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Marjorie Romkes

Publications and source records attributed to Marjorie Romkes.

At least 19 recordsLinked to original sources
PubMed2007

Association of the EGFR intron 1 CA repeat length with lung cancer risk.

Epidermal growth factor receptor (EGFR) plays an important role in the development and progression of lung cancer. A previous report noted that an increased number of polymorphic CA repeats in the first intron of the EGFR gene results in decreased transcriptional activity. To estimate the association of the length of polymorphic CA repeats in intron 1 of the EGFR gene with lung cancer, a case-control study of 176 lung cancer patients and 161 controls was conducted in Caucasians. This case-control study is based on two existing prospective cohorts: the Early Detection Research Network (EDRN) and the Lung Cancer Specialized Program of Research Excellence (SPORE) at the University of Pittsburgh. The frequencies of the SL (one allele>16 repeats), and SS (both allele 36) was 20.5% versus 36.7%, for lung cancer cases versus controls. The lower sum of EGFR-CA repeats associated with the risk of lung cancer; the estimated odds ratio was 2.25 with 95% confidence interval: 1.38-3.66 (P=0.001). Associations involving EGFR-CA repeat genotype and EGFR-CA repeat sum remained significant when adjusted for age, gender, and tobacco exposure. Our study, which is preliminary, demonstrates for the first time that shorter EGFR-CA repeats associate with lung cancer risk. The number of EGFR-CA repeats identifies a possible susceptible population to lung cancer.

Adult↗
PubMed2006

CYP2D6 genotype and venlafaxine-XR concentrations in depressed elderly.

INTRODUCTION: The elderly are at increased risk for medication-related adverse events. Recent reports indicate that venlafaxine may put the elderly at increased risk of cardio- and cerebrovascular adverse events. We investigated the relationship between the CYP2D6 polymorphism and steady-state plasma concentration of venlafaxine (VEN) and its primary metabolite o-desmethylvenlafaxine (ODV) in elderly participants receiving venlafaxine-XR for major depression in order to explore the contribution of pharmacogenetics to medication tolerability. METHODS: Forty-six elderly participants received venlafaxine-XR for the treatment of major depression. CYP2D6 genotype and steady-state plasma levels of VEN and ODV were determined. RESULTS: Sixty-five percent of participants were homozygous of the wild type (WT) allele, whereas 35% carried one or more variant alleles associated with intermediate and poor 2D6 metabolizer status. VEN concentration per unit dose was significantly higher and ODV concentration per unit dose was significantly lower in participants who carried one or more variant alleles compared to participants who were homozygous for the WT allele. The VEN and ODV concentrations per unit dose were also correlated with creatinine clearance. CYP2D6 genotype was not associated with medication associated side-effects. CONCLUSIONS: Plasma dose-corrected concentrations of VEN and ODV correlated with genetically determined CYP2D6 enzymatic activity in depressed elders treated with venlafaxine-XR. This relationship was not masked by the effects of age-related illness or polypharmacy. Future clinical application of pharmacogenetics to examine 2D6-dependent medications may help reduce the incidence of medication adverse events particularly in those elders at higher risk for medication adverse events due to impaired renal or cardiac function.

Aged↗
PubMed2006

Polymorphisms in DNA repair genes XPD and XRCC1 and p53 mutations in lung carcinomas of never-smokers.

The etiology of lung cancer in population with little or no tobacco exposure is not well understood. Individual genetic susceptibility factors have been suggested to contribute to lung cancer risk in this population. Mutations in the p53 tumor suppressor gene are implicated in the development of lung cancer as they are frequently found in lung tumors from both smokers and never-smokers. In order to determine whether genetic polymorphisms affecting DNA repair capacity modulate p53 mutations in lung tumors from never-smokers, we compared p53 mutations with genotypes of XPD 312, XPD 751, and XRCC1 399 in lung tumors from 43 lifetime never-smokers. p53 mutations were identified in 10 (23%) cases and consisted mostly of G/C to A/T transitions. No statistically significant association was found between p53 mutations and genotypes of XPD 312 or XPD 751. However, patients with the XRCC1 399 Gln allele, that results in a lower base excision repair capacity, were more likely to have p53 mutations, compared with patients the wild-type Arg allele (P = 0.03). In addition, the p53 mutation frequency increased with an increasing number of combined genotypes associated with a lower DNA repair capacity of XPD 312, XPD 751, and XRCC1 399 (P = 0.02). These results suggest that individuals who never smoked and had XRCC1 399 Gln allele may be at a greater risk of p53 mutations, especially if combined with the genotypes of XPD 312 and XPD 751 that may result in a lower DNA repair capacity.

Alleles↗
PubMed2006

Validation of incorporating flurbiprofen into the Pittsburgh cocktail.

BACKGROUND: We have previously shown that flurbiprofen metabolism to 4'-hydroxyflurbiprofen provides an in vivo measure of cytochrome P450 (CYP) 2C9 activity. This study evaluated the possibility of incorporating flurbiprofen into the current 5-drug Pittsburgh cocktail. METHODS: In a randomized, 3-way, Latin-square, crossover-design study, 24 healthy subjects (mean age [+/-SD], 47.8 +/- 15.1 years) received flurbiprofen (50 mg) and the Pittsburgh 5-drug cocktail (100 mg caffeine, 100 mg mephenytoin, 10 mg debrisoquin [INN, debrisoquine], 250 mg chlorzoxazone, and 100 mg dapsone) separately and in combination on 3 occasions over a period of 5 weeks. Urine was collected from 0 to 8 hours, and plasma was obtained at 4 and 8 hours after drug administration. Parent drug and metabolite concentrations were measured to determine phenotypic indices for each of the metabolizing enzymes. RESULTS: The geometric mean ratio and 90% confidence interval of the phenotypic indices were included within the 80% to 125% bioequivalence range for each of the probe drugs. There were no statistically significant differences between the phenotypic indices determined after administration of the 5-drug and 6-drug cocktails. However, there was a small but statistically significant increase (7.5%, P = .03) in the 8-hour urinary flurbiprofen recovery ratio after administration of the 6-drug cocktail compared with that after administration of flurbiprofen alone. The 6-drug cocktail was well tolerated. CONCLUSION: The results of this study show that caffeine (CYP1A2), chlorzoxazone (CYP2E1), dapsone (N-acetyltransferase 2), debrisoquin (CYP2D6), flurbiprofen (CYP2C9), and mephenytoin (CYP2C19) can be simultaneously administered in low doses without metabolic interaction.

Administration, Oral↗
PubMed2006

The absence of interaction between drug metabolizing enzyme genotypes and maternal lifestyle factors on glycophorin A somatic mutation frequency levels in newborns.

Prenatal exposure to carcinogens results in newborn DNA damage which in turn is associated with impaired health conditions in both childhood and adulthood. The present study aimed to evaluate whether phase I and II biotransformation enzyme genetic polymorphisms in combination with environmental exposures during pregnancy result in elevated levels of newborn DNA damage. Maternal peripheral and umbilical cord blood samples from 406 mother/newborn pairs were genotyped for a panel of phase I/II metabolic enzymes (CYP1A1, CYP2E1, GSTM1, GSTT1 and NAT2) responsible for the metabolism of tobacco and lifestyle-related mutagens and carcinogens. DNA damage was measured by somatic cell mutation frequency at the glycophorin A (GPA) locus in newborns. No association with elevated somatic cell mutation frequency was observed between the combination of maternal/newborn genotypes and cigarette smoke or lifestyle exposures. The observed variation in newborn GPA frequency might be due to either environmental factors not assessed in this study or inter-individual differences in alternative metabolic or DNA repair pathways.

Adolescent↗
PubMed2006

Relationship of glutathione S-transferase genotypes with side-effects of pulsed cyclophosphamide therapy in patients with systemic lupus erythematosus.

AIMS: Cyclophosphamide (CTX) is an established treatment of severe systemic lupus erythematosus (SLE). Cytotoxic CTX metabolites are mainly detoxified by multiple glutathione S-transferases (GSTs). However, data are lacking on the relationship between the short-term side-effects of CTX therapy and GST genotypes. In the present study, the effects of common GSTM1, GSTT1, and GSTP1 genetic mutations on the severity of myelosuppression, gastrointestinal (GI) toxicity, and infection incidences induced by pulsed CTX therapy were evaluated in patients SLE. METHODS: DNA was extracted from peripheral leucocytes in patients with confirmed SLE diagnosis (n = 102). GSTM1 and GSTT1 null mutations were analyzed by a polymerase chain reaction (PCR)-multiplex procedure, whereas the GSTP1 codon 105 polymorphism (Ile-->Val) was analyzed by a PCR-restriction fragment length polymorphism (RFLP) assay. RESULTS: Our study demonstrated that SLE patients carrying the genotypes with GSTP1 codon 105 mutation [GSTP1*-105I/V (heterozygote) and GSTP1*-105 V/V (homozygote)] had an increased risk of myelotoxicity when treated with pulsed high-dose CTX therapy (Odds ratio (OR) 5.00, 95% confidence interval (CI) 1.96, 12.76); especially in patients younger than 30 years (OR 7.50, 95% CI 2.14, 26.24), or in patients treated with a total CTX dose greater than 1.0 g (OR 12.88, 95% CI 3.16, 52.57). Similarly, patients with these genotypes (GSTP1*I/V and GSTP1*V/V) also had an increased risk of GI toxicity when treated with an initial pulsed high-dose CTX regimen (OR 3.33, 95% CI 1.03, 10.79). However, GSTM1 and GSTT1 null mutations did not significantly alter the risks of these short-term side-effects of pulsed high-dose CTX therapy in SLE patients. CONCLUSIONS: The GSTP1 codon 105 polymorphism, but not GSTM1 or GSTT1 null mutations, significantly increased the risks of short-term side-effects of pulsed high-dose CTX therapy in SLE patients. Because of the lack of selective substrates for a GST enzyme phenotyping study, timely detection of this mutation on codon 105 may assist in optimizing pulsed high-dose CTX therapy in SLE patients.

Adult↗
PubMed2005

Metabolic gene polymorphisms and lung cancer risk in non-smokers. An update of the GSEC study.

BACKGROUND: Since genetic factors may play an important role in lung cancer development at low dose carcinogen exposure, non-smokers are a good model to study genetic susceptibility and its interaction with environmental factors. MATERIALS AND METHODS: We evaluated the role of the metabolic gene polymorphisms CYP1A1MspI, CYP1A1Ile462Val, GSTM1, and GSTT1 in non-smoker lung cancer patients from the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens (GSEC). Non-smokers (defined as subjects who never smoked on a regular basis) were selected from the GSEC database. We pooled the raw data from 21 case-control studies for a total of 2764 Caucasians (555 cases and 2209 controls) and 383 Asians (113 cases and 270 controls). Tests of heterogeneity and of inclusion bias were performed. RESULTS: A significant association between lung cancer and CYP1A1Ile462Val polymorphism was observed in Caucasians (adjusted OR=2.04, 95% CI 1.17-3.54). GSTT1 deletion seems to be a risk factor for lung cancer in Caucasian non smokers only when the analysis was restricted to studies including healthy controls (adjusted OR=1.66, 95% CI 1.12-2.46). A protective effect on lung cancer was observed with the combination of CYP1A1 wild type, GSTM1 null, and GSTT1 non-null genotypes. None of the analysed polymorphisms were associated with lung cancer in Asian non-smokers. DISCUSSION: Our analysis confirms previous findings that CYP1A1Ile462Val polymorphism may play a role in lung carcinogenesis in Caucasian non-smokers.

Adenocarcinoma↗
PubMed2005

Association of polymorphisms in the cyclin D1 and XPD genes and susceptibility to cancers of the upper aero-digestive tract.

DNA repair enzyme genetic polymorphisms have been postulated to increase the risk of certain cancers in the presence of tobacco carcinogen exposures. The XPD protein is an important component of the TFIIH transcription factor complex. XPD genetic polymorphisms resulting in amino acids substitutions may lead to alterations in TFIIH helicase activity, resulting in repair and transcription defects. Cyclin D1 is a key regulatory protein for the transition of cells from the G(1)-S cell cycle phase. The CCND1 G870A polymorphism has been reported to enhance alternate splicing of a stable mRNA variant, which may result in the bypass of the G(1)/S cell cycle checkpoint. In this study, XPD G23591A (Asp312Asn) and A35931C (Lys751Gln) polymorphisms and the CCND1 G870A splice variant frequencies were determined in 273 upper aero-digestive tract cancer cases and 269 controls. The XPD Asp312Asn variant frequency was significantly different among cases and controls and conferred an odds ratio (OR) of 1.3 (95% CI 1.0-1.8). However, individuals with the CCND1 G870A and XPD Lys751Gln variants had higher age adjusted ORs of 3.2 (95% CI 2.2-4.6) and 2.2 (95% CI 1.5-3.2), respectively. Furthermore, a significant gene-gene interaction was observed among cases with at least two variant alleles for both CCND1 and XPD genes [OR 7.09 (95% CI 4.03-12.5)]. Smokers with a combination of at least one variant allele of both CCND1 and XPD genes also had an elevated risk as compared to nonsmokers. This is the first study to suggest an associative interaction between XPD and CCND1 genetic polymorphisms, tobacco exposure, and cancer risk.

Alternative Splicing↗
PubMed2005

Strategies for measurement of biotransformation enzyme gene expression.

The analysis of gene expression is an integral part of any research characterizing gene function. A wide variety of techniques have been developed for this purpose, each with their own advantages and limitations. This chapter seeks to provide an overview of some of the most recent as well as conventional methods to quantitate gene expression. These approaches include Northern blot analysis, ribonuclease protection assay (RPA), reverse transcription polymerase chain reaction, expressed sequence tag (EST) sequencing, differential display, cDNA arrays, and the serial analysis of gene expression (SAGE). Current applications of the information derived from gene expression studies require assays to be adaptable for the quantitative analysis of a large number of samples and end points within a short period coupled with cost effectiveness. A comparison of some of these features of each analytical approach as well as their advantages and disadvantages has also been provided.

Animals↗
PubMed2005

Genotyping technologies: application to biotransformation enzyme genetic polymorphism screening.

Pharmacogenomics encompasses several major areas: the study of polymorphic variations in drug response and disease susceptibility, identification of the effects of drugs/xenobiotics at the genomic level, and genotype/phenotype associations. The most common type of human genetic variations is single-nucleotide polymorphisms (SNPs). Several novel approaches to detection of SNPs are currently available. The range of new methods includes modifications of several conventional techniques, such as PCR, mass spectrometry (ms), and sequencing, as well as more innovative technologies such as fluorescence resonance energy transfer (FRET) and microarrays. The application of each of these techniques is largely dependent on the number of SNPs to be screened and sample size. The current chapter presents an overview of the general concepts of a variety of genotyping technologies, with an emphasis on the recently developed methodologies, including a comparison of the advantages, applicability, cost efficiency, and limitations of these methods.

Biotransformation↗
PubMed2004

Association of metabolic gene polymorphisms with tobacco consumption in healthy controls.

Polymorphisms in genes that encode for metabolic enzymes have been associated with variations in enzyme activity between individuals. Such variations could be associated with differences in individual exposure to carcinogens that are metabolized by these genes. In this study, we examine the association between polymorphisms in several metabolic genes and the consumption of tobacco in a large sample of healthy individuals. The database of the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens was used. All the individuals who were controls from the case-control studies included in the data set with information on smoking habits and on genetic polymorphisms were selected (n = 20938). Sufficient information was available on the following genes that are involved in the metabolism of tobacco smoke constituents: CYP1A1, GSTM1, GSTT1, NAT2 and GSTP1. None of the tested genes was clearly associated with smoking behavior. Information on smoking dose, available for a subset of subjects, showed no effect of metabolic gene polymorphisms on the amount of smoking. No association between polymorphisms in the genes studied and tobacco consumption was observed; therefore, no effect of these genes on smoking behavior should be expected.

Arylamine N-Acetyltransferase↗
PubMed2004

Bioequivalence revisited: influence of age and sex on CYP enzymes.

BACKGROUND AND OBJECTIVE: The activity of cytochrome P450 (CYP) enzymes, which determine the rate of elimination of lipid-soluble drugs, demonstrates considerable interindividual variability. The extent to which age and sex influence CYP activity remains unclear in humans. Our objectives were to determine whether in vivo activity of selected CYP enzymes is affected by age or sex and to evaluate sex bioequivalence in a large sample size. METHODS: We have assessed in vivo activity of the CYP1A2, 2C19, 2D6, 2E1, and 3A4 enzymes in 161 normal subjects (51% female subjects and 40% aged >50 years). After simultaneous administration of a cocktail of selective probes (caffeine, mephenytoin, debrisoquin [INN, debrisoquine], chlorzoxazone, and dapsone, respectively), phenotypic indices for metabolism of these drugs were used as measures of individual CYP activity. Sex bioequivalence analysis used the bootstrap method. RESULTS: There were no sex differences associated with CYP1A2 activity. A significant negative correlation (r = -0.572, P < .01) between enzyme activity and age was observed for CYP2C19, but there were no sex differences. CYP2D6 activity showed no dependence on age or sex. In contrast, CYP2E1 activity showed an age-associated increase (r = 0.393, P < .01), which developed earlier in life in male subjects compared with female subjects. These results were further supported by the sex bioequivalence analysis of CYP phenotypic activity, which revealed that sexes were equivalent with respect to CYP2C19 (90% confidence interval [CI], 0.874-1.04), CYP3A4 (90% CI, 0.95-1.176), and CYP2D6 (90% CI, 0.928-1.09) phenotype and just exceeded the 0.8 to 1.25 limits to be equivalent with respect to CYP2E1 (90% CI, 0.785-1.08) and CYP1A2 (90% CI, 0.736-1.03) phenotype. CONCLUSION: These observations suggest that the presence of selective mechanisms of regulation for individual CYP enzymes can be influenced by age and sex. However, we suggest that sex has a limited ability to explain intersubject variation of activity for these phenotypic measures of CYP enzyme activity.

Adolescent↗
PubMed2004

Maternal/newborn GSTT1 null genotype contributes to risk of preterm, low birthweight infants.

OBJECTIVES: Maternal cigarette smoke exposure during pregnancy has been identified as a risk factor for prematurity and low birthweight. However, little is known about genetic susceptibility and possible interactions with cigarette smoking which may increase risk of these events. METHODS: Maternal peripheral and umbilical cord blood samples from 955 mother/newborn pairs were genotyped for a panel of phase I/II metabolic enzymes responsible for the metabolism of tobacco related mutagens and carcinogens in order to evaluate the association with premature birth. RESULTS: As reported previously, maternal cigarette smoking during the last trimester was significantly associated with premature birth. In addition, maternal glutathione S-transferase T1 (GSTT1) null genotype also increased risk of premature birth. Risk was further elevated among subjects with the combination of maternal and newborn GSTT1 null genotype with or without maternal cigarette smoke. CONCLUSIONS: These observations suggest that women and/or newborns with the GSTT1 null genotype who are exposed to cigarette smoke during pregnancy are at elevated risk for premature delivery. The ability to identify high-risk women by genotyping has potential for reducing the frequency of premature births, a major public health concern.

Adolescent↗
PubMed2003

Association of the DNA repair gene XPD Asp312Asn polymorphism with p53 gene mutations in tobacco-related non-small cell lung cancer.

Lung cancer, a disease related mostly to tobacco smoke exposure and a leading cause of cancer-related death in industrialized countries, is frequently associated with mutations in the p53 tumor suppressor gene. Genetic differences resulting in inter-individual variation in DNA repair capacity may in part account for susceptibility of a cell to genotoxic agents leading to somatic mutations, including p53 mutations, and eventual transformation of a normal cell into a malignant phenotype. The objective of this study is to investigate the relationship between the polymorphisms of two DNA repair genes, the nucleotide excision repair xeroderma pigmentosum group D (XPD) gene (codons 312 and 751) and the base excision repair X-ray repair cross-complementing group 1 (XRCC1) gene (codon 399), and p53 mutations among lung cancer patients. Lung tumors from 204 smokers with non-small cell lung cancer (NSCLC) were analyzed for mutations in exons 5-8 of the p53 gene and genotypes of XPD and XRCC1. p53 mutations were found in 20% (40/204) of the patients. Patients with the XPD codon 312 Asn allele were less likely to have p53 mutations (13.8%) than XPD 312 Asp/Asp (27.3%) [odds ratio (OR) 0.43, 95% confidence interval (CI) 0.20-0.89, P = 0.023]. No association was found between p53 mutations and either XPD Lys751Gln or XRCC1 Arg399Gln. However, the p53 mutation frequency increased with the increased number of the combined genotypes among XPD 312WT (Asp/Asp), XPD 751VT (Lys/Gln or Gln/Gln) or XRCC1 399VT (Arg/Gln or Gln/Gln) (P = 0.01, trend test). These results suggest that individuals who smoke and have the XPD codon 312 Asp/Asp genotype may be at a greater risk of p53 mutations, especially if combined with other polymorphisms that may result in deficient DNA repair.

Alleles↗
PubMed2003

CYP1A1 T3801 C polymorphism and lung cancer: a pooled analysis of 2451 cases and 3358 controls.

CYP1A1 is involved in the metabolism of benzopyrene, a suspected lung carcinogen; it is therefore conceivable that genetically determined variations in its activity modify individual susceptibility to lung cancer. The role of the CYP1A1 MspI polymorphism in lung cancer has been widely studied but has not been fully clarified. We have included 2,451 cases and 3,358 controls in a pooled analysis of 22 case-control studies on CYP1A1 and lung cancer risk. We found a clear association between the CYP1A1 homozygous MspI restriction fragment length polymorphism (RFLP) and lung cancer risk in Caucasians (age- and gender-adjusted odds ratio = 2.36; 95% confidence interval 1.16-4.81); other associations were weaker or not statistically significant. The association with the homozygous variant was equally strong for squamous cell carcinomas and adenocarcinomas among Caucasians. We analyzed the risk by duration of smoking: for Caucasian subjects with the MspI RFLP combined variants (homozygotes plus heterozygotes), the increase in the risk of lung cancer was steeper than among the individuals with the homozygous reference allele. Our analysis suggests that Caucasians with homozygous variant CYP1A1 polymorphism have a higher risk of lung cancer. The data were more consistent among Caucasians, with a strong association between the homozygous variant in both squamous cell carcinomas and adenocarcinomas, and a stronger association in men than in women. The analyses were more inconsistent and failed to reach statistical significance in Asians. This observation might be due to design specificities or unknown effect modifiers in the Asian studies.

Age Factors↗
PubMed2003

Coordinated intrahepatic and extrahepatic regulation of cytochrome p4502D6 in healthy subjects and in patients after liver transplantation.

Cytochrome p450 (CYP) 2D6 activity exhibits wide intersubject variation even among individuals with similar genotypes in whom the active enzyme is expressed. There is, therefore, a need to understand the mechanisms involved in determining its activity. The relationship of messenger ribonucleic acid (mRNA) expression to CYP2D6 activity has been evaluated in hepatic and extrahepatic tissues to test the hypothesis of coordinated regulation. In human liver microsomes, there was a greater than 25-fold variation in both bufuralol hydroxylation and concentration of mRNA for CYP2D6, with a significant association between variables (n = 20; Spearman correlation coefficient [r(s)] = 0.85, P <.001). In normal subjects, there was a similar extent of interindividual variation in in vivo activity of CYP2D6, measured as the debrisoquin (INN, debrisoquine) recovery ratio, and in mRNA for CYP2D6 in peripheral blood mononuclear cells, with a significant association between variables (n = 78; r(s) = 0.56 [95% confidence interval, 0.35 to 0.73], P <.001), whereas no association was found between mRNA for CYP2D6 and CYP2E1 activity. Recipients of liver transplants, at a time of stable liver function, had a similar relationship between debrisoquin recovery ratio and concentration of mRNA for CYP2D6 in peripheral blood mononuclear cells (n = 27; r(s) = 0.74 [95% confidence interval, -0.16 to 0.44], P <.001). Three recipients, who had CYP2D6*4/*4 genotypes, remained phenotypically poor metabolizers for CYP2D6 after liver transplantation. Collectively, these results imply that transcriptional regulation of mRNA for CYP is a major determinant of in vivo activity and that regulation of intrahepatic and extrahepatic enzymes is coordinated, possibly through a mechanism that is predominantly extrahepatic.

Actins↗
PubMed2003

A potential role for the estrogen-metabolizing cytochrome P450 enzymes in human breast carcinogenesis.

PURPOSE: The cytochrome P450 (CYP) enzymes play a critical role in the oxidative metabolism of a variety of endogenous and exogenous compounds, including drugs. Although intermediate CYP metabolites are believed to play a role in carcinogenesis, little is known about tissue-specific CYP expression and the role of local activation in breast carcinogenesis. The goals of this study are to identify CYPs expressed in breast tissue by measuring mRNA levels and to determine whether there are differences in mRNA levels between breast tumors and histologically-normal adjacent breast tissue. EXPERIMENTAL DESIGN: Quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) analysis was used to quantitate mRNA expression levels of 11 CYPs in 29 human breast tumor and non-tumor adjacent tissue pairs. The CYPs examined included: CYP1A1, CYP1A2, CYPB1, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. RESULTS: Only four CYPs were detected in breast tumor or adjacent tissue: CYP1A1, CYPB1, CYP2C9, CYP3A4. Each of these CYPs was expressed in at least 75% of the samples. Three of these CYPs are involved in estradiol hydroxylation (CYP1A1, 2-OH; CYP1B1, 4-OH; CYP3A4, 2- and 16-OH). CYP2C9 is involved in the conversion of estrone sulfate to the 16-hydroxy sulfate metabolite. Higher levels of CYP1B1 and 3A4 were found more often in non-tumor tissue than in tumor tissue (P < 0.04). CYP1A1 was elevated in non-tumor tissue only among pairs in which the tumor expressed the estrogen receptor (ER+, P < 0.03). All of these results were independent of recorded clinical-pathological covariates. CONCLUSIONS: CYPs involved in estrogen metabolism are expressed in both tumor and non-tumor breast tissue. Local activation of estrogen to potentially reactive metabolites by the CYPs in breast tissue may play a role in initiating and promoting the carcinogenic process.

Adult↗