach revealed that the entire CYP profiling can be a way of providing a better understanding on the mode of action of B[a]P in B. koreanus with respect to molecular defense metabolism.

Genetics, Epigenetics, and Regulation of Drug-Metabolizing Cytochrome P450 Enzymes

Of 57 functional human cytochrome P450 (CYP) isoforms, about a dozen liver-expressed, highly variable forms are responsible for the biotransformation of most drugs. Owing to numerous genetic and nongenetic sources of variation, each individual possesses his/her own, rather unique, CYP profile. Here, we explore the potential of new technologies and developments in genetics, epigenetics, and the regulation of gene expression to increase our understanding of the mechanisms that lead to the enormous inter- and intraindividual variability of these enzymes.

Whole Spectrum of Cytochrome P450 Genes and Molecular Responses to Water-Accommodated Fractions Exposure in the Marine Medaka

Water-accommodated fractions (WAFs) of crude oil include chemicals that are potent toxicants in fish. Increasing oil pollution thus demands a better understanding of molecular mechanisms for detoxification, metabolism, toxicity, and adaptation of fish. Previous studies with fish show modulation of expression of key genes in relation to stress response against WAF exposure, but there is still a lack of studies on responses of cytochrome P450 (CYP) genes and changes in biotransformation upon WAF exposure. In this study, we used the full spectrum of CYP genes of the marine medaka, Oryzias melastigma, to understand their potential mode of action on WAFs-triggered molecular mechanisms. We also analyzed further CYP-involved detoxification and endogenous steroidogenic metabolism after exposure to different concentrations of WAFs over different time courses in the marine medaka. Also, detoxification- and antioxidant-related enzymes' activities were analyzed with different concentrations of WAFs. As a result, the WAF exposure induced CYP-involved detoxification mechanism but reduced CYP-involved steroidogenic metabolism in the marine medaka. These data suggest that whole CYP profiling can be a way of understanding and uncovering the mode of action particularly with respect to emerging chemicals such as WAF exposure with the new finding that WAFs have dual functions on CYP-involved metabolisms.

Prediction of Cytochrome P450 Profiles of Environmental Chemicals with QSAR Models Built from Drug-like Molecules.

The human cytochrome P450 (CYP) enzyme family is involved in the biotransformation of many xenobiotics. As part of the U.S. Tox21 Phase I effort, we profiled the CYP activity of approximately three thousand compounds, primarily those of environmental concern, against human CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4 isoforms in a quantitative high throughput screening (qHTS) format. In order to evaluate the extent to which computational models built from a drug-like library screened in these five CYP assays under the same conditions can accurately predict the outcome of an environmental compound library, five support vector machines (SVM) models built from over 17,000 drug-like compounds were challenged to predict the CYP activities of the Tox21 compound collection. Although a large fraction of the test compounds fall outside of the applicability domain (AD) of the models, as measured by k-nearest neighbor (k-NN) similarities, the predictions were largely accurate for CYP1A2, CYP2C9, and CYP3A4 ioszymes with area under the receiver operator characteristic curves (AUC-ROC) ranging between 0.82 and 0.84. The lower predictive power of the CYP2C19 model (AUC-ROC = 0.76) is caused by experimental errors and that of the CYP2D6 model (AUC-ROC = 0.76) can be rescued by rebalancing the training data. Our results demonstrate that decomposing molecules into atom types enhanced the coverage of the AD and that computational models built from drug-like molecules can be used to predict the ability of non-drug like compounds to interact with these CYPs.

Automated Luminescence-Based Cytochrome P450 Profiling Using a Simple, Elegant Robotic Platform

The determination of inhibitory effects that lead compounds have on cytochrome P450 (CYP) enzymes is an important part of today's drug discovery process. Assays can be performed early in the discovery process to predict adverse drug-drug interactions caused by CYP inhibition and to minimize the costs associated with terminating candidates in late stage development or worse, removing a drug from the market after launch. For early discovery work, testing substantial numbers of compounds is desirable, thus automated "mix and read" assays are beneficial. Here, we demonstrate the automation of the CYP profiling process using a simple, yet robust robotic platform. Compound titration, as well as transfer of compounds and assay components was performed by the same automated pipetting system. IC(50)s of small molecule drugs were determined using recombinant CYP enzymes, CYP3A4, -2C9, and -2D6 and luminogenic substrates specific to each. Compounds were profiled against all three enzymes on the same 384-well assay plate.

Multi-parametric analysis of cytochrome P450 expression in rat liver microsomes by LA-ICP-MS

Quantitative analysis of cytochrome P450 (CYP) patterns of cells and tissues is an important aspect in toxicological and pharmacological research as this group of enzymes is largely involved in the metabolism of toxic compounds and drugs. Here we present a method for the multi-parametric and simultaneous quantitative determination of several cytochromes P450 in liver microsomes of untreated and inducer treated rats. The method is based on the binding of specifically lanthanide labelled antibodies to electrophoretically separated and blotted CYP proteins and their subsequent identification and quantification by LA-ICP-MS. CYP1A1, CYP2B1, CYP2C11, CYP2E1 and CYP3A1 were simultaneously quantified and the patterns between microsomal samples were compared. Microsomes of rats treated with 3-methylcholanthrene, phenobarbital and dexamethasone showed increased levels of CYP1A1, CYP2B1 and CYP3A1, respectively. These results coincide with data obtained by independent methods for CYP quantification, i.e.ethoxyresorufinO-deethylase activity for CYP1A1 and pentoxyresorufinO-depentylase for CYP2B1. The presented method is useful for multi-parametric CYP profiling and has further large potential with respect to the number of analysed parameters/proteins and sensitivity.

Relationship between drug-induced interstitial lung diseases and cytochrome P450 polymorphisms

Interstitial lung disease and especially drug-induced interstitial lung disease can occur as a cause of drug(s) or drug-drug interactions. In this review we summarize the possible role of cytochrome P450 (CYP) enzymes in drug-induced interstitial lung disease. The CYP enzyme family plays an important role in the metabolism of all sorts of ingested, injected or inhaled xenobiotic substances. Although the liver is considered to be the major metabolism site of CYP enzymes, in recent years more CYP isoforms have been detected in lung tissue. Polymorphisms in these CYP genes can influence the metabolic activity of the subsequent enzymes, which in turn may lead to localized (toxic) reactions and tissue damage. Drug toxicity can be the consequence of no or very poor enzyme activity, especially if no other metabolic route is available. In the case of reduced enzyme activity, dose reduction or prescribing an alternative drug metabolized by a different, unaffected CYP enzyme is recommended to prevent toxic side effects. Therefore, knowing a patient's CYP profile before drug prescription could be a way to prevent drug-induced interstitial lung disease. Moreover, it might be helpful in explaining serious adverse effects from inhaled, injected or ingested xenobiotic substances.

Identification and characterization of small-molecule inhibitors of Tie2 kinase

Angiopoietins and Tie2 receptor were recently identified as an endothelial cell-specific ligand-receptor system that is critical for vascular development and postnatal pathologic angiogenesis by mediating vascular integrity. In this study, we identified a series of small-molecule Tie2 inhibitors, which blocked Ang1-induced Tie2 autophosphorylation and downstream signaling with an IC 50 value at 0.3 μM. Further optimization yields improved selectivity, aqueous solubility, microsomal stability and cytochrome P450 profile for one of the compounds (compound 7). Both compound 1 and compound 7 inhibit endothelial cell tube formation. Furthermore, in a rat model of Matrigel-induced choroidal neovascularization, compound 7 significantly diminished aberrant vessel growth. Our findings demonstrate a potential clinical benefit by specifically targeting Tie2-mediated angiogenic disorders.

Evidence-based prevention (EBP): A review of cytochrome P450 expression in the bronchial epithelium and new approach to lung cancer prevention

The number of fatalities in Japan attributable to lung cancer exceeded 50000 in 2001. It is socially desirable that various markers, which can be utilized for the prevention of lung cancer, be established. We believe that smoking or exposure to carcinogens in air induces mutations in bronchial and alveolar epithelia, leading to the development of lung cancer. It would be useful to have markers of individual differences in susceptibility to chemical carcinogen-induced lung cancer 1) to identify genetic polymorphisms of enzymes metabolizing chemical carcinogens and 2) to investigate the expression of enzymes metabolizing chemical carcinogens. In this paper, we review CYP expression in the bronchial epithelium. CYP1, CYP2 and CYP3 are expressed in the bronchial epithelium. We also show the relationship between the genetic polymorphisms of cytochrome P450 (CYP) and a person's susceptibility to chemical carcinogen-induced lung cancer. We demonstrate the relationship between cigarette consumption and the CYP expression profile in the bronchial epithelium. To maintain and promote public health, we must apply evidence, such as CYP polymorphisms and CYP profiles to disease prevention and also to aggressively advance evidence-based prevention (EBP) of lung cancer.

Profiling Cytochrome P450 Expression in Ovarian Cancer: Identification of Prognostic Markers

The cytochromes P450 are a multigene family of enzymes with a central role in the oxidative metabolism of a wide range of xenobiotics, including anticancer drugs and biologically active endogenous compounds. The purpose of this study was to define the cytochrome P450 profile of ovarian cancer and identify novel therapeutic targets and establish the prognostic significance of expression of individual cytochrome P450s in this type of cancer. Immunohistochemistry for a panel of 23 cytochrome P450s and cytochrome P450 reductase was done on an ovarian cancer tissue microarray consisting of 99 primary epithelial ovarian cancers, 22 peritoneal metastasis, and 13 normal ovarian samples. The intensity of immunoreactivity in each sample was established by light microscopy. In primary ovarian cancer, several P450s (CYP1B1, CYP2A/2B, CYP2F1, CYP2R1, CYP2U1, CYP3A5, CYP3A7, CYP3A43, CYP4Z1, CYP26A1, and CYP51) were present at a significantly higher level of intensity compared with normal ovary. P450 expression was also detected in ovarian cancer metastasis and CYP2S1 and P450 reductase both showed significantly increased expression in metastasis compared with primary ovarian cancer. The presence of low/negative CYP2A/2B (log rank = 7.06, P = 0.008) or positive CYP4Z1 (log rank = 6.19, P = 0.01) immunoreactivity in primary ovarian cancer were each associated with poor prognosis. Both CYP2A/2B and CYP4Z1 were also independent markers of prognosis. The expression profile of individual P450s has been established in ovarian cancer. Several P450s show increased expression in ovarian cancer and this provides the basis for developing P450-based therapeutics in ovarian cancer. Expression of CYP2A/2B or CYP4Z1 in primary ovarian cancer were independent markers of prognosis.