Network Analysis of Biomarkers Associated with Occupational Exposure to Benzene and Malathion.

Complex diseases are associated with the effects of multiple genes, proteins, and biological pathways. In this context, the tools of Network Medicine are compatible as a platform to systematically explore not only the molecular complexity of a specific disease but may also lead to the identification of disease modules and pathways. Such an approach enables us to gain a better understanding of how environmental chemical exposures affect the function of human cells, providing better perceptions about the mechanisms involved and helping to monitor/prevent exposure and disease to chemicals such as benzene and malathion. We selected differentially expressed genes for exposure to benzene and malathion. The construction of interaction networks was carried out using GeneMANIA and STRING. Topological properties were calculated using MCODE, BiNGO, and CentiScaPe, and a Benzene network composed of 114 genes and 2415 interactions was obtained. After topological analysis, five networks were identified. In these subnets, the most interconnected nodes were identified as: IL-8, KLF6, KLF4, JUN, SERTAD1, and MT1H. In the Malathion network, composed of 67 proteins and 134 interactions, HRAS and STAT3 were the most interconnected nodes. Path analysis, combined with various types of high-throughput data, reflects biological processes more clearly and comprehensively than analyses involving the evaluation of individual genes. We emphasize the central roles played by several important hub genes obtained by exposure to benzene and malathion.

Maximal vs. explosive knee extensor strength in professional soccer players: inter-limb asymmetries and relationship with knee function.

The main aims of this study were to compare the magnitude of inter-limb asymmetry (ILA) and the relation with self-reported knee function between maximal and explosive knee extensor strength outcomes in professional soccer players. Forty-six male soccer players completed different maximal isokinetic and isometric contractions of the knee extensors for the assessment of maximal strength (peak torque and maximal voluntary contraction (MVC) torque) and explosive strength (early, intermediate, late, and peak rate of torque development (RTD)). Self-reported knee function was assessed with the International Knee Documentation Committee (IKDC) and Lysholm knee scoring scales. Peak torque and MVC torque showed comparable ILAs (8-9%), both being significantly lower than all RTD ILAs (16% on average; p < 0.001). ILAs for early RTD (21%) and peak RTD (19%) were significantly higher than all the other variables (p < 0.05). Only early and intermediate RTD were significantly correlated - though weakly - with both IKDC (rho = 0.32 for both) and Lysholm (rho = 0.36 and 0.30, respectively) scores. We conclude that explosive knee extensor strength - early RTD in particular - exhibited larger ILAs and better relations with self-reported knee function than peak torque and MVC torque in professional soccer players. These results confirm the validity and functional relevance of early RTD and the need for its inclusion in routine performance testing for soccer players.Highlights Professional soccer players exhibited larger inter-limb deficits in knee extension strength for explosive actions than for the widely-used isokinetic test.Self-reported knee function was significantly correlated with explosive strength of the knee extensor muscles but not with maximal strength.The first 50 ms of an explosive knee extension seem to be crucial for self-perceived sport performance and possibly for injury prevention.

Chronic Cadmium Exposure and Genetic Polymorphisms of MMP-2 and MMP-9 in a Population Exposed to Steel Slag in the State of Rio de Janeiro, Brazil: A Cross-Sectional Study.

Genetic polymorphisms in the matrix metalloproteinases (MMPs) family genes may be associated with cadmium (Cd) levels and its adverse effects. This study investigated the impact of MMP-2 and MMP-9 polymorphisms on Cd levels in 238 residents of a condominium in Rio de Janeiro, Brazil, built over an industrial steel slag waste. Polymorphisms were genotyped using TaqMan validated assays, and the Cd levels were measured in blood (BCd) and urine (UCd) samples by atomic absorption spectrometry. Associations were evaluated by linear correlation coefficients and multiple logistic regression, using odds ratios (OR) and 95% confidence intervals (CI). Mean age was 50 ± 15 years; 58% were female, 69% non-smokers. Mean concentrations for BCd and UCd were 0.70 ± 0.2 µg L-1 and 0.56 ± 0.55 µg L-1, respectively. Smoking status was associated with BCd ≥ 0.70 µg L-1 (OR = 2.9; 95% CI = 1.6-5.9). MMP-9 rs17576 A > G was associated with BCd ≥ 0.70 µg L-1 (OR = 2.11; 95% CI = 1.10-4.05) and UCd ≥ 0.56 µg L-1 (OR = 3.38; 95% CI = 1.82-7.65). Knowing possible individual predisposing factors is essential to understand Cd toxicity, and to improve the monitoring of high-risk populations.

Repercussions of the COVID-19 pandemic on athletes: a cross-sectional study.

The COVID-19 pandemic has presented significant challenges and implications for the sports community. Thus, this study aimed to describe the prevalence of COVID-19 in Brazilian athletes and identify the epidemiological, clinical, athletic, life and health factors associated with the disease in these individuals. A cross-sectional study was performed involving 414 athletes from 22 different sports using an online questionnaire from August to November 2020. The association between the athletes' characteristics and COVID-19 was evaluated using a logistic regression model. The prevalence of COVID-19 was 8.5%, although only 40% of athletes reported having been tested. Being under 27 years of age (3-fold), having children (~5-fold), having a teammate test positive for COVID-19 (2.5-fold), and smoking (14-fold) were associated with a possible higher risk of disease. Almost 20% of athletes self-reported musculoskeletal injuries during the period of the pandemic that was studied. Athletes with a university education (P = 0.02), a profession other than sports (P < 0.001), those from a low-income family (P = 0.01), and public health system users (P = 0.04) were significantly less frequently tested for COVID-19, whereas international competitors, athletes who received a wage, and athletes who had a teammate who tested positive for COVID-19 were 2-, 3-, and 15-fold more likely to be tested for COVID-19, respectively. Approximately 26% of the athletes who tested negative or were untested reported more than three characteristic COVID-19 symptoms, and 11% of athletes who tested positive for COVID-19 were asymptomatic. The identification of modifiable (have children, smoking, and teammates positively tested) and non-modifiable (age under 27 years) factors related to COVID-19 in athletes can contribute to implementing surveillance programmes to decrease the incidence of COVID-19 in athletes and its negative impacts in sports.

Genetic Factors Influencing Warfarin Dose in Black-African Patients: A Systematic Review and Meta-Analysis.

Warfarin is the most commonly used oral anticoagulant in sub-Saharan Africa. Dosing is challenging due to a narrow therapeutic index and high interindividual variability in dose requirements. To evaluate the genetic factors affecting warfarin dosing in black-Africans, we performed a meta-analysis of 48 studies (2,336 patients). Significant predictors for CYP2C9 and stable dose included rs1799853 (CYP2C9*2), rs1057910 (CYP2C9*3), rs28371686 (CYP2C9*5), rs9332131 (CYP2C9*6), and rs28371685 (CYP2C9*11) reducing dose by 6.8, 12.5, 13.4, 8.1, and 5.3 mg/week, respectively. VKORC1 variants rs9923231 (-1639G>A), rs9934438 (1173C>T), rs2359612 (2255C>T), rs8050894 (1542G>C), and rs2884737 (497T>G) decreased dose by 18.1, 21.6, 17.3, 11.7, and 19.6 mg/week, respectively, whereas rs7294 (3730G>A) increased dose by 6.9 mg/week. Finally, rs12777823 (CYP2C gene cluster) was associated with a dose reduction of 12.7 mg/week. Few studies were conducted in Africa, and patient numbers were small, highlighting the need for further work in black-Africans to evaluate genetic factors determining warfarin response.

Matrix metalloproteinases 3 polymorphism increases the risk of developing advanced endometriosis and infertility: A case-control study.

OBJECTIVE: Endometriosis has a complex and multifactorial pathology, and it is considered one of the main causes of infertility nowadays. The angiogenic process, which involves remodeling of extracellular matrix, is crucial for the development of this disease, mainly by the action of the matrix metalloproteinase 3 (MMP-3). It is known that genetic factors can influence endometriosis, thus; we investigated the role of MMP3 276G>A polymorphism as a risk factor for the development of the disease and its symptoms. STUDY DESIGN: This case-control study included 283 women with endometriosis (cases) and 217 women without the disease (controls) who were submitted to laparoscopic or laparotomy surgery. Real-time polymerase chain reaction performed by TaqMan system was applied for all polymorphisms. A multivariate logistic regression was performed to evaluate the association between polymorphism and endometriosis or clinical and gynecological characteristics of the disease, using their respective odds ratios (OR) and 95% confidence intervals (CI). RESULTS: The allelic frequency of the MMP3 276 G > A polymorphism was 33.6% in controls and 40.3% in endometriosis cases. The allelic distribution was significantly different between the two (P = 0.03). The variant genotype of MMP3 276AA was associated with increased endometriosis risk in the advanced endometriosis cases (OR: 2.08, 95% CI: 1.05 - 4.07 and OR: 1.87, 95% CI: 1.01 - 3.45). Regarding the symptoms, endometriosis-related infertile women had a positive association with the presence of MMP3 276 G > A polymorphism (OR: 3.13, 95% CI: 1.08-9.08 and OR: 3.30, 95% CI: 1.31 - 8.33). CONCLUSIONS: These findings suggest that the MMP3 276A polymorphism is involved with advanced endometriosis cases and infertility, and these associations may implicate in the behavior of disease.

Environmental Assessment and Evaluation of Oxidative Stress and Genotoxicity Biomarkers Related to Chronic Occupational Exposure to Benzene.

Environmental and occupational exposure to benzene from fuels is a major cause for concern for national and international authorities, as benzene is a known carcinogen in humans and there is no safe limit for exposure to carcinogens. The objective of this study was to evaluate the genotoxic effects of chronic occupational exposure to benzene among two groups of workers: filling station workers (Group I) and security guards working at vehicles entrances (Group II), both on the same busy highway in Rio de Janeiro, Brazil. Sociodemographic data on the workers were evaluated; the concentration of benzene/toluene (B/T) in atmospheric air and individual trans,trans-muconic acid (ttMA) and S-phenylmercapturic acid (S-PMA) were measured; oxidative stress was analyzed by catalase (CAT), glutathione S-transferase (GST), superoxide dismutase (SOD), thiol groups (THIOL) and malondialdehyde (MDA); genotoxicity was measured by metaphases with chromosomal abnormalities (MCA) and nuclear abnormalities, comet assay using the enzyme formamidopyrimidine DNA glycosylase (C-FPG), and methylation of repetitive element LINE-1, CDKN2B and KLF6 genes. Eighty-six workers participated: 51 from Group I and 35 from Group II. The B/T ratio was similar for both groups, but Group I had greater oscillation of benzene concentrations because of their work activities. No differences in ttMA and S-PMA, and no clinical changes were found between both groups, but linearity was observed between leukocyte count and ttMA; and 15% of workers had leukocyte counts less than 4.5 × 109 cells L-1, demanding close worker's attention. No differences were observed between the two groups for THIOL, MDA, MCA, or nuclear abnormalities. A multiple linear relationship was obtained for the biomarkers MCA and C-FPG. A significant correlation was found between length of time in current job and the biomarkers C-FPG, MCA, GST, and MDA. Although both populations had chronic exposure to benzene, the filling station workers were exposed to higher concentrations of benzene during their work activities, indicating an increased risk of DNA damage.

Genome-wide association study of warfarin maintenance dose in a Brazilian sample.

AIM: Extreme discordant phenotype and genome-wide association (GWA) approaches were combined to explore the role of genetic variants on warfarin dose requirement in Brazilians. METHODS: Patients receiving low (≤ 20 mg/week; n = 180) or high stable warfarin doses (≥ 42.5 mg/week; n = 187) were genotyped with Affymetrix Axiom(®) Biobank arrays. Imputation was carried out using data from the combined 1000 Genomes project. RESULTS: Genome-wide signals (p ≤ 5 × 10(-8)) were identified in the well-known VKORC1 (lead SNP, rs749671; OR: 20.4; p = 1.08 × 10(-33)) and CYP2C9 (lead SNP, rs9332238, OR: 6.8 and p = 4.4 × 10(-13)) regions. The rs9332238 polymorphism is in virtually perfect LD with CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910). No other genome-wide significant regions were identified in the study. CONCLUSION: We confirmed the important role of VKORC1 and CYP2C9 polymorphisms in warfarin dose. Original submitted 14 January 2015; Revision submitted 26 May 2015.

The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected.

Based on pre-DNA racial/color methodology, clinical and pharmacological trials have traditionally considered the different geographical regions of Brazil as being very heterogeneous. We wished to ascertain how such diversity of regional color categories correlated with ancestry. Using a panel of 40 validated ancestry-informative insertion-deletion DNA polymorphisms we estimated individually the European, African and Amerindian ancestry components of 934 self-categorized White, Brown or Black Brazilians from the four most populous regions of the Country. We unraveled great ancestral diversity between and within the different regions. Especially, color categories in the northern part of Brazil diverged significantly in their ancestry proportions from their counterparts in the southern part of the Country, indicating that diverse regional semantics were being used in the self-classification as White, Brown or Black. To circumvent these regional subjective differences in color perception, we estimated the general ancestry proportions of each of the four regions in a form independent of color considerations. For that, we multiplied the proportions of a given ancestry in a given color category by the official census information about the proportion of that color category in the specific region, to arrive at a "total ancestry" estimate. Once such a calculation was performed, there emerged a much higher level of uniformity than previously expected. In all regions studied, the European ancestry was predominant, with proportions ranging from 60.6% in the Northeast to 77.7% in the South. We propose that the immigration of six million Europeans to Brazil in the 19th and 20th centuries--a phenomenon described and intended as the "whitening of Brazil"--is in large part responsible for dissipating previous ancestry dissimilarities that reflected region-specific population histories. These findings, of both clinical and sociological importance for Brazil, should also be relevant to other countries with ancestrally admixed populations.

VKORC1 polymorphisms in Brazilians: comparison with the Portuguese and Portuguese-speaking Africans and pharmacogenetic implications.

AIMS: The heterogeneity of the Brazilian population renders the extrapolation of pharmacogenomic data derived from well-defined ethnic groups inappropriate. We investigated the influence of self-reported 'race/color', geographical origin and genetic ancestry on the distribution of four VKORC1 SNPs and haplotypes in Brazilians. Comparative data were obtained from two major ancestral roots of Brazilians: Portuguese and Africans from former Portuguese colonies. MATERIALS & METHODS: A total of 1037 healthy adults Brazilians, recruited at four different geographical regions and self identified as white, brown or black (race/color categories), 89 Portuguese and 216 Africans from Angola and Mozambique were genotyped for the VKORC1 3673G>A (rs9923231), 5808T>G (rs2884737), 6853G>C (rs8050894) and 9041G>A (rs7294) polymorphisms using TaqMan(®) (Applied Biosystems, CA, USA) assays. VKORC1 haplotypes were statistically inferred using the haplo.stats software. We inferred the statistical association between the distribution of the VKORC1 polymorphisms among Brazilians and self-reported color, geographical region and genetic ancestry by fitting multinomial log linear models via neural networks. Individual proportions of European and African ancestry were used to assess the impact of genetic admixture on the frequency distribution of VKORC1 polymorphisms among Brazilians, and for the comparison of Brazilians with Portuguese and Africans. RESULTS: The frequency distribution of the 3673G>A and 5808T>G polymorphisms, and VKORC1 haplotypes among Brazilians varies across geographical regions, within self-reported color categories and according to the individual proportions of European and African genetic ancestry. Notably, the frequency of the warfarin sensitive VKORC1 3673A allele and the distribution of VKORC1 haplotypes varied continuously as the individual proportion of European ancestry increased in the entire cohort, independently of race/color categorization and geographical origin. Brazilians with more than 80% African ancestry differ significantly from Angolans and Mozambicans in frequency of the 3673G>A, 5808T>G and 6853G>C polymorphisms and haplotype distribution, whereas no such differences are observed between Brazilians with more than 90% European ancestry and Portuguese individuals. CONCLUSION: The diversity of the Brazilian population, evident in the distribution of VKORC1 polymorphisms, must be taken into account in the design of pharmacogenetic clinical trials and dealt with as a continuous variable. Warfarin dosing algorithms that include 'race' terms defined for other populations are clearly not applicable to the heterogeneous and extensively admixed Brazilian population.

Exploring warfarin pharmacogenomics with the extreme-discordant-phenotype methodology: impact of FVII polymorphisms on stable anticoagulation with warfarin.

PURPOSE: To explore the pharmacogenomics of warfarin using the extreme-discordant-phenotype (EDP) methodology. METHODS: The target phenotype was the stable warfarin dose prescribed to 353 patients. Pharmacogenetic polymorphisms assessed were coagulation factor VII (FVII) -401G>T and FVII -402G>A, VKORC1 3673G>A, and CYP2C9*2, *3, *5, and *11 alleles. The EDP analyses contrasted the frequencies of these polymorphisms at different cutoff points (5th through 30th percentiles of the warfarin dose distribution) at opposite ends of the warfarin dose distribution. RESULTS: Significant differences existed in FVII -402G>A genotype frequency at the 5th percentile with an over-representation of the wildtype GG genotype at low warfarin doses and in VKORC1 3673G>A and CYP2C9 polymorphisms at all cutoff points where the variant alleles were overrepresented at low warfarin doses. CONCLUSION: The EDP methodology provides increased statistical power for detection of small contributions of genetic polymorphisms to multiple drug-response phenotypes, such as warfarin dose requirement for adequate anticoagulation.

VKORC1 polymorphisms in Amerindian populations of Brazil.

Noncoding polymorphisms in the VKORC1 gene associate with variation of interindividual dosing requirements of warfarin and other coumarin anticoagulants. The frequency of VKORC1 polymorphisms displays distinct interpopulation differences. Here, we report the distribution of the VKORC1 3673G>A, 5808T>G, 6853G>C and 9041G>A SNPs in three endogamous Amerindian (Native American) populations, namely, Guarani-Kaiowá, Guarani-Nandeva and Kaingang. Individual DNA from 180 healthy adults was genotyped for the VKORC1 polymorphisms using TaqMan Detection System assays. The ARLEQUIN 3.1 software package was used to estimate haplotype frequency and linkage disequilibrium. The VKORC1 3673G>A, 5808T>G, 6853G>C and 9041G>A polymorphisms were in Hardy-Weinberg equilibrium in each population. The 5808G allele was absent or rare (<3%), whereas 3673A, 6853C and 9041A were frequent (34-63%) in the three Amerindian populations. No difference was detected in allele or genotype frequency bewteen the two Guarani populations, whereas significant differences were observed between Kaingang and Guarani. Polymorphisms 3673G>A, 6853G>C and 9041G>A were in significant linkage disequilibrium in both Guarani and Kaingang (pairwise r2 values: 0.77-1.0). Haplotypes ATCG and GTGA accounted for more than 94% of the haplotypes in both populations, ATCG being the most common in Guarani (49.5%) and GTGA in Kaingang (54%). These data disclose the uniqueness of the frequency distribution of the VKORC1 SNPs in the Amerindians, compared with Asian, African and European populations. In view of the vast interpopulational diversity among Amerindians, the present data should not be interpreted as representative of other extant Amerindian peoples. Our estimates that 40% of Kaingang and 60% of Guarani have haplotypes including the variant 3673A allele suggest that these two Amerindian populations comprise high proportions of individuals requiring reduced warfarin doses.

Impact of population admixture on the distribution of the CYP3A5*3 polymorphism.

OBJECTIVE: To compare the effectiveness of self-identified ethnic/color and marker-based biogeographical ancestry classifications in genotyping the CYP3A5*3 polymorphism in the Brazilian population. METHODS: Individual DNA from 308 healthy Brazilians, self-identified as white, intermediate and black was genotyped for the CYP3A5*3 polymorphism and for a set of insertion-deletion polymorphisms, validated as ancestry informative markers (AIMs). The Structure software was used to analyze the AIMs data and to obtain estimates of the African component of ancestry (ACA). Nonlinear logistic regression modeling was developed to describe the association between the CYP3A5*3 polymorphism and the individual ACA values. RESULTS: The CYP3A5*3 allele and genotype distribution differed significantly across the self-reported 'color' groups (p < 0.0001, Fisher exact test), with a trend for decreasing frequency of both the CYP3A5*3 allele and the *3/*3 genotype from white to intermediate to black individuals (p < 0.0001, chi(2) test for trend in proportions). When the population sample was proportioned in quartiles according to the individual ACA values, the frequency of the CYP3A5*3 allele and the *3/*3 genotype declined progressively from the lowest (<0.25 ACA) to the highest (>0.75 ACA) quartile. Nonlinear logistic regression showed that the odds of having the CYP3A5*3 allele decreases monotonically (p < 0.0001, Wald statistics) with the increase of the ACA, throughout the ACA range (0.15-0.93) observed in the overall population sample. CONCLUSION: Interethnic admixture is a source of cryptic population structure that may lead to spurious genotype-phenotype associations in pharmacogenetic/-genomic studies. Logistic regression modeling of CYP3A5*3 polymorphism shows that admixture must be dealt with as a continuous variable, rather than proportioned in arbitrary subcategories for the convenience of data quantification and analysis.

Influence of CYP2C9 genotypes on the pharmacokinetics and pharmacodynamics of piroxicam.

OBJECTIVE: Our objective was to evaluate the influence of cytochrome P450 (CYP) 2C9 polymorphisms on the pharmacokinetics and pharmacodynamics of the nonsteroidal anti-inflammatory drug piroxicam. METHODS: Thirty-five healthy subjects with CYP2C9 genotypes *1/*1 (n=17), *1/*2 (n=9), and *1/*3 (n=9) received a single oral dose of piroxicam (20 mg). Blood samples were collected at various time points up to 240 hours for measurements of the concentrations of piroxicam and thromboxane B2 (TXB2). RESULTS: Piroxicam's area under the plasma concentration-time curve from time 0 to infinity and oral clearance corrected for body weight were 154+/-37 microg.mL-1.h and 2.0+/-0.5 mL.h-1.kg-1, respectively, in CYP2C9*1/*1 individuals, as compared with 256+/-97 mL.h-1 (P=.002) and 1.3+/- 0.4 mL.h-1.kg-1 (P=.002), respectively, in CYP2C9*1/*2 individuals and 259+/- 95 mL.h-1 (P=.002) and 1.3+/- 0.4 mL.h-1.kg-1 (P=.002), respectively, in CYP2C9*1/*3 individuals. There were no significant differences between CYP2C9*1/*2 and CYP2C 9*1/*3 individuals in these pharmacokinetic parameters (P=.95 for area under the plasma concentration-time curve from time 0 to infinity and P=.94 for oral clearance corrected for body weight). The formation of TXB2, reflecting cyclooxygenase type 1 activity, showed significant differences in the area above the effect-time curves (expressed as percent of baseline TXB2.h) between CYP2C9*1/*1 (10,190 +/- 2632) and either CYP2C9*1/*2 (19,255+/-1,291 [P=.00003]) or CYP2C9*1/*3 (18,241+/- 2397 [P=.00003]). The minimum serum TXB2 concentration, however, did not differ among the different genotypes (P=.32, ANOVA). CONCLUSION: Piroxicam's oral clearance was impaired and its inhibitory effect on cyclooxygenase 1 activity was increased in CYP2C9*1/*2 or CYP2C9*1/*3 individuals, as compared with CYP2C 9*1 homozygous individuals.

CYP2C9 genotypes and the pharmacokinetics of tenoxicam in Brazilians.

OBJECTIVE: Cytochrome P450 (CYP) 2C9, the product of the polymorphic gene CYP2C9, provides the major catabolic pathway for several anti-inflammatory drugs, including tenoxicam. Our objectives were (1) to determine the frequency of 2 common CYP2C9 variant alleles (*2 and *3) in the Brazilian population and (2) to evaluate the effects of these polymorphisms on the pharmacokinetics of tenoxicam. METHODS: Polymerase chain reaction-restriction fragment length polymorphism methods were used to identify CYP2C9*2 and CYP2C9*3 in 331 healthy Brazilians, classified as white (n = 136), black (n = 77), or intermediate (n = 118). A validated HPLC procedure was used for measuring the plasma concentrations of tenoxicam, after single oral doses of 20 mg, administered to 21 individuals with CYP2C9*1/*1 (n = 12), CYP2C9*1/*2 (n = 4), or CYP2C9*1/*3 genotypes (n = 5), confirmed by deoxyribonucleic acid sequencing. A 2-compartment pharmacokinetic model was used for fitting the plasma concentration versus time data, and the individual model descriptive parameters were used to simulate the plasma tenoxicam concentrations during repeated dosing for 7 consecutive days. RESULTS: The frequencies of CYP2C9*1, CYP2C9*2, and CYP2C9*3 in the study population were 0.849, 0.086, and 0.065, respectively. The distribution of CYP2C9 alleles differed across the Brazilian color groups (P = .016), with the frequencies of the variant alleles being 2.5 to 3 times lower in black Brazilians than in white Brazilians (P = .003). After a single dose of tenoxicam, the area under the plasma concentration-time curve (AUC) from time 0 to infinity and the oral clearance of tenoxicam were 190 +/- 48 microg x mL(-1) x h and 113 +/- 30 mL x h(-1), respectively, in wild-type homozygous subjects (CYP2C9*1/*1), as compared with 261 +/- 14 microg x mL(-1) x h (P = .013) and 77 +/- 4 mL x h(-1) (P = .036), respectively, in CYP2C9*1/*2 heterozygous subjects and 335 +/- 126 microg x mL(-1) x h (P = .003) and 67 +/- 23 mL x h(-1) (P = .008) in CYP2C9*1/*3, respectively, heterozygous subjects. After 7 simulated daily doses, significant differences were observed between CYP2C9*1/*1 and CYP2C9*1/*3 individuals in relation to the minimum plasma (trough) tenoxicam concentration (Cmin, 5.2 +/- 1.3 microg x mL(-1) versus 7.6 +/- 2.6 microg x mL(-1); P = .021), maximum tenoxicam plasma concentration (Cmax, 7.4 +/- 1.9 microg x mL(-1) versus 10.5 +/- 3.0 microg x mL(-1); P = .020), and 24-hour AUC (152 +/- 39 microg x mL(-1) x h versus 219 +/- 72 microg x mL(-1) x h). No significant differences were observed in Cmin, Cmax, or AUC between CYP2C9*1/*2 and either CYP2C9*1/*1 or CYP2C9*1/*3 individuals. CONCLUSION: The allelic and genotypic frequencies of CYP2C9*1, *2, and *3 in white and black Brazilians are similar to those reported for other white (Caucasian) and black (African and African American) populations, respectively. Heterozygosis for CYP2C9*3, and to a lesser degree CYP2C9*2, increases the exposure to tenoxicam during single and repeated doses.